An integrated approach to evaluate different tetracycline derivatives for formulary decisions.

PURPOSE: Stenotrophomonas maltophilia has emerged as a critical opportunistic pathogen associated with significant morbidity and mortality. Tetracycline derivatives have been recognized as alternative treatment options, but they have varied pharmacokinetic properties. An integrated approach to different tetracycline derivatives for formulary decisions is reported. METHODS: The minimum inhibitory concentration (MIC) data from clonally diverse bloodstream S. maltophilia isolates were examined, along with the pharmacokinetic profiles of 4 tetracycline derivatives, to predict achievable pharmacodynamic exposures with standard intravenous dosing regimens. Antimicrobial therapy was assessed using the ratio of daily drug acquisition cost relative to the ratio of the free-drug area under the time-concentration curve (fAUC) to minimum inhibitory concentration (MIC) for 90% of isolates (fAUC/MIC90). RESULTS: In our analysis, minocycline had the greatest fAUC/MIC90. Doxycycline was the most financially preferred agent, as calculated using 2020 average wholesale price for base-case estimates of drug acquisition cost. CONCLUSION: An integrated evaluation for antimicrobial formulary decision-making addressed local susceptibility data, pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This comprehensive method is more objective than the conventional approach and warrants validation.

MIC profiling of ceftazidime/avibactam against two carbapenemase-producing Klebsiella pneumoniae isolates.

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 < 100%). These observations are consistent with the clinical course of the patients. CONCLUSIONS: The discordant patient outcomes could be potentially explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing in predicting positive clinical outcome of CAZ/AVI therapy, and the clinical utility of this approach should be further investigated.