Pharmacokinetics of Meropenem 0.5 and 2 g Every 8 Hours as a 3‐Hour Infusion

Vaborbactam (formerly RPX7009) is a member of a new class of ␤-lactamase inhibitor with pharmacokinetic properties similar to those of many ␤-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single-and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort.

Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Griffith

Loutit

Morgan

et al. 2016

“…2C, where regrowth was evident beyond 24 h by using an identical meropenem exposure. The meropenem C min of 1.7 mg/liter can be clinically achieved by a prolonged (3-h) infusion (5). By using this dosing strategy, suppression of spontaneous pseudomonal resistance is likely to be achieved in immunocompetent patients when it is used in combination with an aminoglycoside.…”

Section: Discussionmentioning

confidence: 99%

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

Tam

Schilling

Neshat

et al. 2005

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 ...

“…Meanwhile, the mean serum drug concentrations when administration was by a 3-h infusion of 2 g of meropenem were above 8 and 16 g/ml for 72 and 57% of an 8-h period, respectively. In a previous study with healthy volunteers, a 3-h infusion of 2 g of meropenem could maintain serum drug concentrations above the MICs of 4 and 16 g/ml for 73 and 48% of an 8-h period, respectively (6). Thus, for the treatment of infections caused by isolated pathogens with intermediate resistance, the meropenem dosage administered by a 3-h infusion should be increased to a maximum of 2 g every 8 h.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Pharmacodynamics of Meropenem in Patients with Ventilator-Associated Pneumonia following Administration by 3-Hour Infusion or Bolus Injection

Jaruratanasirikul

Sriwiriyajan

Punyo

2005

136

The time that concentrations in serum are above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of ␤-lactam antibiotics. The aim of this study was to demonstrate the T>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the T>MICs of 16, 8, 4, and 1 g/ml were 28.33% ؎ 11.67%, 45.89% ؎ 22.90%, 57.00% ؎ 24.82%, and 74.67% ؎ 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 g/ml were 37.78% ؎ 20.57%, 58.11% ؎ 24.38%, 72.67% ؎ 21.97%, and 93.56% ؎ 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 g/ml were 57.89% ؎ 24.26%, 72.89% ؎ 22.40%, 85.56% ؎ 16.42%, and 98.56% ؎ 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater T>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 g/ml for almost 60% of an 8-h interval.