Prolonged infusions of beta-lactam antibiotics
- Rebekah Moehring, MD, MPH
Rebekah Moehring, MD, MPH
- Assistant Professor
- Duke University Medical Center
- Christina Sarubbi, PharmD, BCPS
Christina Sarubbi, PharmD, BCPS
- Infectious Diseases/Antimicrobial Stewardship Pharmacist Co-Chair
- Antimicrobial Stewardship and Evaluation Team (ASET)
- Duke University Medical Center
Beta-lactam antibiotics demonstrate a time-dependent effect on bacterial eradication. Prolonged infusions attain the pharmacodynamic efficacy target defined for beta-lactam antibiotics more effectively than short infusions. Thus, a prolonged infusion administration strategy may improve microbiologic and clinical cure, especially when pathogens demonstrate higher minimum inhibitory concentrations (MIC). Prolonged infusion administration strategies for intravenous beta-lactam antibiotics may include either a continuous infusion (over the entire dosing interval) or an extended infusion (over 3 to 4 hours).
This article will discuss beta-lactam pharmacodynamics, clinical evidence available for prolonged infusion strategies, the benefits and risks, and recommendations for dosing of prolonged infusion beta-lactam antibiotics.
Beta-lactam antibiotics kill sensitive bacteria by inactivating key enzymes involved in cell wall synthesis, termed penicillin-binding proteins. The specific beta-lactam agents have different half-lives, but all demonstrate time-dependent killing . This refers to the phenomenon that the duration that the pathogen is exposed to the beta-lactam drug is the most important determinant of bacterial eradication and clinical response. This is in contrast to other antibiotic classes that exhibit concentration-dependent killing and post-antibiotic effect, such as aminoglycosides.
The duration of exposure is commonly measured as the percentage of the dosing interval that the concentration of free drug remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT >MIC). The maximal bactericidal effect is achieved when the free drug concentration exceeds the pathogen’s MIC by approximately fourfold for 40 to 60 percent of the dosing interval . The optimal targets for %fT >MIC vary depending on the specific drug (table 1). Maximizing the duration of exposure can be accomplished in three possible ways: increasing the dose, shortening the dosing interval, or prolonging the infusion time (figure 1) . Prolonged infusion administration strategies for intravenous beta-lactam antibiotics may include either a continuous infusion (over the entire dosing interval) or an extended infusion (over 3 to 4 hours) as opposed to traditional, intermittent infusion times (over 30 to 60 minutes).
Although high-quality, randomized controlled trials to support prolonged infusion beta-lactam strategies are not available, rationale for this practice is in part based on pharmacodynamic principles and evidence of clinical benefit from observational studies and limited trials without evidence of additional toxicity. In addition, this practice is supported by a theoretical benefit of reduced emergence of drug resistance and, in some cases, measurable economic benefits.
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- PHARMACOLOGIC BACKGROUND
- Possible clinical benefit
- Pharmacologic advantage
- - Less susceptible pathogens
- - Patients with altered pharmacokinetics
- Reduced selection for drug resistance
- Cost benefit
- Ease of administration in the outpatient setting
- Logistical barriers
- CLINICAL EFFICACY
- Adult populations
- - Pooled data
- - Piperacillin-tazobactam
- - Carbapenems
- - Cephalosporins
- - Other beta-lactams
- Pediatric populations
- POTENTIAL INDICATIONS
- Loading doses
- INSTITUTIONAL IMPLEMENTATION
- SUMMARY AND RECOMMENDATIONS