Does susceptibility testing have a role in predicting
clinical or microbiological outcome?
Alasdair MacGowan
North Bristol NHS Trust & University of Bristol
Southmead Hospital
Bristol, UK
The paradigm
pharmacodynamic
index size
Cmax/MIC
AUC/MIC
T>MIC
microbiological
outcome
clinical
outcome
The Pharmacodynamic world - students view
Cmax/MIC
fluoroquinolones
aminoglycosides
daptomycin
(metronidazole)
AUC/MIC
fluoroquinolones
daptomycin
aminoglycosides
ketolides
metronidazole
tetracyclines
glycopeptides
oxazolidinones
T > MIC
macrolides
clindamycin
oxazolidinones
B lactams
glycopeptides
The Pharmacodynamic world - shades of grey
AUC/MIC
tetracyclines
ketolides
Oxazolidinones
glycopeptides
AUC/MIC;
Cmax/MIC
fluoroquinolones
aminoglycosides
(daptomycin)
? Dalbavancin
T > MIC
Blactams
erythromycin
clindamycin
Cmax/MIC
Clinical studies showing a relationship between
pharmacodynamic index and outcome
drug
gentamicin/
amikacin/
netilmicin
pD index
Cmax/MIC
size
>10
reference
Moore et al, 1987
gentamicin/
tobramycin
cefipime
ciprofloxacin
grepafloxacin
levofloxacin
Cmax/MIC
>10
Kashuba et al, 1999
T>MIC
AUC/MIC
AUC/MIC
Cmax/MIC
AUC/MIC
AUC/MIC
?
>125
>175
>12
>120
>35
Tam et al, 2002
Forrest et al, 1993
Forrest et al, 1997
Preston et al, 1998
AUC/MIC
AUC/MIC
>87
>100
AUC/MIC
T>MIC
>100
>85
Drusano et al, 2004
Schentag et al,
in press
Rayner et al, 2000
gatifloxacin/
levofloxacin
levofloxacin
vancomycin
linezolid
Ambrose et al, 2003
Pharmacokinetics and susceptibility
pD index
Cmax/MIC
pharmacokinetics
Cmax (mg/L)
susceptibility
MIC (mg/L)
AUC/MIC
Dose. F (mg/L.h)
Clp
MIC (mg/L)
Cmax t½ (mg/L.h)
0.692
MIC (mg/L)
T>MIC
Cmax
log Cmic Kel
Which is dominant - pharmacokinetics or susceptibility?
Pharmacokinetic variability
agent/dose
ciprofloxacin/various
levofloxacin, 500mg
gatifloxacin, 400mg
moxifloxacin, 400mg
linezolid, 600mg
total drug AUC (mg.L.h)
patients with
volunteers
infection
mean
%CV
mean
%CV
20
77
48
20
73
70
34
16
51
40
48
12
48
180
34
165
56
range
(112-980)
Susceptibility variability - MICs
(www.bsacsurv.org; www.EUCAST.org)
Wild type (EUCAST)
ciprofloxacin - E. coli
levofloxacin - E. coli
moxifloxacin - E. coli
Variation
0.002-0.06 mg/L
x30
0.002-0.06 mg/L
x30
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; hence
in situations where MIC ranges are large, categorical
sensitivity testing should be predictive.
Antibiotic resistance and bacteraemia (1)
General cases
Phillips et al, 1990
St Thomas’ Hospital, London
bacteraemias 1969-88, retrospective analysis
Staphylococci, Enterococci, Enterobacteriaceae, P. aeruginosa
Outcomes
died
therapy
n.
survived
infection
disease
appropriate
1346
84%
9%
7%
inappropriate
159
68%
17%
15%
Antibiotic resistance and bacteraemia (2)
Behrendit et al, 1999
Department of Medicine, University Hospital, Frankfurt
1989-93, retrospective analysis
Outcome: 28d mortality
therapy
any appropriate
non appropriate
appropriate in 48h
not appropriate in 48h
n.
survived (%)
817
164
84
72
85
69
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
therapy
inappropriate
n.
147
% mortality
61.9
RR 2.18 (1.77 – 2.69)
appropriate
304
28.4
Multiple logistic regression:inadequate antimicrobial therapy as independent determinant of
mortality RR 6.9 (5.1 - 9.3, p < 0.001)
Commonest resistant isolates - VRE, Candida sp, MRSA, CONS,
P. aeruginosa - also highest mortality
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
factor
Hazards
ratio
ratio
APACHE II at onset
1.08
(1.04 – 1.12)
number of organ dysfunctions
1.39
(1.11 – 1.65)
appropriate antimicrobial therapy
0.35
(0.2 – 0.63)
Antibiotic resistance and bacteraemia (5)
Specific pathogens: S. aureus
Gonzalez et al, 1999
Madrid, Spain, 1990-1994
S. aureus, pneumonia + bacteraemia
prospective cohort study
Group
MSSA
treatment
n, treated
(%)
vancomycin
17 (41.5)
n, died
(%)
8 (47)
p<0.01
(n = 41)
cloxacillin
10 (24.4)
0
MRSA
vancomycin
20 (91)
10 (50)
(n=22)
Antibiotic resistance and bacteraemia (6)
Specific pathogen - S. aureus
Chang et al, 2003
Multi centre, prospective observational study of 505 patients in USA.
End points were persistent and relapsed infection
Factors relate to relapse in multi variant analysis • infective endocarditis
• vancomycin therapy (vs nafcillin) for MSSA
Outcomes when IE excluded
patients with
persistent
bacteraemia
>7d
relapse
failure
MSSA
nafcillin
vancomycin
0/18
8/70
0/18
5/70
0/18
13/70
MRSA
vancomycin
4/83
4/83
8/83
Antibiotic resistance and bacteraemia (7)
Specific pathogen - S. aureus
Sakoulas et al, 2004
30 patients with S. aureus bacteraemia recruited into
clinical trials. (PIII/IV) treated with vancomycin
logistic regression indicated significant relationship
between MIC (and killing) and treatment success
MIC (mg/L)
< 0.5
1-2
success
57%
9.5%
Antibiotic resistance and bacteraemia (8)
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
shock
MRSA
OR 17.0
OR 8.9
OR 4.2
MRSA bacteraemia more likely to have inappropriate therapy in first
48h
Antibiotic resistance in bacteraemia (9)
Specific pathogen: P. aeruginosa
appropriate therapy improves outcome
Yes
- acute leukaemia
Yes
- general group in HIV
No
- general group
No
- ICU patients
Bodey et al, 1985
Vidal et al, 1996
Hilf et al, 1989
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)
Antibiotic resistance in bacteraemia (10)
Specific pathogen P. aeruginosa
Chamot et al, 2003
115 patients with P. aeruginosa in historical cohort between 1988-98, in
Switzerland
Cox proportional hazard model to 30d follow-up
EMPIRICAL THERAPY
adequate combination
adequate monotherapy
inadequate
DEFINATIVE THERAPY
adequate combination
adequate monotherapy
inadequate
ICU STAY
No
Yes
URINARY/VASCULAR ORIGIN
No
Yes
HR
95%
P
1.0
3.7
5.0
1.0-14.1
12.-20.4
0.05
0.02
1.0
0.7
2.6
0.3-1.7
1.1-6.7
0.42
0.04
1.0
3.2
1.2-8.9
0.02
1.0
0.21
0.05-0.9
0.04
Pseudomonas aeruginosa bacteraemia
Zelenitsky et al, 2003
retrospective study of 38 patients
serum concentrations, MIC determined
Outcome measured as
- persistent infection (21%)
- death to 30d (21%)
- cure (58%)
Cmax/MIC ratio of >8 predicted > 90% cure for
aminoglycosides 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 cefipime
50% (2/4) mortality with piperacillin-tazobactam
combination 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. pneumoniae
Strain MIC > 2mg/L to 3rd generation cephlosporins
Patients treated with extended spectrum cephalosporin (most received
aminoglycoside)
day 3
day 5
end of therapy
favourable response
ESBL +
ESBL 6/17 (35%)
33/51 (65%)
6/17 (35%)
36/50 (72%)
9/7 (53%)
47/50 (94%)
P
0.035
0.007
<0.001
Extended spectrum Blactamase (3)
Piperacillin - tazobactam
Burgess (2003)
ESBL + E. coli or Klebsiella
overall 6/18 patients failed
4/9 piperacillin-tazobactam
2/9 other agents
Ambrose et al, 2003
Piperacillin-tazobactam 3.375g 6hrly
0.50 - 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 the
urinary tract
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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
Antibiotic resistance in pneumonia (1)
Definition of penicillin resistance:penicillin
susceptible  0.06mg/L
intermediate 0.1 - 1.0mg/L
resistant
 2mg/L
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
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
overall mortality related to
(n = 5837)
older age
underlying disease
Asian race
living in Toronto
Excluding early deaths i.e. <4 days:Antimicrobial
Penicillin
MIC  4mg/L
MIC 0.1 – 1.0mg/L
Cefotaxime
MIC  2mg/L
MIC 1mg/L
Adjusted OR
7.1 (1.7 – 13.0)
1.0 (0.3 – 3.0)
5.9 (1.1 – 33.0)
1.2 (0.3 – 7.4)
Feikin et al, 2000
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
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 therapeutic
significance once MIC values are  2-4mg/L
Putting it together (1)
wild type
distributions
microbiological
cut offs
MIC
pD index
microbiological outcomes
clinical outcomes
pharmacokinetics
clinical
breakpoints
Putting it together (2)
Wild type
distributions
microbiological
cut off
Penicillin-S. pneumoniae
MIC
most drug-bacteria
cephalosporin-ESBL
Blactam-MRSA
pD index
Vancomycin-MSSA
P. aeruginosa
P/T - ESBLs
pharmacokinetics
microbiological
outcome
clinical outcome
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