Pharmacokinetic-Pharmacodynamic-Model-Guided Doripenem Dosing in Critically Ill Patients

Abstract

The growing number of infections caused by multidrug-resistant pathogens has prompted a more rational use of available antibiotics given the paucity of new, effective agents. Monte Carlo simulations were utilized to determine the appropriateness of several doripenem dosing regimens based on the probability of attaining the critical drug exposure metric of time that drug concentrations remain above the drug MIC (T>MIC) for 35% (and lower thresholds) of the dosing interval in >80 to 90% of the population (T>MIC 35% target). This exposure level generally correlates with in vivo efficacy for carbapenems. In patients with creatinine clearance of >50 ml/min, a 500-mg dose of doripenem infused over 1 h every 8 h is expected to be effective against bacilli with doripenem MICs of <1 g/ml based on a T>MIC 35% target and MICs of <2 g/ml based on lower targets. A longer, 4-hour infusion time improved target attainment in most cases, such that the T>MIC was adequate for pathogens with doripenem MICs as high as 4 g/ml. Efficacy is expected for infections caused by pathogens with doripenem MICs of <2 g/ml in patients with moderate renal impairment (creatinine clearance, 30 to 50 ml/min) who receive doripenem at 250 mg infused over 1 h every 8 h and in patients with severe impairment (creatinine clearance between 10 and 29 ml/min) who receive doripenem at 250 mg, infused over 1 h or 4 h, every 12 h. Results of pharmacokinetics/pharmacodynamics (PK/PD) modeling can guide dose optimization, thereby potentially increasing the clinical efficacy of doripenem against serious Gram-negative bacterial infections.

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

“…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.…”

“…As per local antibiotic guidelines, patients receiving doripenem in a Malaysian intensive care unit (ICU) typically receive a standard dose of 500 mg every 8 h as a 1-h intravenous (IV) infusion. However, the appropriateness of this dosing regimen is disputable, as it is based on PK/PD data derived from earlier studies which mostly recruited heterogeneous cohorts of healthy volunteers and noncritically ill Caucasian patients (3)(4)(5)(6). Importantly, results of subsequent PK/PD studies suggest that current recommendations may be grossly flawed in critically ill patients and that optimal dosing requirements may significantly differ from that initially proposed (7)(8)(9).…”

Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae

“…Our laboratory did not report the actual MICs for the organism when they were Ͼ4 g/ml. The lack of knowledge of the precise MIC may limit whether or not ertapenem added any benefit to meropenem or doripenem, since it is possible to achieve useful concentrations above minimally elevated carbapenem MICs with aggressive dosing (17,18). Though some patients had concurrent and deep-seated infections and we believe the concurrent infections were adequately treated, it is difficult to evaluate which resulted in clinical failure.…”

Pharmacodynamic Variability beyond That Explained by MICs

“…It was also demonstrated that prolonged infusion regimens achieved greater effect following administration of 1 or 2 g against isolates with MICs Յ8 and 16 mg/liter, respectively, achieving a Ն2-log-unit reduction in bacterial density (19,20). The ability of similar doripenem dosage regimens to attain optimal drug exposure against a range of strains with differing MICs has also been studied in various MCS (6,8,9,11). However, in all of these studies, it must first be recognized that the human protein binding value of ϳ8.5% was employed for data analyses, which is markedly different from the murine protein binding value of ϳ25.2% applied in the present study (15).…”

“…These models have been applied to various MCS in attempts to optimize doripenem exposure across a range of MICs (6,[8][9][10][11]. The existence of extensive PD variability among bacterial species has been previously demonstrated (particularly for ␤-lactam agents), with researchers reporting differences in the magnitude of PK/PD targets associated with activity for different organisms, as well as differences between and within drug classes (12).…”