The BSAC Resistance Surveillance Programmes

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The BSAC Resistance Surveillance Programmes in
the UK and Ireland The Clinical Significance of
Antimicrobial Resistance Alasdair
MacGowan Bristol Centre for Antimicrobial
Research Evaluation University of Bristol
North Bristol NHS Trust Southmead Hospital Bristol
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• Topics
• what is antibiotic resistance
• how has clinical failure been defined
• antibiotic resistance and
• bacteraemia/septicaemia
• respiratory tract
• urinary tract
• conclusions

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• What is antibiotic resistance?
• phenotypic change in susceptibility compared
• to the normal bacterial population
• presence of a genotypic change which adversely
• impacts on susceptibility
• level of susceptibility likely to result in a
  higher
• than expected level of therapeutic failure

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• How can significance be measured -
• mortality
• morbidity fever days
• resolution of WBC
• length of stay
• ICU admission/days
• pathogen persistence/resistance
• financial cost

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• Methodologies used-
• prospective cohort or case control studies
• retrospective cohort or case control studies
• no randomised controlled clinical trials

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Antibiotic resistance and bacteraemia
(1) Phillips et al, 1990 St Thomas Hospital,
London bacteraemias 1969-88, retrospective
analysis Staphylococci, Enterococci,
Enterobacteriaceae, P. aeruginosa Outcomes
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Antibiotic resistance and bacteraemia
(2) Behrendit et al, 1999 Department of
Medicine, University Hospital, Frankfurt 1989-93,
retrospective analysis Outcome 28d mortality
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Antibiotic resistance and bacteraemia
(3) Specific settings - ICU Ibrahim et al,
2000 St Louis USA, Medical Surgical ICU (37
beds) 1997-99 Prospective cohort study
Multiple logistic regression- inadequate
antimicrobial therapy as independent determinant
of mortality RR 6.9 (5.1 - 9.3, p lt
0.001) Commonest resistant isolates - VRE,
Candida sp, MRSA, CONS, P. aeruginosa - also
highest mortality
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Antibiotic resistance and bacteraemia
(4) Specific settings - ICU Harbarth et al,
2002 Geneva, Switzerland, Surgical ICU (22 beds)
1994-7 retrospective cohort study of 244
bacteraemias In multivariate analysis
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Antibiotic resistance and bacteraemia
(5) Specific pathogens S. aureus Gonzalez et
al, 1999 Madrid, Spain, 1990-1994 S. aureus,
pneumonia bacteraemia prospective cohort study
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Antibiotic resistance and bacteraemia
(6) Specific pathogen S. aureus Conterno et
al, 1998 Sâo Paulo, Brazil, 1991-92 retrospective
case control study comparing MSSA to MRSA (n
136) Multivariate analysis - 3 risk factors for
death - lung as site of entry OR
17.0 shock OR 8.9 MRSA OR 4.2 MRSA
bacteraemia more likely to have inappropriate
therapy in first 48h
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Antibiotic resistance in bacteraemia
(7) Specific pathogen P. aeruginosa appropriat
e therapy improves outcome Yes - acute
leukaemia Bodey et al, 1985 Yes - general group
in HIV Vidal et al, 1996 No - general
group Hilf et al, 1989 No - ICU
patients Carmeli et al, 1999 combination
therapy improves outcome Yes - general
group Hilf et al, 1989 Yes - acute
leukaemia Bodey et al, 1985 (monotherapy with
aminoglycoside) No - general group inc HIV Vidal
et al, 1996 No - cancer Chatzinikolaou et al,
2000 (monotherapy with ceftazidime or imipenem)
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Antibiotic resistance in pneumonia
(1) Definition of penicillin resistance- penici
llin susceptible ? 0.06mg/L intermediate 0.1
- 1.0mg/L resistant ? 2mg/L
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• Antibiotic resistance in pneumonia (2)
• penicillin non susceptibility does not impact on
  clinical
• response 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

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• 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

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• Penicillin non susceptibility does have a
  clinical impact
• pneumococcal pneumonia (n 5837)
• overall mortality related to older age
• underlying disease
• Asian race
• living in Toronto
• Excluding early deaths i.e. lt4 days-

Feikin et al, 2000
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• 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 disease
• multilobar infiltrate
• effusion on CXR
• hispanic
• high level penicillin resistance
• Turrett et al, 1999

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• Penicillin non susceptibility does have a
  clinical impact
• adults with bacteraemic pneumococcal pneumonia
  (n 192)
• gt increased risk of suppurative complication
  after adjustment
• for other factors
• Metlay et al, 2000
• children with invasive infection -
• mainly bacteraemia (n 304)
• gt longer ITU stay all other factors similar
• Quach et al, 2000

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Conclusion for S. pneumoniae- penicillin
resistance probably only has therapeutic signifi
cance once MIC values are ? 2-4mg/L
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Antibiotic resistance in Urinary tract
infection Talan et al, 2000 Los Angeles, USA as
part of a randomised double blind comparative
study of ciprofloxacin 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
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• Why is susceptibility not always associated with
  outcome ?
• uncontrolled patient factors
• pharmacodynamic factors i.e., only component of
• pK/pD index
• i.e. AUC/MIC Cmax/MIC or TgtMIC

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Pharmacodynamic index in man
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• Therefore -
• as MIC and hence categorical interpretation is
• only a part of the picture so relationships
  between
• S/I/R and outcomes will sometimes be weak

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• Conclusions
• most clinical studies retrospective and poorly
  controlled
• inappropriate early therapy probably improves
  outcome (that is treating
• infection to which the potential pathogen(s)
  are sensitive)
• applies in a range of clinical contexts and
  pathogens
• pharmacodynamic links between in vitro/animal
  models and human studies
• have improved significantly
• clinical breakpoints should improve in their
  predictive value in future.
• microbiological breakpoints may be
  therapeutically misleading
• (i.e. penicillin and S. pneumoniae)