Matthew P. Rowan

Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration

ABSTRACT While colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonal Acinetobacter baumannii and receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of ≥60 at an MIC of ≥1 μg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 μg/ml, with free colistin levels ranging from 0.4 to 2.2 μg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy.

Elevations in inflammatory cytokines are associated with poor outcomes in mechanically ventilated burn patients.

BACKGROUND The treatment of burn patients who undergo mechanical ventilation is complicated by many factors; patient outcomes and mortality could potentially be improved with predictive biomarkers. Severe burn provokes a systemic inflammatory response characterized by the release of a host of cytokines. Recent studies evaluated the prognostic value of temporal changes in cytokine levels in several patient populations, but few have compared differences in the cytokine profiles of survivors and nonsurvivors following severe burn. We previously compared high-frequency percussive ventilation and low-tidal-volume ventilation and found no difference in mortality or cytokine levels between the two treatments. Since it is unknown whether cytokine levels are predictive of mortality in these patients, we performed a post hoc analysis comparing cytokine levels in survivors and nonsurvivors. METHODS We evaluated plasma levels of several cytokines (interleukin 1&bgr; [IL-1&bgr;], IL-6, IL-8, granulocyte–macrophage colony-stimulating factor, and tumor necrosis factor &agr;) for their prognostic biomarker potential related to mortality at 0, 3, and 7 days in survivors and nonsurvivors of burns. RESULTS While the majority of values for IL-1&bgr;, granulocyte–macrophage colony-stimulating factor, and tumor necrosis factor &agr; fell below the limit of quantification, univariate analysis demonstrated higher plasma levels of IL-6 and IL-8 in nonsurvivors on Day 7. Logistic regression revealed that elevated plasma IL-8 was independently associated with an increased likelihood of the composite end point of death or ventilator-associated pneumonia with odds ratios of 7.9, 26, and 7.3 on Days 0, 3, and 7, respectively. CONCLUSION Early increases in plasma IL-8 are associated with a multifold increase in death or ventilator-associated pneumonia in mechanically ventilated burn patients. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level IV; therapeutic study, level IV.

Perioperative Temperature Management During Burn Care.

Major physiologic alterations following a severe thermal injury disrupt thermal homeostasis and predispose burn patients to hypothermia. An important recommendation in many clinical practice guidelines is to increase the ambient temperature during the care of severely burned patients in the operating room and intensive care unit to mitigate the loss of thermoregulation, prevent hypothermia, and minimize the impact of hypermetabolism. However, the scientific support for this recommendation remains unclear. This review summarizes the current knowledge regarding the pathophysiology and treatment of thermal injury–induced hypermetabolism and hypothermia, with special emphasis on alterations in ambient temperature. Current evidence on the value of increasing ambient temperature during the care of severely burned patients in the operating room or intensive care unit is limited, with minimal human studies investigating physiologic benefit or potential adverse effects.

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

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 needed to expand the menu of antimicrobial agents for which therapeutic drug monitoring is available to guide dose modification within a clinically actionable time frame.

Vitamin C in Burn Resuscitation.

The inflammatory state after burn injury is characterized by an increase in capillary permeability that results in protein and fluid leakage into the interstitial space, increasing resuscitative requirements. Although the mechanisms underlying increased capillary permeability are complex, damage from reactive oxygen species plays a major role and has been successfully attenuated with antioxidant therapy in several disease processes. However, the utility of antioxidants in burn treatment remains unclear. Vitamin C is a promising antioxidant candidate that has been examined in burn resuscitation studies and shows efficacy in reducing the fluid requirements in the acute phase after burn injury.

A Survey of Temperature Management Practices Among Burn Centers in North America

Maintaining body temperature is a unique challenge with burn care. We sought to describe core temperature goals in the operating room (OR) and the methods used to achieve and maintain these goals, along with current methods of warming in the intensive care unit (ICU), the perception of effect of increased ambient temperature on work performance, and concerns with contamination of sterile fields due to increased ambient temperature. A 24 question survey was disseminated to burn centers in the United States and Canada. The questions included demographics, target core and ambient temperatures, warming methods, and beliefs on ambient temperatures effects. Of 121 burn centers, 52 questionnaires were completed (43% response rate). The majority of centers targeted a core temperature between 36 and 38°C in the OR and an ambient temperature between 75 and 95°F in the ICU. The most common methods for maintaining core temperature included warmed ambient temperature, forced air devices, and intravenous fluids. Although the majority of centers reported the belief that increased ambient temperature benefits patients, many also reported that there is a negative impact on staff performance and risk of staff perspiration contaminating sterile fields. Burn centers reported a range of target core temperatures and methods to reach target temperatures. More than a third of respondents perceived a negative impact work performance while more than half acknowledged the potential for contamination of sterile fields. A prospective observational study is needed to determine actual temperature regulation practice patterns and its impact on outcomes.

Comparison of military and civilian burn patients admitted to a single center during 12 years of war

OBJECTIVE The current conflicts in Iraq and Afghanistan resulted in an increased incidence of burn injury in the military population. We sought to compare the characteristics and outcomes of this population to a civilian cohort cared for at the same burn center over the same time-period. METHODS A retrospective review was performed to examine differences in the demographics, etiology, mortality, and functional status over a 12-year period. Descriptive analyses were performed. Logistic regression was used to calculate the likelihood of mortality. RESULTS A total of 3814 patients were included in this analysis; 1069 were military casualties. When compared to civilians, military patients were younger, had a higher incidence of flame-induced burn injury, mean total body surface area burned (% TBSA), rate of inhalation injury, and lower mortality. Civilian patients presented with a higher Baux score. Although most military patients had a full functional recovery, they had a greater incidence of severe disability. In a univariate model, likelihood of mortality was higher in civilians. No difference in mortality between the two cohorts was found after adjusting for age, inhalation injury, gender, % TBSA and percent full-thickness burn. CONCLUSIONS Military patients exhibited improved survival and functional recovery over their civilian counterparts. However, mortality did not differ between civilian and military patients after controlling for known covariates. Further studies are needed to improve functional outcomes in civilian patients, who may not have the inherent advantages of younger age and healthier physical status found in military patients.

Thermal stability of mafenide and amphotericin B topical solution

OBJECTIVE Fungal infections remain a major cause of mortality in the burned population. Mafenide acetate/amphotericin B solution (SMAT) has been used topically for prophylaxis and treatment of these infections. Current manufacturer guidelines only guarantee the stability of mafenide solution and amphotericin B at room temperature. Additionally, the recommended maximum storage time for mafenide solution is 48h, leading to significant financial and material loss when unused solutions are discarded. The purpose of this study was to characterize the chemical stability, structure and bioactivity of SMAT stored at 2°C, 25°C, and 40°C for up to 90 days. METHODS Stability analyses of SMAT solutions containing 2.5% or 5% mafenide plus 2μg/mL amphotericin B were performed using high performance liquid chromatography. Chemical structure was assessed using Fourier-transform infrared spectroscopy. Bioactivity against clinically relevant species was examined. RESULTS The chemical structure and stability of mafenide did not change over 90days at all temperatures. Amphotericin B was undetectable in SMAT solutions after two days at high temperatures, which was slowed by refrigerated storage. Against Staphylococcus aureus, SMAT activity began to decrease generally between two and seven days. Against Pseudomonas aeruginosa, activity slowly tapered and was gone by day 90. SMAT retained high bioactivity against Candida albicans for over 40days and was not affected by temperature. CONCLUSIONS The amphotericin B component of SMAT is degraded within 2days under warm storage. While mafenide was stable over 90 days, the bioactivity of SMAT solution may be lost within 2days as well.

641: ANTIBIOTIC WOUND PENETRANCE DURING NEGATIVE PRESSURE WOUND THERAPY

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