something new something old - wits physicians update · something new something old ......

39
Something New Something Old Ebrahim Variava HOD Internal Medicine KTC

Upload: hatu

Post on 06-Jul-2018

223 views

Category:

Documents


0 download

TRANSCRIPT

Something New Something Old

Ebrahim Variava

HOD Internal Medicine

KTC

Declaration

bull I have no conflict of interest

bull I am PI of several novel TB drug studies

Overview of talk

bull Origins

bull landmarks

bull Risk groups

bull Latent TB

bull Diagnostics

bull Treatment

ldquoTuberculosis is an ancient scourge It has plagued humankind throughout known history and human prehistory It has surged in great epidemics and then receded thus behaving like other infectious diseases but with a time scale that challenges accepted explanations for epidemic cycles Mycobacterium tuberculosismay have killed more persons than any other microbial pathogenrdquo

Daniel ndashResp med 2006

Deep into the history of TB

bull May have been around in the form of Mycobacteria ulcerans during the Jurassic period

bull Is the history of TB linked to the history of mankind

bull Cohabited from prehistory and lives with us in current in the Post m-T(echnology) age

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Declaration

bull I have no conflict of interest

bull I am PI of several novel TB drug studies

Overview of talk

bull Origins

bull landmarks

bull Risk groups

bull Latent TB

bull Diagnostics

bull Treatment

ldquoTuberculosis is an ancient scourge It has plagued humankind throughout known history and human prehistory It has surged in great epidemics and then receded thus behaving like other infectious diseases but with a time scale that challenges accepted explanations for epidemic cycles Mycobacterium tuberculosismay have killed more persons than any other microbial pathogenrdquo

Daniel ndashResp med 2006

Deep into the history of TB

bull May have been around in the form of Mycobacteria ulcerans during the Jurassic period

bull Is the history of TB linked to the history of mankind

bull Cohabited from prehistory and lives with us in current in the Post m-T(echnology) age

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Overview of talk

bull Origins

bull landmarks

bull Risk groups

bull Latent TB

bull Diagnostics

bull Treatment

ldquoTuberculosis is an ancient scourge It has plagued humankind throughout known history and human prehistory It has surged in great epidemics and then receded thus behaving like other infectious diseases but with a time scale that challenges accepted explanations for epidemic cycles Mycobacterium tuberculosismay have killed more persons than any other microbial pathogenrdquo

Daniel ndashResp med 2006

Deep into the history of TB

bull May have been around in the form of Mycobacteria ulcerans during the Jurassic period

bull Is the history of TB linked to the history of mankind

bull Cohabited from prehistory and lives with us in current in the Post m-T(echnology) age

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

ldquoTuberculosis is an ancient scourge It has plagued humankind throughout known history and human prehistory It has surged in great epidemics and then receded thus behaving like other infectious diseases but with a time scale that challenges accepted explanations for epidemic cycles Mycobacterium tuberculosismay have killed more persons than any other microbial pathogenrdquo

Daniel ndashResp med 2006

Deep into the history of TB

bull May have been around in the form of Mycobacteria ulcerans during the Jurassic period

bull Is the history of TB linked to the history of mankind

bull Cohabited from prehistory and lives with us in current in the Post m-T(echnology) age

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Deep into the history of TB

bull May have been around in the form of Mycobacteria ulcerans during the Jurassic period

bull Is the history of TB linked to the history of mankind

bull Cohabited from prehistory and lives with us in current in the Post m-T(echnology) age

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

bull Mycobacterium TB-low mutation rate

bull Appears to have originated amongst early hominids

bull Questions arise

ndash Selection advantage

ndash Survival of fittest

ndash Use of this technology to study evolution of TB and possibly humanity

Ramakrishnan et al

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

TB existed in Perumdashprior to any meeting with any pale face

Moved prior to continental drift

Proc Natl Acad Sci U S A 1994

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Hippocrates understood its clinical presentation ndashand predilection for young

Galen a doctor to an emperor in 174 suggested air fresh milk and sea voyages

European monarch believed that touch of royalty cured scrofulamdashthe saying ldquoroyal touchrdquo

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Laennac (1771-1826)Died of TB(Inventor of stethescope in1810Described clinical pulmonological signsDescribed the pathology of TBModern understanding of TB begins

Villemin demonstrated infectivity of TB by injection a rabbit with pulmonary samples from postmortem cavities

24th March 1882 history of TB changes with Kochrsquos lecture ldquoDie Aetiologie der TuberculoseIdentified protein tuberclin and injected himselfmdashlater in 1907 Von Piquet(allergyallergen) developed skin testing

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

bull 1908 Mantoux cannulated needle that contained tuberculin

bull 1930rsquos Seibert develop PPDmdashan understanding of latent TB began

bull TB Surged and inexplicably receded prior to public health measures and antibiotics ndash Cannot wholly be explained by

bull Herd immunitybull Improved socio economics statusbull No longer young adults but more identification of risks

groupsbull Genetic susceptibility

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Pre-HIV Global TB

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

bull With decline of TB additional risk groups identified ndashndash Proximity to contact (45 prevalence)

ndash HIV 8-10 fold riskbull Reduced but remains 2-3 fold on ART

ndash Silicosis 4-6 fold

ndash Chronic renal disease 8-14 fold

ndash Diabetes 3 fold risk and increase risk of death

ndash Malnutrition 4 fold

ndash Alcohol RR 29

ndash Smokers and indoor pollution 2 fold

ndash Age (HIV -ve extremes of age)

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Household contact tracing

Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Latent TB treatment

bull Eskimo study efficacy of INH for prolonged protection gt20yrs

bull Most evidence from trials of LTBI in HIV

reduces risk 60 PPD+

bull Choicendash INH for 6-9months (non HIVsilicosis)

ndash Weekly INH ndashRifapentine for12 weeks (phase II trials)

ndash Not recommended rifPZA ndash hepatic toxicitiies

MMWRDecember 9 2011 60(48)1650-1653)

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Tests for LTBI

bull PPD---need to read after 72 hours

bull IGRA---quantiferon gamma assay-blood test

ndash More sensitive

ndash Expensive

ndash Problems with collection (3 tubes 1 ml shake Temp etc)

ndash lab issues Time to lab incubation etc

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Duration of Preventive Treatment

bull Other high risk based on evidence of latent infection-6 months INH

bull Silicosis-36 months

bull Guideline for HIV

ndash PPD unknown-6 months INH

ndash PPD pos for 36 months INH irrespective of ART

ndash PPD neg on ARTmdash6 months INH

- PPD neg not on ART-no INH

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

All May Change

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Clinical

bull Recognized and well described

bull 1928 Oslers Principles and Practice of Med

bull Describes 3 categories of pulmonary TB

ndash Acute PneumoniaBronchopneumonia

bull Referred as galloping consumption

ndash Chronic Pneumonia with TB

ndash Chronic Fibrotic lung with no TB

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Diagnosticsbull From ldquosimple stainingrdquo microscopy to florescent

microscopy

bull Culture on solid media to automated liquid MGIT culture with automated indicators

bull The advent of antibiotics to gold standard of phenotypic sensitivity testing

bull New predictive genetic testing for predictive resistance testing in a short period

bull Highly sensitive GXP and line probes that assist with assessing 1st second pre or XDR

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Wizardry

bull Resusitation promotion factors (Rpfrsquos) Attempt to use products of mtcobacterialgrowth to stimulate latent or dormant mycobacterial quasi ndashspecies

bull Mycobacterial genotyping (Spoligo RFLP MIRU-VNTR WGS)ndash Molecular epi (transmission and clustering)

ndash Virulence (Beijing)

ndash Re-infection v reactivationrecurrence

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Resistance mutations

bull Most Resistance mutations noted PCR based testing more reliable for some (rifINHaminoglycosidesquinolones)-less reliable for ethambutol

bull INH A ndash mutation can be overcome with high dose INHndash pts with this often resistant to ethionamide

bull Kat Gndash Total INH resistance (can use ethionamide)

bull pncAndash New molecular signal of resistance to PZA

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Treatment

bull Treatment varied-from mercury to other poisons

bull Sanatoriums

bull Surgical techniques

bull Pharmacotherapy

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Pharmacotherapy

bull First anti TB treatment was PAS than streptomycin(1944)

bull After resistance to strepmdashpolypharmacy for better results

bull Initial treatments gt24 months

bull Additional agents reduced to 6 months in the 1980s

bull Now novel agents to reduce to 4 months

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

REF Isseman MD Euro Resp Journal 2002

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Meta analysis of duration of treatment

REF Isseman MD Euro Resp Journal 2002

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

WHO group of drugsGroup Drug Comments

Group 1 First line INH Rif PZAEthamNew generation rifamycin-rifabutin rifapentine

Most potent agent

Group 2 Injectables amikacin kanamycincapreomycin streptomycin

All patients with MDR should receive injectable

Group 3 Fluroquinolones-moxigatilevo or oflox

All pts with MDR should have a quinolone

Group 4 Bacteriostatic drugs thioamides (ethionamide prothioamide) cycloserinetervalidin PAS

Group 5 Unclear efficacy linezolid clofazamine imepenem co-amoxy clav high dose INH

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

History of Drug development

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Mechanism of action group 1

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Mech of action for MDR drugs

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Current Novel agents

bull Bedaquiline (diarlyquinolone)ndash Registered for MDR in SAndash Rapid approval based on rapid clearance of sputa after

phase II study (mortality higher in bedaqndash ATP synthetase inhibitorndash Used as additional agentndash Prolongs QTmdashcontraindicated with other drugs that

prolong QTndash For those where injectable contraindicatedndash Problem with EFVLop-ritmdashsafe with raltegravir and

rilpivirine

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Nitroimidazole

ndash Late effect on mycobacterial wall synthesis

bull Pretominid(PA 824)ndash Phase II rapid clearance of sputa

ndash Combined with PZAMoxi for STAND study

ndash Create one new drug for all TB-

bull Delamanid(Outsuka)-ndash Phase III trial

ndash With OBR

ndash Approved US for MDR based on phase III studies

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

More drugs

bull Rifamycinsndash Rifabutin and rifapentine(long acting-given weekly)

bull Oxazolidinonesndash Inhibit 70S ribosomal initiation complexndash Linezolidsutezolid(new-PNU10048-fewer SE)

bull For XDRbull Neuropathy bull Optic neuritis

bull SQ-109 (Ethylenediamines)ndash Derivative of ethambutolndash Interacts synergistically with INH and rifampicin

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Mechanism of action of novel TB drugs

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Monitoring of treatment

bull No biomarker (unlike HIVmdashVLDM-HbA1C)

bull Monitor sputa culture conversion

ndash time to positive

ndash smear grading

ndash colony count

ndash Weight x ray clinical

bull Holy Grail---treatment response marker

ndash Eg use of rpf to increase rate of growth

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Adjunctive therapy

bull Vaccinationndash More for therapeutic toolndash BCG Attenuates severe illness in peads

bull Steroids-use for TBMPericardialIRISbull NSAIDs use bein investigated

bull Efflux pump inhibitorsmdashthis enables drugs to remain and have effectmdashverapamel

bull Recent phase I trial of autologogous mesenchymalstem cell transplant with anti TB treatment showed more rapid clinical improvement on XDR patients

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

Two pandemicscombine as a nuke HIV v TB

bull TB A super slow form--slow replicative ratelatency low mutation ratendash Long time passes before we first see our companion (Koch)--TBndash Slow rate of diagnostic developmentndash Stuttering development of treatmentndash Shorter duration of therapyndash Causesresponsible for large proportion of disabilitiesndash Nurse based treatmentmdashdoctors withdraw

bull HIV Sonically chargedmdashhigh high mutation ratendash Quick Identificationndash Rapid developments in treatmentndash Permanent therapy ndash Many direct effects reversible-less permanent disabilityndash Referred for nurse based ART---doctors withdraw

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

bull Thanks for you attention

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017

references

bull Hayman J Mycobacterium ulcerans an infection from Jurassic time Lancet 198421015ndash6bull Gutierrez MC Brisse S Brosch R Fabre M Omaıumls B Marmiesse M et al Ancient origin and gene mosaicism of the progenitor of Mycobacterium

tuberculosis PloS Pathog 20051e5bull Nerlich AG Haas CJ Zink A Szeimies U Hagedorn HG Molecular evidence for tuberculosis in an ancient Egyptian mummy Lancet 19973501404bull Daniel TM The origins and precolonial epidemiology of tuberculosis in the Americas can we figure them out Int J Tuberc Lung Dis 20004395ndash400

19 bull Salo W Aufderheide AC Buikstra J Holcomb TA Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy Proc Natl

Acad Sci USA 1994912091ndash4 Morse D Tuberculosis In Brothwell D Sandison AT editors Diseases in antiquity A survey of the diseases injuries and surgery of early populations Springfield IL Charles C Thomas 1967

bull Simons SO1 van der Laan T Mulder A van Ingen J Rigouts L Dekhuijzen PN Boeree MJ van Soolingen D Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm Clin Microbiol Infect 2014 Oct20(10)1015-20 doi 1011111469-069112696 Epub 2014 Jul 16

bull Balasingham SV1 Davidsen T Szpinda I Frye SA Toslashnjum T Molecular diagnostics in tuberculosis basis and implications for therapy Mol Diagn Ther 200913(3)137-51 doi 10216501250444-200913030-00001

bull G J Churchyard R E Chaisson G Maartens H Getahun Tuberculosis preventive therapy An underutilised strategy to reduce individual risk of TB and contribute to TB control S Afr Med J 2014104(5)339-343 DOI107196SAMJ8290

bull Jeon CY Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis A systematic review of 13 observational studies PLoS Med 5(7) e152 doi101371 journalpmed0050152

bull Baker M Harries A Jeon C Hart J Kapur A Lonnroth K et al The impact of diabetes on tuberculosis treatment outcomes a systematic review BMC Medicine 20119 article 81 [PMC free article

bull Shapiro AE Variava E Rakgokong MH Moodley N Luke B Salimi S Chaisson RE Golub JE Martinson NA Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa Am J Respir Crit Care Med 2012 May 15185(10)1110-

bull David AJ Moore Liz Lightstone Babak Javid and Jon S Friedland High Rates of Tuberculosis in End-Stage Renal Failure the Impact of International Migration Emerg Infect Dis 2002 Jan 8(1) 77ndash78doi 103201eid0801010017