A human antibody facilitates opsonophagocytic killing, inhibits attachment of Pseudomonas aeruginosa, and exerts protective effects in several animal models of P. aeruginosa infection.

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 ...

BackgroundOsteomyelitis is a challenging infection that can involve 4–6 weeks of intravenous (IV) antibiotics. Dalbavancin, approved for acute bacterial skin and skin structure infections, has potent activity against gram-positive pathogens. This study assessed the efficacy and safety of dalbavancin as a 2-dose regimen for osteomyelitis.MethodsThis study was a randomized, open-label, comparator-controlled trial in adults with a first episode of osteomyelitis defined by clinical symptoms, radiologic findings, and elevated C-reactive protein. Patients were randomized 7:1 to dalbavancin (1500 mg IV on days 1 and 8) or standard of care (SOC) for osteomyelitis (oral or IV) per investigator judgment for 4–6 weeks. The primary endpoint was clinical response at day 42, defined as recovery without need for additional antibiotics in the clinically evaluable (CE) population. Clinical response was also assessed at day 21, 6 months, and 1 year.ResultsEighty patients were randomized to dalbavancin (n = 70) or SOC (n = 10). All had baseline debridement; Staphylococcus aureus was the most common pathogen (60% of patients). Clinical cure at day 42 was seen in 65/67 (97%) and 7/8 (88%) patients in the dalbavancin group and SOC group in the CE population, respectively. Clinical response was similar in the dalbavancin group at day 21 (94%), 6 months, and 1 year (96%). Treatment-emergent adverse events occurred in 10 patients in the dalbavancin group; no patient discontinued treatment due to an adverse event.ConclusionsA 2-dose regimen of weekly dalbavancin is effective and well tolerated for the treatment of osteomyelitis in adults.Clinical Trials RegistrationNCT02685033.

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of ␤-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC ELF /AUC plasma ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/ plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC ELF / AUC plasma ratio. The range of AUC ELF /AUC plasma penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.Ventilator-associated pneumonia (VAP) remains a frequent cause of morbidity and mortality among intensive care unit patients despite advances in antimicrobial therapy, better supportive care modalities, and the use of a wide range of preventive measures (1, 26). Prompt delivery of empirical therapy for patients likely to have VAP is of paramount importance, since delays in appropriate antibiotic therapy have been associated with deleterious outcomes (1,18,19,24,25). An important consideration when selecting empirical therapy for VAP is the agent's ability to adequately penetrate the infected site and achieve sufficient concentrations for the desired endpoint. For extracellular respiratory tract pathogens, the determination of drug concentration in epithelial lining fluid (ELF) currently provides the best estimate for ascertaining the degree of antibiotic exposure for these organisms in patients with 12,[15][16][17]21,25,27,28).While it is well established that the efficacy of an antibiotic regimen largely depends on its penetration in the infection site, relatively few studies have focused on the penetration of antibiotics into the ELF (3-8, 12, 15-17, 21, 23, 25, 27, 28). Of those available, most have been among patients treated with fluoroquinolones and macrolides (12,15,16,23,27,28). A surprisingly small body of data is available for the penetration of ␤-lactam agents into the ELF. In the older li...