Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an in vitro hollow fiber infection model against multidrug-resistant Escherichia coli.

IMPORTANCE: Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical Escherichia coli isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.

Pharmacokinetic/pharmacodynamic evaluation of tigecycline dosing in a hollow fiber infection model against clinical bla-KPC producing Klebsiella Pneumoniae isolates.

The FDA announced a boxed warning for tigecycline due to progression of infections caused by Gram-negative bacteria and increased risk of mortality during treatment. Plasma exposure of tigecycline might not prevent bacteraemia in these cases from the focuses. Hence, we evaluated intensified dosing regimens and breakpoints that might suppress bloodstream infections, caused by progression of infection by e.g., Gram-negatives. A pharmacometric model was built from tigecycline concentrations (100-600 mg daily doses) against clinical Klebsiella pneumoniae isolates (MIC 0.125-0.5 mg/L). Regrowth occurred at clinically used doses and stasis was only achieved with 100 mg q8h for the strain with the lowest studied MIC of 0.125 mg/L. Stasis at 24 h was related to fAUC/MIC of 38.5. Our study indicates that even intensified dosing regimens might prevent bloodstream infections only for MIC values ≤0.125 mg/L for tigecycline. This indicates an overly optimistic breakpoint of 1 mg/L for Enterobacterales, which are deemed to respond to the tigecycline high dose regimen (EUCAST Guidance Document on Tigecycline Dosing 2022).

Operational characteristics of full random effects modelling ('frem') compared to stepwise covariate modelling ('scm').

An adequate covariate selection is a key step in population pharmacokinetic modelling. In this study, the automated stepwise covariate modelling technique ('scm') was compared to full random effects modelling ('frem'). We evaluated the power to identify a 'true' covariate (covariate with highest correlation to the pharmacokinetic parameter), precision, and accuracy of the parameter-covariate estimates. Furthermore, the predictive performance of the final models was assessed. The scenarios varied in covariate effect sizes, number of individuals (n = 20-500) and covariate correlations (0-90% cov-corr). The PsN 'frem' routine provides a 90% confidence intervals around the covariate effects. This was used to evaluate its operational characteristics for a statistical backward elimination procedure, defined as 'fremposthoc' and to facilitate the comparison to 'scm'. 'Fremposthoc' had a higher power to detect the true covariate with lower bias in small n studies compared to 'scm', applied with commonly used settings (forward p < 0.05, backward p < 0.01). This finding was vice versa in a statistically similar setting. For 'fremposthoc', power, precision and accuracy of the covariate coefficient increased with higher number of individuals and covariate effect magnitudes. Without a backward elimination step 'frem' models provided unbiased coefficients with highly imprecise coefficients in small n datasets. Yet, precision was superior to final 'scm' model precision obtained using common settings. We conclude that 'fremposthoc' is also a suitable method to guide covariate selection, although intended to serve as a full model approach. However, a deliberated selection of automated methods is essential for the modeller and using those methods in small datasets needs to be taken with caution.

Tigecycline Dosing Strategies in Critically Ill Liver-Impaired Patients.

This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development of a population pharmacokinetic model. The typical tigecycline clearance was strongly reduced (8.6 L/h) as compared to other populations. Different models were developed based on liver and kidney function-related covariates. Monte Carlo simulations were used to guide dose adjustments with the most predictive covariates: Child-Pugh score, total bilirubin, and MELD score. The best performing covariate, guiding a dose reduction to 25 mg q12h, was Child-Pugh score C, whereas patients with Child-Pugh score A/B received the standard dose of 50 mg q12h. Of note, the obtained 24 h steady-state area under the concentration vs. time curve (AUCss) range using this dosing strategy was predicted to be equivalent to high-dose tigecycline exposure (100 mg q12h) in non-ICU patients. In addition, 26/39 study participants died, and therapy failure was most correlated with chronic liver disease and renal failure, but no correlation between drug exposure and survival was observed. However, tigecycline in special patient populations needs further investigations to enhance clinical outcome.

Stability studies with tigecycline in bacterial growth medium and impact of stabilizing agents.

PURPOSE: This study aimed to examine the degradation of tigecycline in Mueller Hinton broth (ca-MHB), as knowledge about bacterial susceptibility is key for therapeutic decisions. METHODS: Antioxidative stabilizers were evaluated on tigecycline stability in a quantitative chromatography assay and tigecycline induced kill against Staphylococcus aureus (ATCC29213) was determined in time kill studies. RESULTS: Ascorbic acid caused rapid degradation of tigecycline and resulted in loss of antibacterial activity. Tigecycline was stabilized in aged broth by 2% pyruvate and bacterial growth, and tigecycline killing was similar to fresh broth without supplementation, but independent of age. CONCLUSION: Our results underline the importance of using freshly prepared ca-MHB or the need for stabilizers for tigecycline susceptibility testing while using aged ca-MHB.