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

Abstract

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 ...

Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

“…Tam et al showed that for meropenem, the PD target needed to suppress the emergence of resistance in P. aeruginosa was a C min :MIC ratio of 1.7. 38 Further study is still needed in the area of resistance suppression but the current data suggest that obtaining the PK/PD target against the range of MIC encountered clinically is not likely with conventional b-lactam dosing and will most likely require more intensive regimens administered over extended periods of time. 38 …”

Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

“…This is commonly referred to as the free drug time above the MIC (fT Ͼ MIC). The level of exposure required for a bactericidal effect also varies depending on the ␤-lactam class, with carbapenem, penicillin, and cephalosporin antibiotics, in general, requiring approximately 40%, 50%, and 50 to 70% fT Ͼ MIC, respectively, for a bactericidal effect (27); however, some reports have demonstrated a benefit to providing greater exposures (i.e., 100% fT Ͼ MIC) (24). As a result of this knowledge, numerous approaches have been made to maximize the fT Ͼ MIC by altering antibiotic dosage regimens in an effort to improve patient outcomes and lower antibiotic-related costs.…”

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

“…This intrinsic tolerance of ␤-lactams likely accounts for the fact that when P. aeruginosa infections are treated, optimal microbiological outcomes occur when ␤-lactam concentrations are maintained at 4 to 6.6 times the MIC throughout the majority of the dosing period (13). Furthermore, ␤-lactam tolerance by P. aeruginosa can lead to the emergence of spontaneous ␤-lactam-resistant strains (12,14). Thus, ␤-lactam tolerance provides significant challenges for clinicians when treating P. aeruginosa infections.…”