New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical ␤-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pumpoverexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2-to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.Pseudomonas aeruginosa causes severe infections resulting in considerable mortality and morbidity, particularly in intensive care unit patients with ventilator-associated pneumonia. No single agent is adequate to provide a cell kill sufficient to allow an optimal clinical outcome and simultaneously suppress amplification of less susceptible subpopulations of organisms, when examined by Monte Carlo simulation across a broad range of exposures. For instance, this laboratory has demonstrated that levofloxacin can suppress less-susceptible-subpopulation amplification when an exposure of an AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 157 was attained (10). When Monte Carlo simulation was employed to examine how often such a ratio was attained in patients treated with 750 mg levofloxacin given once daily and across a distribution of levofloxacin MIC values, only 61% were expected to achieve such an exposure for a collection of Pseudomonas aeruginosa isolates. When this method was employed with ciprofloxacin for Pseudomonas in patients with hospital-acquired pneumonia, the outcomes correlated quite closely with resistance emer...

New broad-spectrum ␤-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of ␤-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-␤-lactam ␤-lactamase inhibitor. In this evaluation, we examined organisms carrying defined ␤-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 ␤-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was "cured" of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal ␤-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that "time > threshold" was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.