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