Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States

Koomanachai, Pornpan; Bulik, Catharine C.; Kuti, Joseph L.; Nicolau, David P.

doi:10.1016/j.clinthera.2010.04.003

Cited by 52 publications

(49 citation statements)

References 30 publications

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“…Our data suggest that, for such an MIC, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL CR of 30 to 100 ml/min and that a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL CR Ͼ100 ml/ min. Such recommendations are consistent with several large pharmacodynamic simulation studies conducted in the Asia-Pacific region (50,51) as well as in other parts of the world (3,52). This study provides additional PK/PD data to support an alternative doripenem dosing approach in critically ill patients, particularly when pathogens with high MICs are involved.…”

Section: Discussionsupporting

confidence: 67%

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abdul‐Aziz

Rahman

Mat-Nor

et al. 2016

Antimicrob Agents Chemother

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g Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL CR ), such that a 30-ml/min increase in the estimated CL CR would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL CR of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL CR of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

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Section: Discussionsupporting

confidence: 67%

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abdul‐Aziz

Rahman

Mat-Nor

et al. 2016

Antimicrob Agents Chemother

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“…A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of cefepime to achieve bactericidal activity against the organism. The model and its pharmacokinetic parameters are described in detail elsewhere (22). Pharmacodynamic exposures for the simulated cefepime were assessed at 60% fT Ͼ MIC.…”

Section: Pharmacodynamic Analysismentioning

confidence: 99%

Extended-Infusion Cefepime Reduces Mortality in Patients with Pseudomonas aeruginosa Infections

Bauer

West

O’Brien

et al. 2013

Antimicrob Agents Chemother

135

106

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In an era of escalating resistance and a lack of new antimicrobial discovery, stewardship programs must utilize knowledge of pharmacodynamics to achieve maximal exposure in the treatment of Pseudomonas aeruginosa infections. We evaluated the clinical and economic outcomes associated with extended-infusion cefepime in the treatment of P. aeruginosa infections. This single-center study compared inpatients who received cefepime for bacteremia and/or pneumonia admitted from 1 January 2008 through 30 June 2010 (a 30-min infusion of 2 g every 8 h) to those admitted from 1 July 2010 through 31 May 2011 (a 4-h infusion of 2 g every 8 h). The overall mortality was significantly lower in the group that received extended-infusion treatment (20% versus 3%; P ‫؍‬ 0.03). The mean length of stay was 3.5 days less for patients who received extended infusion (P ‫؍‬ 0.36), and for patients admitted to the intensive care unit the mean length of stay was significantly less in the extended-infusion group (18.5 days versus 8 days; P ‫؍‬ 0.04). Hospital costs were $23,183 less per patient, favoring the extended-infusion treatment group (P ‫؍‬ 0.13). We conclude that extended-infusion treatment with cefepime provides increased clinical and economic benefits in the treatment of invasive P. aeruginosa infections.A ntimicrobial resistance has emerged as a global health crisis, gaining the attention of the World Health Organization and the U.S. Department of Health and Human Services (1). As antimicrobial resistance continues to emerge and new antimicrobial development stagnates, antimicrobial stewardship programs are being implemented worldwide. The goal of antimicrobial stewardship is to optimize antimicrobial therapy with maximal impact on the subsequent development of resistance (2-4). The Healthcare Infection Control Practices Advisory Committee, in partnership with the U.S. Department of Health and Human Services, lists antimicrobial stewardship as a top 5 message for health care workers (5).Pseudomonas aeruginosa infections constitute a tremendous burden on hospitals in the United States in terms of morbidity, mortality, and health care costs. P. aeruginosa infections are associated with a mortality rate of 18 to 60%, and the cost of treatment is substantial, ranging from $20,000 to $80,000 per infection (6-11). Antimicrobial therapy for P. aeruginosa is limited because of the organism's multiple resistance mechanisms, often resulting in higher .Cefepime is a "fourth-generation" cephalosporin with activity against Gram-positive and Gram-negative organisms, including P. aeruginosa. Because of its broad activity, cefepime is used as empirical antibiotic therapy for serious infections, including pneumonia and bacteremia. Like other ␤-lactam antibiotics, cefepime displays time-dependent bactericidal activity, and its efficacy is optimized when free drug concentrations exceed the MIC (fT Ͼ MIC) for at least 60 to 70% of the dosing interval (15-18). Recent evidence suggests that conventional regimens may not attain this fT Ͼ MIC (19-21). ...

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“…The CLSI decision to maintain current cefepime breakpoints was based on reports showing that current standard (or usual) doses of intravenous cefepime (Ն3 to 4 g/day) have a high likelihood of achieving optimal exposure against Enterobacteriaceae categorized as susceptible to this drug (15,16). Additionally, it has been reported recently that KPC-2 expression in Enterobacteriaceae is not enough to confer cefepime resistance (17).…”

mentioning

confidence: 99%

Klebsiella pneumoniae Carbapenemase-Producing Enterobacteriaceae Testing Susceptible to Cefepime by Reference Methods

et al. 2013

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Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States

Cited by 52 publications

References 30 publications

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Extended-Infusion Cefepime Reduces Mortality in Patients with Pseudomonas aeruginosa Infections

Klebsiella pneumoniae Carbapenemase-Producing Enterobacteriaceae Testing Susceptible to Cefepime by Reference Methods

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