Does susceptibility testing have a role in predicting clinical or microbiological outcome?

Alasdair MacGowanNorth Bristol NHS Trust & University of BristolSouthmead HospitalBristol, UK

The paradigm

pharmacodynamic microbiological clinical index size outcome outcome

Cmax/MICAUC/MICT>MIC

The Pharmacodynamic world - students view

AUC/MICfluoroquinolonesdaptomycinaminoglycosidesketolidesmetronidazoletetracyclinesglycopeptidesoxazolidinones

Cmax/MICfluoroquinolonesaminoglycosidesdaptomycin(metronidazole)

T > MICmacrolidesclindamycinoxazolidinonesB lactamsglycopeptides

The Pharmacodynamic world - shades of grey

AUC/MICtetracyclines

ketolides

Oxazolidinonesglycopeptides

AUC/MIC;Cmax/MIC

fluoroquinolonesaminoglycosides

(daptomycin)

? Dalbavancin

Cmax/MIC

T > MICBlactams

erythromycinclindamycin

Clinical studies showing a relationship between pharmacodynamic index and outcome

drug pD index size referencegentamicin/amikacin/netilmicin

gentamicin/tobramycin

Cmax/MIC

Cmax/MIC

>10

>10

Moore et al, 1987

Kashuba et al, 1999

cefipime T>MIC ? Tam et al, 2002ciprofloxacingrepafloxacinlevofloxacin

gatifloxacin/levofloxacinlevofloxacin

AUC/MICAUC/MICCmax/MICAUC/MICAUC/MIC

AUC/MIC

>125>175>12

>120>35

>87

Forrest et al, 1993Forrest et al, 1997Preston et al, 1998

Ambrose et al, 2003

Drusano et al, 2004vancomycin AUC/MIC >100 Schentag et al,

in presslinezolid AUC/MIC

T>MIC>100>85

Rayner et al, 2000

Pharmacokinetics and susceptibility

pD index pharmacokinetics susceptibilityCmax/MIC

AUC/MIC

T>MICCmax

log Cmic Kel

Cmax (mg/L)

Dose. F (mg/L.h) Clp

Cmax t½ (mg/L.h)0.692

MIC (mg/L)

MIC (mg/L)

MIC (mg/L)

Which is dominant - pharmacokinetics or susceptibility?

Pharmacokinetic variability

total drug AUC (mg.L.h)

volunteerspatients with

infectionagent/dose

mean %CV mean %CVciprofloxacin/variouslevofloxacin, 500mggatifloxacin, 400mgmoxifloxacin, 400mglinezolid, 600mg

-483448180

2020161234

-7351-

165

7770404856

range (112-980)

Susceptibility variability - MICs(www.bsacsurv.org; www.EUCAST.org)

Wild type (EUCAST) Variationciprofloxacin - E. coli 0.002-0.06 mg/L x30levofloxacin - E. coli 0.002-0.06 mg/L x30moxifloxacin - E. coli 0.008-0.25 mg/L x30

Present (BSAC)ciprofloxacin - E. coli 0.002 - > 512 >250,000

Which is dominant - pharmacokinetics or susceptibility?

Usually susceptibility drives changes in pD index; hencein situations where MIC ranges are large, categorical sensitivity testing should be predictive.

Antibiotic resistance and bacteraemia (1)General casesPhillips et al, 1990

St Thomas’ Hospital, Londonbacteraemias 1969-88, retrospective analysisStaphylococci, Enterococci, Enterobacteriaceae, P. aeruginosa

Outcomes

died

therapy n. survived infection disease

appropriate

inappropriate

1346

159

84%

68%

9%

17%

7%

15%

Antibiotic resistance and bacteraemia (2)

Behrendit et al, 1999Department of Medicine, University Hospital, Frankfurt1989-93, retrospective analysis

Outcome: 28d mortality

therapy n. survived (%)

any appropriatenon appropriate

817164

8472

appropriate in 48hnot appropriate in 48h

8569

Antibiotic resistance and bacteraemia (3)

Specific settings - ICUIbrahim et al, 2000St Louis USA, Medical & Surgical ICU (37 beds) 1997-99Prospective cohort study

Multiple logistic regression:-inadequate antimicrobial therapy as independent determinant ofmortality RR 6.9 (5.1 - 9.3, p < 0.001)

Commonest resistant isolates - VRE, Candida sp, MRSA, CONS,P. aeruginosa - also highest mortality

therapy n. % mortalityinappropriate

appropriate

147

304

61.9 RR 2.18 (1.77 – 2.69) 28.4

Antibiotic resistance and bacteraemia (4)

Specific settings - ICU

Harbarth et al, 2002Geneva, Switzerland, Surgical ICU (22 beds) 1994-7retrospective cohort study of 244 bacteraemias

In multivariate analysis

factor Hazards

ratio

ratio

APACHE II at onset

number of organ dysfunctions

appropriate antimicrobial therapy

1.08

1.39

0.35

(1.04 – 1.12)

(1.11 – 1.65)

(0.2 – 0.63)

Antibiotic resistance and bacteraemia (5)

Specific pathogens: S. aureus

Gonzalez et al, 1999Madrid, Spain, 1990-1994S. aureus, pneumonia + bacteraemiaprospective cohort study

Group treatment n, treated(%)

n, died(%)

MSSA

(n = 41)

vancomycin

cloxacillin

17 (41.5)

10 (24.4)

8 (47) p<0.01

0

MRSA

(n=22)

vancomycin 20 (91) 10 (50)

Antibiotic resistance and bacteraemia (6)

Specific pathogen - S. aureusChang et al, 2003Multi centre, prospective observational study of 505 patients in USA.End points were persistent and relapsed infectionFactors relate to relapse in multi variant analysis -

• infective endocarditis • vancomycin therapy (vs nafcillin) for MSSA

Outcomes when IE excluded

patients withpersistent

bacteraemia>7d

relapse failure

MSSAnafcillinvancomycin

MRSAvancomycin

0/188/70

4/83

0/185/70

4/83

0/1813/70

8/83

Antibiotic resistance and bacteraemia (7)

Specific pathogen - S. aureus

Sakoulas et al, 2004

30 patients with S. aureus bacteraemia recruited intoclinical trials. (PIII/IV) treated with vancomycinlogistic regression indicated significant relationshipbetween MIC (and killing) and treatment success

MIC (mg/L) success< 0.51-2

57%9.5%

Antibiotic resistance and bacteraemia (8)

Specific pathogen: S. aureus

Conterno et al, 1998Sâo Paulo, Brazil, 1991-92retrospective case control study comparingMSSA to MRSA (n = 136)

Multivariate analysis - 3 risk factors for death -

lung as site of entry OR 17.0shock OR 8.9MRSA OR 4.2

MRSA bacteraemia more likely to have inappropriate therapy in first48h

Antibiotic resistance in bacteraemia (9)

Specific pathogen: P. aeruginosa

appropriate therapy improves outcomeYes - acute leukaemia Bodey et al, 1985Yes - general group in HIV Vidal et al, 1996No - general group Hilf et al, 1989No - ICU patients Carmeli et al, 1999

combination therapy improves outcomeYes - general group Hilf et al, 1989Yes - acute leukaemia Bodey et al, 1985

(monotherapy with aminoglycoside)No - general group inc HIV Vidal et al, 1996No - cancer Chatzinikolaou et al, 2000

(monotherapy with ceftazidime or imipenem)

Antibiotic resistance in bacteraemia (10)

Specific pathogen P. aeruginosaChamot et al, 2003115 patients with P. aeruginosa in historical cohort between 1988-98, inSwitzerlandCox proportional hazard model to 30d follow-up

HR 95% PEMPIRICAL THERAPYadequate combinationadequate monotherapyinadequateDEFINATIVE THERAPYadequate combinationadequate monotherapyinadequateICU STAYNoYesURINARY/VASCULAR ORIGINNoYes

1.03.75.0

1.00.72.6

1.03.2

1.00.21

1.0-14.112.-20.4

0.3-1.71.1-6.7

1.2-8.9

0.05-0.9

0.050.02

0.420.04

0.02

0.04

Pseudomonas aeruginosa bacteraemia

Zelenitsky et al, 2003

retrospective study of 38 patientsserum concentrations, MIC determined

Outcome measured as - persistent infection (21%)- death to 30d (21%)- cure (58%)

Cmax/MIC ratio of >8 predicted > 90% cure foraminoglycosides and ciprofloxacin

Extended spectrum Blactamase (1)

Paterson et al, 1998

400 consecutive blood stream isolates of K. pneumoniae, 11 hospitals

Overall mortality - 24%

Mortality lower if carbapenem used in first 5 days (5% vs 43%, p=0.01)

21% mortality if treated with ciprofloxacin and susceptible

50% (2/4) mortality with cefipime50% (2/4) mortality with piperacillin-tazobactamcombination of active Blactam plus amikacin did not improve outcome(mortality 15% vs 17% p>0.2)

Extended spectrum Blactamase (2)

Kim et al, 2002

142 blood isolates in Korea, E. coli or K. pneumoniaeStrain MIC > 2mg/L to 3rd generation cephlosporins

Patients treated with extended spectrum cephalosporin (most receivedaminoglycoside)

favourable responseESBL + ESBL - P

day 3day 5end of therapy

6/17 (35%)6/17 (35%)9/7 (53%)

33/51 (65%)36/50 (72%)47/50 (94%)

0.0350.007

<0.001

Extended spectrum Blactamase (3)

Piperacillin - tazobactam

Burgess (2003)ESBL + E. coli or Klebsiellaoverall 6/18 patients failed

4/9 piperacillin-tazobactam2/9 other agents

Ambrose et al, 2003Piperacillin-tazobactam 3.375g 6hrly0.50 - 0.73 target ascertainment of ESBL positive E. coli,K. pneumoniae in Monte Carlo simulations(4.5g 8hrly probably similar; 4.5g 6hrly better)

Extended spectrum Blactamase (4)

treatment of E. coli/Klebsiella with ESBLs in theurinary tract

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Antibiotic resistance in urinary tract infection

Talan et al, 2000

Los Angeles, USAas part of a randomised double blind comparative study ofciprofloxacin & TMP/SMX conducted between 1994-7(n = 378)

Resistance to TMP/SMX 18% in E. coli(90% of pathogens)

TMP/SMX associated with higher bacteriological/clinical failures

Antibiotic resistance in pneumonia (1)

Definition of penicillin resistance:-

penicillin susceptible 0.06mg/Lintermediate 0.1 - 1.0mg/Lresistant 2mg/L

Antibiotic resistance in pneumonia (2)

penicillin non susceptibility does not impact on clinicalresponse or outcomes for therapy with penicillin/amoxicillin± clavulanate

• paediatric community acquired pneumococcal pneumonia (retrospective; n = 207), Friedland & Klugman 1992• adults with pneumococcal pneumonia (retrospective; n = 23) Sandches et al 1992• paediatric bacteraemic pneumococcal infection (prospective), Friedland, 1995• adults with pneumococcal pneumonia (prospective; n = 504) Pallarres et al, 1995• invasive pneumococcal infection + bacteraemia (retrospective; n = 106) Choi & Lee, 1998

Penicillin non susceptibility does not impact (continued)

• paediatric invasive pneumococcal infection, mainly bacteraemia (retrospective) Deeks et al, 1999• hospitalised patients with pneumococcal community acquired pneumonia (retrospective; n = 101; pen R 2mg/L) Ewig et al, 1999• hospitalised patients with pneumococcal bacteraemia (retrospective; n = 156) Farinas-Alvarez et al, 2000• community acquired pneumococcal pneumonia (prospective, n = 465) Bedos et al, 2001• hospitalised patients with invasive pneumococcal pneumonia (prospective, n = 146) Moroney et al, 2001

Penicillin non susceptibility does have a clinical impact

• pneumococcal pneumonia (n = 5837) overall mortality related to older age

underlying diseaseAsian raceliving in Toronto

Excluding early deaths i.e. <4 days:-

Feikin et al, 2000

Antimicrobial Adjusted ORPenicillin

Cefotaxime

MIC 4mg/LMIC 0.1 – 1.0mg/LMIC 2mg/LMIC 1mg/L

7.1 (1.7 – 13.0)1.0 (0.3 – 3.0)5.9 (1.1 – 33.0)1.2 (0.3 – 7.4)

Penicillin non susceptibility does have a clinical impact

• pneumococcal pneumonia (retrospective study, n = 462) multivariate analysis identified the following as independent predictors of mortality - older age

severe diseasemultilobar infiltrateeffusion on CXRhispanichigh level penicillin resistance

Turrett et al, 1999

Penicillin non susceptibility does have a clinical impact

• adults with bacteraemic pneumococcal pneumonia (n = 192) > increased risk of suppurative complication after adjustment for other factors

Metlay et al, 2000

• children with invasive infection - mainly bacteraemia (n = 304) > longer ITU stay; all other factors similar

Quach et al, 2000

Conclusion for S. pneumoniae:-

penicillin “resistance” probably only has therapeuticsignificance once MIC values are 2-4mg/L

wild typedistributions

microbiologicalcut offs

MIC

pD index pharmacokinetics

microbiological outcomes clinicalbreakpoints

clinical outcomes

Putting it together (1)

Wild typedistributions

microbiologicalcut off

Penicillin-S. pneumoniae

MIC

most drug-bacteriacephalosporin-ESBLBlactam-MRSA

Vancomycin-MSSAP. aeruginosaP/T - ESBLs

pD index pharmacokinetics

microbiological outcome

clinical outcome

Putting it together (2)

Conclusions

> clinical data on resistance significance is weaker than animal/in vitro data> appropriate early therapy probably improves patient outcomes> applies in a wide range of clinical contexts and pathogens but not everywhere> categorical sensitivity testing (S/I/R) is a crude approximate of the true drug - pathogen - host relationship> clinical breakpoints should have improved predictive value as pD principles are understood> microbiological breakpoints may be therapeutically misleading