Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time-kill experiments: agreement with in silico predictions.

OBJECTIVES: Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time-kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments. METHODS: Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time-kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations. RESULTS: The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions. CONCLUSIONS: Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time-kill data to predict the activity of antibiotic combinations at dynamic drug concentrations.

Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units.

BACKGROUND: Only about 50% of intensive care unit (ICU) patients reach a free trough concentration above MIC (100% fT > MIC) of beta-lactam antibiotics. Although dose adjustments based on therapeutic drug monitoring (TDM) could be beneficial, TDM is not widely available. We investigated serum creatinine-based estimated GFR (eGFR) as a rapid screening tool to identify ICU patients at risk of insufficient exposure. METHOD: Ninety-three adult patients admitted to four ICUs in southeast Sweden treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Beta-lactam trough concentrations were measured. The concentration target was set to 100% fT > MICECOFF (2, 4, and 16 mg/L based on calculated free levels for meropenem, cefotaxime, and piperacillin, respectively). eGFR was primarily determined via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and compared to three other eGFR equations. Data was analysed using logistic regression and receiver operative characteristic (ROC) curves. RESULTS: With intermittent standard dosing, insufficient exposure was common in patients with a relative eGFR ≥48mL/min/1.73m2 [85%, (45/53)], particularly when treated with cefotaxime [96%, (24/25)]. This eGFR cut-off had a sensitivity of 92% and specificity of 82% (AUC 0.871, p < 0.001) in identifying insufficient exposure. In contrast, patients with eGFR <48mL/min/1.73m2 had high target attainment [90%, (36/40)] with a wide variability in drug exposure. There was no difference between the four eGFR equations (AUC 0.866-0.872, cut-offs 44-51 ml/min/1.73m2). CONCLUSION: Serum creatinine-based eGFR is a simple and widely available surrogate marker with potential for early identification of ICU patients at risk of insufficient exposure to piperacillin, meropenem, and cefotaxime.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model.

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MICCIP 0.023-1 mg/L and MICCST 0.5-0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC50) in combination was 160% of the EC50 in monodrug experiments, while for colistin, the change in EC50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.