Joseph L. Kuti

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

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 suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

Use of Monte Carlo Simulation to Design an Optimized Pharmacodynamic Dosing Strategy for Meropenem

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), there by 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.

Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections.

ABSTRACT Studies of β-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. Pharmacodynamic indices [percentage of the dosing interval that free drug concentrations remain above the MIC (% fT > MIC), f(maximum concentration of drug in serum) (fCmax)/MIC, fCmin/MIC, and f(area under the concentration-time curve) (fAUC)/MIC] were calculated based on the baseline pathogen with the highest drug MIC for each patient. The median (range) of percent fT > MIC, fCmax/MIC, fCmin/MIC, and fAUC/MIC were 100% (0 to 100%), 728.8 (0.8 to 15,777), 19.9 (0.01 to 278), and 3,605.4 (2.7 to 60,865.9), respectively. CART identified the following breakpoints as significant predictors for microbiological response: >54% fT > MIC, a fCmax/MIC > 383, and a fCmin/MIC > 5; fCmin/MIC > 5 was the only significant predictor of clinical response. Due to 100% fT > MIC achieved in the majority of LRTI patients, fCmin/MIC was the statistically significant parameter associated with meropenem clinical and microbiological response in the adults with LRTI. The findings for LRTI patients can be applied to optimize meropenem dose regimens to achieve clinical success and microbiological eradication in clinical practice.

Impact of Extended-Spectrum β -Lactamase–Producing Escherichia coli and Klebsiella Species on Clinical Outcomes and Hospital Costs: A Matched Cohort Study

OBJECTIVES To evaluate the economic and clinical impact of infection with extended-spectrum beta -lactamase (ESBL)-producing Escherichia coli and Klebsiella species (ESBL-EK). DESIGN A matched-cohort analysis of the cost of illness. SETTING An 810-bed, urban, community hospital in Hartford, Connecticut. PATIENTS Twenty-one case patients infected with ESBL-EK at a site other than the urinary tract were matched with 21 control subjects infected with a non-ESBL-producing organism on the basis of pathogen species, age, anatomic site of infection, hospitalization in the intensive care unit (ICU) during the time of infection, date of hospitalization, and initial antibiotics received. RESULTS Mean infection-related costs per patient were significantly greater for case patients than for control patients (

Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital.

41,353 vs

The current state of multidrug-resistant gram-negative bacilli in North America.

24,902; P=.034). Infection-related length of stay was the main driver of cost, which was prolonged for case patients, compared with control patients (21 vs 11 days; mean difference, 9.7 days [95% confidence interval {CI}, 3.2-14.6 days]; P=.006). The additional cost attributed to the presence of an ESBL-EK infection was

Population Pharmacokinetic Analysis and Dosing Regimen Optimization of Meropenem in Adult Patients

16,450 per patient (95% CI,

Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

965-

Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram: Data Collected in North America in 2002

31,937). Case patients were more likely than control patients to have clinical failure (P=.027), and the rate of treatment success for case patients whose initial treatment involved antibiotics other than carbapenems was lower than that for their matched control patients (39% vs 83%; P=.013). Treatment was successful in patients for whom initial treatment was with a carbapenem, regardless of the ESBL status of the pathogen. CONCLUSION The cost of non-urinary tract infections caused by ESBL-EK was 1.7 times the cost of non-urinary tract infections caused by non-ESBL producers. Prompt recognition and appropriate antimicrobial selection may minimize this ESBL-related impact on hospital costs.

Optimizing antimicrobial pharmacodynamics: dosage strategies for meropenem

Study Objective. To compare continuous versus intermittent administration of piperacillin‐tazobactam with regard to clinical, microbiologic, and economic outcomes.