Intravenous Antibiotic and Antifungal Agent Pharmacokinetic-Pharmacodynamic Dosing in Adults with Severe Burn Injury

• Published in: Clinical therapeutics 2016-09, Vol.38 (9), p.2016-2031
• Main Authors: Cota, Jason M., PharmD, FakhriRavari, Alireza, PharmD, Rowan, Matthew P., PhD, Chung, Kevin K., MD, Murray, Clinton K., MD, Akers, Kevin S., MD
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Antibiotic Prophylaxis - methods; Antibiotics; Antifungal agents; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - therapeutic use; Antiinfectives and antibacterials; Antimicrobial activity; Bacterial infections; Bacteriology; Biopsy; Burns; Burns - complications; Burns - metabolism; Casualties; Chemical compounds; Computer simulation; Creatinine; Dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Fungal infections; Fungicides; Humans; Injuries; Internal Medicine; Medical Education; Microbial Sensitivity Tests; Monitoring; Monte Carlo Method; Morbidity; Mortality; Multidrug resistant organisms; Neutropenia; Opportunistic Infections - complications; Opportunistic Infections - metabolism; Opportunistic Infections - prevention & control; Optimization; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pneumonia; Population; Probability; Skin; Technology assessment; Therapeutic drug monitoring
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2016.08.001

Abstract Purpose Despite advances in the care of patients with severe burn injury, infection-related morbidity and mortality remain high and can potentially be reduced with antimicrobial dosing optimized for the infecting pathogen. However, anti-infective dose selection is difficult because of the highly abnormal physiologic features of burn patients, which can greatly affect the pharmacokinetic (PK) disposition of these agents. We review published PK data from burn patients and offer evidence-based dosing recommendations for antimicrobial agents in burn-injured patients. Methods Because most infections occur at least 48 hours after initial burn injury and anti-infective therapy often lasts ≥10 days, we reviewed published data informing PK-pharmacodynamic (PD) dosing of anti-infectives administered during the second, hypermetabolic stage of burn injury, in those with >20% total body surface area burns, and in those with normal or augmented renal clearance (estimated creatinine clearance ≥130 mL/min). Analyses were performed using 10,000-patient Monte Carlo simulations, which uses PK variability observed in burn patients and MIC data to determine the probability of reaching predefined PK-PD targets. The probability of target attainment, defined as the likelihood that an anti-infective dosing regimen would achieve a specific PK-PD target at the single highest susceptible MIC, and the cumulative fraction of response, defined as the population probability of target attainment given a specific dose and a distribution of MICs, were calculated for each recommended anti-infective dosing regimen. Findings Evidence-based doses were derived for burn-injured patients for 15 antibiotics and 2 antifungal agents. Published data were unavailable or insufficient for several agents important to the care of burn patients, including newer antifungal and antipseudomonal agents. Furthermore, available data suggest that antimicrobial PK properties in burned patients is highly variable. We recommend that, where possible, therapeutic drug monitoring be performed to optimize PK-PD parameter achievement in individual patients. Implications Given the high variability in PK disposition observed in burn patients, doses recommended in the package insert may not achieve PK-PD parameters associated with optimal infectious outcomes. Our study is limited by the necessity for fixed assumptions in depicting this highly variable patient population. New rapid-turnaround analytical technology is