Pharmacodynamics of cefepime in patients with Gram-negative infections

182

151

Suppression of resistance in a dense Pseudomonas aeruginosa population has previously been shown with optimized quinolone exposures. However, the relevance to ␤-lactams is unknown. We investigated the bactericidal activity of meropenem and its propensity to suppress P. aeruginosa resistance in an in vitro hollow-fiber infection model (HFIM). Two isogenic strains of P. aeruginosa (wild type and an AmpC stably derepressed mutant [MIC ‫؍‬ 1 mg/liter]) were used. An HFIM inoculated with approximately 1 ؋ 10 8 CFU/ml of bacteria was subjected to various meropenem exposures. Maintenance doses were given every 8 h to simulate the maximum concentration achieved after a 1-g dose in all regimens, but escalating unbound minimum concentrations (C min s) were simulated with different clearances. Serial samples were obtained over 5 days to quantify the meropenem concentrations, the total bacterial population, and subpopulations with reduced susceptibilities to meropenem (>3؋ the MIC). For both strains, a significant bacterial burden reduction was seen with all regimens at 24 h. Regrowth was apparent after 3 days, with the C min /MIC ratio being <1.7 (time above the MIC, 100%). Selective amplification of subpopulations with reduced susceptibilities to meropenem was suppressed with a C min /MIC of >6.2 or by adding tobramycin to meropenem (C min /MIC ‫؍‬ 1.7). Investigations that were longer than 24 h and that used high inocula may be necessary to fully evaluate the relationship between drug exposures and the likelihood of resistance suppression. These results suggest that the C min /MIC of meropenem can be optimized to suppress the emergence of non-plasmid-mediated P. aeruginosa resistance. Our in vitro data support the use of an extended duration of meropenem infusion for the treatment of severe nosocomial infections in combination with an aminoglycoside.Bacterial resistance is a rapidly spreading and serious problem that threatens our therapeutic armamentarium. Given that the drug development process takes many years, it is imperative that the utilities of currently available agents be preserved through the judicious and optimal use of these agents. It has been shown that suboptimal dosing represents a selective pressure that is imposed on the bacteria and that facilitates the emergence of resistance (9, 11). On the other hand, all bacterial subpopulations are killed with optimal dosing, which results in the sustained suppression of both total and resistant populations over time. It has also previously been shown that the emergence of resistance in Pseudomonas aeruginosa could be suppressed by optimizing the exposure of quinolones (11, 28). However, it is less certain if the same is true for the ␤-lactam antibiotics.The pharmacodynamics of ␤-lactams have been relatively well elucidated. The time above the MIC (T Ͼ MIC) of the pathogen has repeatedly been shown to be the pharmacodynamic variable most closely linked to bactericidal activity (2, 21). However, the breakpoint of optimal activity is controversial, and none of the ...

Section: Discussionsupporting

confidence: 86%

Optimization of Meropenem Minimum Concentration/MIC Ratio To Suppress In Vitro Resistance of Pseudomonas aeruginosa

Tam

Schilling

Neshat

et al. 2005

182

151

“…Studies in animal infection models have shown that, for most ␤-lactams, concentrations do not need to exceed the MIC for 100% of the dosing interval to achieve significant antibacterial effects (8,9), and bactericidal effects of carbapenems against Escherichia coli and Pseudomonas aeruginosa in a murine thigh infection model are observed when plasma drug concentrations are above the MIC for 40% of the dosing interval (20). Moreover, optimal killing properties have been observed in critically ill patients when concentrations are maintained at 4ϫMIC, with higher concentrations providing little added benefit (21,22). However, there is no consensus regarding which strategy (T ϾMIC versus T Ͼ4ϫ MIC ) is better.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

Jaruratanasirikul

Thengyai

Wongpoowarak

et al. 2015

c Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT >MIC ) and 80% fT >MIC . The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 g/ml, the PTAs of 40% fT >MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 g/ml in immunocompromised hosts, the PTAs of 80% fT >MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

“…Even the NCCLS frequently relies on healthy-subject data to assess the viability of MIC breakpoints. When possible, PK data should be derived from the population of interest (1,12,22,30,32,33). In summary, 3.375 g of piperacillin-tazobactam given intravenously every 6 h performed well, achieving excellent target attainment rates for MICs of Յ8 (piperacillin) and 4 (tazobactam) mg/liter.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

Lodise

Lomaestro

Rodvold

et al. 2004

112

The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 g/ml.In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint-h 3 concentrations of a 6-h dosing interval-between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of <8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of <16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.Antimicrobial pharmacodynamics is a term used to describe the relationship between drug exposure and antimicrobial activity. In recent years there have been tremendous strides in understanding the relationship between the pharmacodynamics of beta-lactams and treatment outcomes. Beta-lactams, in contrast to aminoglycosides and fluoroquinolones, exhibit little concentration-dependent bacterial killing (7-9, 14, 24, 25, 29, 30). This phenomenon was observed in early Staphylococcus aureus time-kill curve studies, which demonstrated that the rate of bacterial killing was not improved by increasing the concentration of penicillin (19). For beta-lactams, the time during which the free (unbound) serum drug concentration exceeds the MIC of the drug for the organism (T Ͼ MIC) appears to be the best predictor of outcomes (7-9, 24, 25). The serum free-beta-lactam concentration does not have to remain above the MIC for the entire dosing interval, and the fraction of the dosing interval during which it is required to remain above the MIC for the maximal antimicrobial effect varies for the different types of beta-lactams (7-9). Although the T Ͼ MIC varies for different drug-bacteria combinations, satisfactory outcomes (near-maximal bactericidal effect) are achieved when the free (unbound)-antibiotic concentration remains above the MIC for t...