DOSING OF COMBINATION ANTIBIOTICS

To advocate for Food and Drug Administration-approved standardized labeling of combination antibiotics with dosing instructions that include each component in a clear and unambiguous manner; further,

To support the continuous evaluation and streamlining of combination antibiotic formulation ratios; further,

To advocate for information system vendors to incorporate discrete data fields and for drug reference resources to reflect each antibiotic component; further,

To encourage healthcare organizations to adopt strategies that ensure appropriate dosing of combination antibiotics; further,

To educate stakeholders and the public regarding the safe dosing and administration of combination antibiotics for pediatrics and adults.

Rationale

Combination antibiotics pose a unique challenge for pharmacists because each product contains two active components, each with its own strength, and variations in how doses are calculated can create confusion in dosing, dispensing, and administration. In adults, dosing and dispensing of these drugs is done with standard doses equivalent to the sum of the two antibiotic components and are provided from manufacturers in standardized formulations, often in ready to administer bags. Conversely, pediatric patients are often dosed based on the weight-based dosing of one component of the combination drug (e.g the beta-lactam or the trimethoprim component) with a few exceptions based upon the goal of treatment. While most intravenous concentrations of these medications are standardized, there are 11 dosage formulations of amoxicillin-clavulanate on the US market, including five different amoxicillin to clavulanate ratios (i.e., 2:1, 4:1,7:1, 14:1, 16:1). These multiple ratio formulations further increase the risk of prescribing, dispensing, and administration errors which can impact the effectiveness and/or the toxicity of these antibiotics. While this phenomenon is decreasing, many manufacturers’ labeling and dosing references describe doses in a variety of ways, and multiple presentations exist even within the same reference. This has also led to dosing errors with the intravenous antibacterial drugs due to confusion about the drug strength displayed on the vial and carton labels.

Furthermore, many pediatric patients are not treated at standalone children’s hospitals where there is infrastructure and support, including pediatric specific order sets, pump libraries, drug information and pharmacists trained to care for pediatric patients exist.  A 2024 study in Journal of Pediatric Pharmacology and Therapeutics  (JPPT) surveyed pharmacists treating pediatric patients in a variety of settings cited that barriers to dosing and administration of combination drugs including: extended infusions, infusion pump interoperability challenges, CPOE (computerized physician order entry) auto-adjustments, dose rounding, drug shortages, premade adult products, non-formulary drugs, and different ordering processes for pediatric and adult patients.  This study also found that order sets, guidelines, and intranet pages were the most common sources of internal antibiotic dosing recommendations, where dosing may be different than what is found in external antibiotic dosing references including Lexicomp, Micromedex, Sanford Guide and more. A 2023 study from JPPT reviewed amoxicillin-clavulanate use at standalone and children’s hospitals within acute care hospitals and found that significant formulation selection variability exists across the United States with these institutions carrying on average five amoxicillin-clavulanate products.

In the outpatient setting, medication errors during order entry and dispensing include: information and knowledge gaps about medication indications or doses for pediatric patients, communication gaps between health care providers and caregivers, and product preparation vulnerabilities.  An additional study that looked at pediatric medication errors, found that antibiotics emerged as the most frequently implicated drug class.