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Acinetobacter baumannii is a pathogenic bacterium commonly associated with multidrug resistance. In this issue of Antimicrobial Agents and Chemotherapy , a challenging case of ventilator-associated pneumonia is presented in which bacteriophage therapy was used as a last resort treatment in combination with systemic antibiotics. The data are promising, and several key areas are highlighted for future research.

Antimicrobial resistance has been steadily increasing in prevalence, and combination therapy is commonly used to treat infections due to multidrug resistant bacteria. Under certain circumstances, combination therapy of three or more drugs may be necessary, which makes it necessary to simulate the pharmacokinetic profiles of more than two drugs concurrently in vitro. Recently, a general theoretical framework was developed to simulate three drugs with distinctly different half-lives. The objective of the study was to experimentally validate the theoretical model. Clinically relevant exposures of meropenem, ceftazidime, and ceftriaxone were simulated concurrently in a hollow-fiber infection model, with the corresponding half-lives of 1, 2.5, and 8 h, respectively. Serial samples were obtained over 24 h and drug concentrations were assayed using validated LC-MS/MS methods. A one-compartment model with zero-order input was used to characterize the observed concentration-time profiles. The experimentally observed half-lives corresponding to exponential decline of all three drugs were in good agreement with the respective values anticipated at the experiment design stage. These results were reproducible when the experiment was repeated on a different day. The validated benchtop setup can be used as a more flexible preclinical tool to explore the effectiveness of various drug combinations against multidrug resistant bacteria.

Objectives: The aim of this study was to correlate the results of a modified susceptibility testing method with outcomes of ceftazidime/avibactam (CAZ/AVI) therapy. Methods: Two bloodstream K. pneumoniae isolates (CAZ/AVI-susceptible) from an abdominal source were recovered from two unrelated patients. Both patients were treated with CAZ/AVI but had discordant outcomes: KP118 (eradication within 24 h) and KP286 (persistent bacteraemia for over 30 days). Carbapenemase production in the two isolates was confirmed by Carba NP test. The CAZ minimum inhibitory concentration (MIC) was determined with escalating AVI concentrations (0–16 mg/L). The concentration–response was characterised by the sigmoid inhibitory maximum effect model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5 g every 8 h). These CAZ/AVI exposures were simulated in a hollow-fibre infection model (HFIM), and the bacterial responses were correlated with observed clinical outcomes. Results: The AVI-dependent reduction in CAZ MIC was well characterised in both bacterial isolates (r2 ≥ 0.98). In the HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi

Background Carbapenemases confer resistance against a broad range of beta-lactams with a prevalence of 40-60% among CRE (carbapenem-resistant Enterobacteriaceae). CAZ-AVI is commonly used to treat infections due to CPE (carbapenemase-producing Enterobacteriaceae), typically guided by susceptibility testing with a single AVI concentration. This methodology does not take into consideration varying AVI concentration observed in vivo, and may not reliably predict positive clinical outcomes. Our objective was to investigate a novel susceptibility testing method to guide CAZ-AVI therapy. Methods Two bloodstream K. pneumoniae isolates (CAZ/AVI susceptible) from an abdominal source were recovered from 2 unrelated patients. Both patients were treated with CAZ/AVI, but had discordant outcomes: KP118 (eradication within 24h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the 2 isolates was confirmed via Carba NP test, and CAZ susceptibility was determined in a clinically relevant range of AVI concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect (Emax) model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5g q8h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes. Results The AVI-dependent reduction in CAZ MIC was well characterized in both strains (R2 > 0.98). In HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi < 100%). These observations are consistent with the clinical courses of the patients. Conclusion The discordant patient outcomes could be explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing, and the clinical utility of this approach should be further investigated. Disclosures All Authors: No reported disclosures