Extended-Interval Dosing of Aminoglycoside Antibiotics in Critically Ill Patients

Abstract

Although aminoglycosides remain an essential part of therapy of severe gram-negative infections in critically ill patients, the use of extended-interval aminoglycoside dosing (EIAD) in this population is highly controversial. The rationale for EIAD is based on major pharmacodynamic characteristics of the aminoglycosides, which include concentration-dependent bactericidal effects, postantibiotic effect, and adaptive resistance. Alterations in the pharmacokinetics of aminoglycosides in the critically ill have been well documented, including changes in both drug distribution and elimination. These pharmacokinetic alterations may prevent critically ill patients from realizing the potential benefits of EIAD by reducing serum concentrations achieved by recommended EIAD regimens and may perhaps place patients at risk of therapeutic failure. Although numerous studies of EIAD have been conducted, there is a lack of data specifically concerning the efficacy and safety of EIAD in the critically ill. The most appropriate methods for monitoring EIAD in this population are also not clearly established. There are thus many questions regarding the suitability of EIAD in the critically ill. This article briefly reviews the rationale for EIAD and data related to the pharmacokinetics, efficacy, safety, and clinical monitoring of EIAD in critically ill patients. Considerations and recommendations for use of EIAD in the critically ill are provided.A MINOGLYCOSIDE ANTIBIOTICS have had a central role in the treatment of gram-negative bacterial infections for more than 50 years. Aminoglycosides continue to be commonly used in the treatment of infections in critically ill patients due to their rapid bactericidal activity, potential for synergy with β-lactam agents in the treatment of infections due to common pathogens such as Pseudomonas aeruginosa, and relatively low acquisition costs. Although the efficacy of the aminoglycosides is well established, the use of these agents has been limited by the potential for nephrotoxicity and ototoxicity, the need for frequent dosing, and the need for monitoring of serum drug concentrations. Various dosing methods have been developed in an attempt to prevent or minimize these toxicities while preserving their antimicrobial activity and simplifying their administration. Extended-interval aminoglycoside dosing (EIAD), also known as single daily dosing or once-daily dosing, is characterized by administration of the total daily dosage of aminoglycosides as a single large dose rather than in traditional multiple daily dosing (MDD) regimens. The concept of EIAD was first introduced in the mid-1980s and has steadily grown in clinical use until it is now quite common; a recent study found that 75% of surveyed hospitals now use EIAD. 1 Although EIAD has gained rapidly in use, data specifically related to the success of this practice in critically ill populations are still lacking. The purpose of this article is to briefly review the literature pertaining to EIAD in critically ill patients. JUSTIFICATION FOR...

Correlation of Pharmacokinetic/Pharmacodynamic–Derived Predictions of Antibiotic Efficacy with Clinical Outcomes in Severely Ill Patients with Pseudomonas aeruginosa Pneumonia

“…Critically ill patients are known to exhibit a high degree of variability in antibiotic pharmacokinetics due to alterations in many pathophysiologic factors . Studies in severely ill patients often document variability of 30–50% or more within PK parameters such as CL T , Vd, C max , and AUC 0–24 . Without the ability to actually measure plasma concentrations of most antibiotics during therapy, this variability makes it difficult to estimate pharmacokinetics of specific drugs within individual patients with any degree of certainty.…”

“…Additional calculated parameters included area under the concentration‐time curve from time 0 to 24 hours (AUC 0–24 ) and the maximum serum concentration (C max ). Specific PK parameters for individual patients receiving various antibiotics were calculated according to the equations shown in Appendix S1 …”

“…For all patients, 5000‐patient Monte Carlo simulations were also conducted using PK data sets that included measures of variability as directly reported in, or calculated from, the original published studies . Pharmacokinetic parameters were therefore also derived during Monte Carlo simulation rather than by direct estimates as previously described.…”

Antimicrobial Resistance: Factors and Outcomes

“…Newer dosing strategies also have been employed for concentration-dependent antimicrobials to optimize their pharmacodynamic properties and maximize efficacy. Such strategies include the use of extendedinterval dosing regimens for aminoglycosides and the use of high doses of fluoroquinolones to achieve high concentrations relative to the pathogen MICs [56][57][58].…”

Recommendations of Gentamicin Dose Based on Different Pharmacokinetic/Pharmacodynamic Targets for Intensive Care Adult Patients: A Redefining Approach

“…Changes in the Vd (range from 0.27–0.83 L/kg) parameter have been reported in critically ill patients admitted in intensive care units. 38 To date, PK/PD targets for gentamicin mostly depend on the plasma concentration and severity of the infection. 5 In vitro studies data suggest that C max /MIC ~8–10 is sufficient for all pathogens, even Enterobacteriaceae .…”