Summary Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in sub-optimal outcomes. In this paper, we review the patient- and pathogen-related challenges that contribute to inadequate antibiotic dosing and discuss how a process for individualised antibiotic therapy, that increases the accuracy of dosing, can be implemented to further optimise care for the critically ill patient. The process for optimised antibiotic dosing firstly requires determination of the physiological derangements in the patient that can alter antibiotic concentrations including altered fluid status, microvascular failure, serum albumin concentrations as well as altered renal and hepatic function. Secondly, knowledge of the susceptibility of the infecting pathogen should be determined through liaison with the microbiology laboratory. The patient and pathogen challenges can then be solved by combining susceptibility data with measured antibiotic concentration data (where possible) into a clinical dosing software. Such software uses pharmacokinetic-pharmacodynamic (PK/PD) models from critically ill patients to accurately predict the dosing requirements for the individual patient with the aim of optimising antibiotic exposure and maximising effectiveness.

Studies of ␤-lactam pharmacodynamics in infected patients are sparse. In this study, classification and regression tree (CART) and logistic regression analyses were used to identify which pharmacodynamic indices and magnitudes were significant predictors of meropenem efficacy for 101 adult patients with lower respiratory tract infections (LRTI). Using demographic data, a validated population pharmacokinetic model was employed to predict pharmacokinetic parameters and free serum concentrations in the studied patients.

The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.

Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (%T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested.

Continuous infusion of piperacillin-tazobactam provided clinical and microbiologic outcomes equivalent to those for intermittent infusion. Compared with intermittent infusion, continuous infusion significantly shortened the time to temperature normalization, while also offering a significant reduction in level 2 expenditures.