ICAAC 2004 Use of Pharmacokinetic-Pharmacodynamic and Monte Carlo Simulation as Decision Support for the Re-Evaluation of NCCLS Cephem Susceptibility Breakpoints for Enterobacteriaceae PG AMBROSE, SM BHAVNANI, RN JONES, WA CRAIG, MN DUDLEY Cognigen Corp., Buffalo, NY; University at Buffalo, Buffalo, NY; JONES Group/JMI Laboratories, North Liberty, IA; University of Wisconsin, Madison, WI; and Diversa Corporation, San Diego, CA Animal PK-PD Models
Current, PK-PD-based, PK-PD-based-population distribution adjusted breakpoints
A M E N D E D A B S T R A C T
¥ Neutropenic murine-thigh infection models were used to study PK-PD indices that correlated
for antimicrobial agents in NCCLS M100-S14 Table 2A.
best with efficacy for Enterobacteriaceae, including both EBSL- and non-ESBL producing
Background: As cephem-resistant Enterobacteriaceae, including ESBL-producing strains,
have continued to emerge, the appropriateness of current NCCLS susceptibility breakpoints
Potential susceptibility breakpoints could be stratified into one of five groups
Table 2 shows current cephem NCCLS susceptibility breakpoints, PK-PD based
have been the focus of recent attention. In the face of limited clinical data, Pharmacokinetic-
¥ Indices of efficacy explored include: Duration of time (T) drug concentration remain above the
based upon probability of PK-PD target attainment and examination of
breakpoints, and MIC population-adjusted PK-PD breakpoints.
Pharmacodynamics (PK-PD) and Monte Carlo simulation have been increasingly used as
MIC (T > MIC), ratio of the peak concentration of the agent to the MIC of the pathogen (Cmax:MIC
decision support for establishing breakpoints. NCCLS susceptibility breakpoints for cephems
ratio), ratio of the 24-hour area under the concentration-time curve (AUC0-24) of the agent to
against Enterobacteriaceae were re-evaluated using this approach. Figure 3. Fractional PK-PD target attainment of cefuroxime against Escherichia coli and Methods:
Susceptibility breakpoints did not bisect MIC distribution (Example, Figures
Using published mean PK parameter estimates and dispersion measures from
. The probability of PK-PD target attainment is greater than
¥ Non-linear regression using a Hill-type model was used to describe relationship between the
volunteer studies and PK-PD targets derived from a murine infection model (% free-drug (f)
2A and 2B): Ceftazidime, Ceftriaxone, Cefotaxime, Cefepime, Cefamandole,
0.9 up to MIC values of 4 mg/L when cefuroxime is dosed 0.75 g every 8 hours
above PK-PD measures and response to therapy.
time > MIC ~50), Monte Carlo simulation (10,000 subjects) was used to evaluate the probability
and 8 mg/L when dosed 1.5 g every 8 hours.
of PK-PD target attainment (³ 90%) for standard cephem dosing regimens.
¥ Figure 1 shows the relationship between cephem exposure, as measured by %T > MIC, and
Results: Simulation results support lowering susceptibility breakpoints 2-16-fold for most
response in neutropenic murine-thigh infection models
involving Gram-negative bacteria.
Susceptibility breakpoints bisecting MIC population distributions could be
agents (see table below). Except for cefoxitin and cefazolin, breakpoints do not bisect
- 50% T>MIC was associated with a 0.8 to 2.4 log-unit reduction in bacterial burden.
avoided assuming higher of labeled doses used for serious infections
contemporary MIC population distributions (SENTRY Program). Monte Carlo Simulation
¥ The following PK-PD structural model was used in the simulations:
T >MIC = (ln Dose/(V§/f) Ð ln MIC)/(CLT/V§) where V§ is the volume estimated from the
Susceptibility breakpoints bisect MIC distribution (Example, Figure 4):
terminal elimination phase half-life (§) for a two-compartment model, CL
f is the fraction of unbound drug. Probability of Target Attainment
¥ Pharmacokinetic parameters for each simulated patient were based on mean pharmacokinetic
Contemporary MIC populations not available: Ceftizoxime, Cefotetan,
parameter estimates and measures of dispersion.
- A log-normal distribution was assumed for clearance and volume terms.
¥ 10,000 patients were simulated for each drug regimen.
Consider removal from NCCLS table 2A due to lack of use and unavailability
Figure 4. Fractional PK-PD target attainment of cefoxitin against Escherichia coli and Klebsiella
- Simulations were conducted using the computer software Crystal Ball 2000.1 by
pneumoniae. The probability of PK-PD target attainment is greater than 0.9 at a
of contemporary MIC data: Cephalothin, Cefonicid, Moxalactam
C O N C L U S I O N S
MIC of 2 mg/L when cefoxitin is dosed 1 g every 6 hours and 4 mg/L when dosed
Susceptibility Breakpoint Determinations Figure 2A. Fractional PK-PD target attainment of ceftriaxone against Escherichia coli and
¥ 50% T>MIC was utilized as the PK-PD goal of therapy. Klebsiella pneumoniae. The probability of PK-PD target attainment is essentially
Simulation results suggest that susceptibility breakpoints for
1.0 up to MIC values of 1 mg/L when ceftriaxone is dosed 1 g every 24 hours and
Conclusions: Simulation results suggest that susceptibility breakpoints for most cephems
¥ The susceptibility breakpoint was the highest MIC value associated with at least a 90%
most cephems against Enterobacteriaceae should be reduced
2 mg/L when dosed 2 g every 24 hours.
against Enterobacteriaceae should be reduced to insure that most patients attain PK-PD
probability of PK-PD target attainment.
to insure that most patients attain PK-PD exposures associated
¥ Contemporary MIC population distributions were considered (Escherichia. coli and KlebsiellaMIC Probability I N T R O D U C T I O N
- If a major portion of the MIC distribution was bisected by a PK-PD susceptibility breakpoint,
Probability of Target Attainment
alternative breakpoints were chosen to avoid division but ensure high probabilities of PK-
As cephem-resistant Enterobacteriaceae, including ESBL-producing strains, have continued to
PD target attainment. In these cases, only susceptible and resistant breakpoints chosen.
Adjustment of NCCLS breakpoints to lower values may negate
MIC (mg/L) MIC Probability
emerge, the appropriateness of current NCCLS susceptibility breakpoints have been the focus
the clinical need for ESBL screening and confirmatory tests. Probability of Target Attainment Figure 1.
Relationship between T>MIC and change in bacterial density in thighs of mice at
- Re-evaluation of susceptibility breakpoints for MIC and
Information from animal infection models, as well as limited clinical data, suggest that ESBL-
24 hours. Each data point represents data for one mouse. The dotted line reflects
Pharmacokinetic parameters utilized for simulations. MIC (mg/L)
producing strains with lower MIC values may be effectively treated using appropriate cephem
the number of bacteria at the beginning of therapy. The T>MIC required for efficacy
corresponding disk zone diameters to better predict
is not affected by ESBL-production status.
Pharmacokinetic Parameter Estimates (mean (SD or range))
presence of ESBLs while potentially eliminating separate
Figure 2B. Fractional PK-PD target attainment of cefepime against Escherichia coli and
Given the paucity of clinical data, pharmacokinetics-pharmacodynamics (PK-PD) and Monte
Klebsiella pneumoniae. The probability of PK-PD target attainment is greater than
screening tests has been completed (see Poster D-303,
Carlo simulation have been increasingly used as decision support for establishing breakpoints.
0.9 for MIC values of 4 mg/L irrespective of the three regimens considered. When
cefepime is dosed 2 g every 12 hours or 1 g every eight hours, the probability of
In view of the above limitations, susceptibility breakpoints for cephems against Enterobacteriaceae
PK-PD target attainment is 0.9 and 0.77 for a MIC of 8 mg/L, respectively.
were re-evaluated using this approach.
- Current NCCLS Enterobacteriaceae susceptibility
breakpoints remain acceptable based on error rate analysis
M AT E R I A L S A N D M E T H O D S
for contemporary isolates. Lower breakpoints could eliminate
Pharmacokinetic Parameter Estimates
¥ Pharmacokinetic data from healthy volunteers were extracted from the medical literature
the routine need for separate ESBL screening tests and
MIC Probability 0.3
disk diffusion zone correlates can be selected to maximize
Probability of Target Attainment
inter-method accuracy pending final approval by the NCCLS. Microbiological Susceptibility Data MIC (mg/L)
¥ Obtained from the SENTRY Antimicrobial Surveillance Program (2001-2003).
Ön az alábbiak közül mely problémákhoz kapcsolódó kiadásokkal szembesült már?Gyermekbetegségek – lázcsillapító (Panadol), lázmérő Háztartási baleset – sebtapasz, BetadinVédőoltások – infl uenza elleni oltás, agyhártyagyulladás Szakorvosi vizsgálatok – fogorvos, szemész stb. Magánorvosi vizsgálatok – fog