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

      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 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.

      Key words

      Burn Infection Epidemiology

      Infection Risk in Patients With Burn Injury

      Despite advances in the care of patients with severe burn injury, infection-related morbidity and mortality remain high.
      2015 National Burn Repository
      Report of Data From 2005–2014.
      Damage to the skin barrier disrupts the innate immune system and increases systemic exposure to infectious pathogens. The US Army Burn Center serves both the military population, including burn-injured combat casualties, and the surrounding civilian population as a major burn care referral center in the south Texas region. Data collected from 2003 to 2008 in the US Army Burn Center suggested that pneumonia was the leading infectious complication overall, with a respiratory tract culture source representing 39% of recovered isolates.
      • Keen 3rd, E.F.
      • Robinson B.J.
      • Hospenthal D.R.
      • et al.
      Incidence and bacteriology of burn infections at a military burn center.
      Pneumonia was followed by bacteremia, with blood cultures representing 25% of recovered isolates. The burn wound was the source of 7% of recovered isolates, likely reflecting standard-of-care practices at our burn center. Burn wound infection rates may have decreased because of early excision of the burn eschar coupled with early skin grafting and the use of topical antibiotics to prevent infection. These data are inferential because these conclusions are derived from a retrospective survey of bacterial cultures rather than from patients meeting predefined criteria for infection.
      In contrast to our experience, a multicenter study of 573 patients from civilian burn centers in the United States found that burn wound infection occurred in 54% of patients ≥16 years old, pneumonia in 43%, and sepsis in 11% of these patients.
      • Jeschke M.G.
      • Pinto R.
      • Kraft R.
      • et al.
      Morbidity and survival probability in burn patients in modern burn care.
      Less frequent infectious complications observed in our burn center include infective endocarditis, which was observed in 0.4% of burn unit admissions and 9% of patients with bacteremia that persisted for >24 hours.
      • Regules J.A.
      • Glasser J.S.
      • Wolf S.E.
      • et al.
      Endocarditis in burn patients: clinical and diagnostic considerations.
      Central nervous system infections were exceedingly rare, with an incidence of 0.1%.
      • Calvano T.P.
      • Hospenthal D.R.
      • Renz E.M.
      • et al.
      Central nervous system infections in patients with severe burns.
      According to data from the American Burn Association National Burn Repository, the most prevalent complications of patients hospitalized with burn injury in the past decade include pneumonia, cellulitis, and urinary tract infections.
      2015 National Burn Repository
      Report of Data From 2005–2014.
      Given the high infection risk, rapid diagnosis and prompt empiric anti-infective therapy initiation are important. In selecting empiric anti-infectives, clinicians caring for patients with burns should account for the bacteriology of these infections.

      Bacteriology of Infections in Patients With Burn Injury

      The bacteriologic mechanism of infections in the burned patient consists of human pathogenic bacteria similar to nonburned patients. In the above-mentioned review of isolates from the US Army Burn Center, Acinetobacter baumannii was the most frequent isolate from respiratory cultures among military combat casualties, although this may not currently be the case given the decrease in burn admissions from Iraq and Afghanistan. Staphylococcus aureus was the most frequently isolated pathogen from civilian patients.
      • Keen 3rd, E.F.
      • Robinson B.J.
      • Hospenthal D.R.
      • et al.
      Prevalence of multidrug-resistant organisms recovered at a military burn center.
      Pseudomonas aeruginosa was the second most frequent respiratory isolate in both groups. Among bacteremia isolates, P aeruginosa and Klebsiella pneumoniae were the most commonly isolate organisms. These organisms have been associated with mortality among burn patients, and their treatment is complicated by the potential for antimicrobial resistance among these organisms.
      • Ressner R.A.
      • Murray C.K.
      • Griffith M.E.
      • et al.
      Outcomes of bacteremia in burn patients involved in combat operations overseas.
      Organisms resistant to multiple antimicrobials (termed multidrug-resistant organisms [MDROs]) are a growing concern globally, including in the care of burn patients. Among patients in our burn center between 2003 and 2008, 53% of the initial isolates of A baumannii met MDRO criteria (resistant to at least 3 of the following 4 drug classes: penicillins/cephalosporins, carbapenems, aminoglycosides, fluoroquinolones). In addition, 59% of the MDRO A baumannii were resistant to all 4 classes.
      • Keen 3rd, E.F.
      • Robinson B.J.
      • Hospenthal D.R.
      • et al.
      Prevalence of multidrug-resistant organisms recovered at a military burn center.
      Rates of MDR were much lower for P aeruginosa (15%) and K pneumoniae (17%). Interestingly, the frequency of MDRO isolation increased along with stratified total body surface area (TBSA) burned: 23% for <30% TBSA, 33% for 30% to 60% TBSA, and 33% for TBSA >60%. This finding was driven by increasing MDR A baumannii isolation. Notably, 95% of initial, single-patient isolates of A baumannii were nonsusceptible to imipenem. Despite such concerning statistics, recovery of A baumannii, even from blood cultures, does not appear to adversely affect mortality overall in our burn-injured population.
      • Albrecht M.C.
      • Griffith M.E.
      • Murray C.K.
      • et al.
      Impact of Acinetobacter infection on the mortality of burn patients.
      In contrast, K pneumoniae was independently associated with increased mortality.
      • Ressner R.A.
      • Murray C.K.
      • Griffith M.E.
      • et al.
      Outcomes of bacteremia in burn patients involved in combat operations overseas.
      Invasive fungal infections from mold species merit special mention in the setting of burn patients. Thermal injury disrupts local cell-mediated immunity within dermal tissues, allowing ubiquitous fungal spores to settle and germinate on the burn skin wound. A review of 3751 burn admissions during a 12-year period with 228 deaths and 97 autopsies revealed 43 patients having fungal elements identified on histopathologic analysis.
      • Murray C.K.
      • Loo F.L.
      • Hospenthal D.R.
      • et al.
      Incidence of systemic fungal infection and related mortality following severe burns.
      Of these, death was attributable to fungal infection in 14, and 13 of these yielded an Aspergillus species. Although surface colonization is not associated with mortality, small areas of localized mold growth can be difficult to detect visually but have the potential to develop into a fatal disseminated invasive infection.
      • Horvath E.E.
      • Murray C.K.
      • Vaughan G.M.
      • et al.
      Fungal wound infection (not colonization) is independently associated with mortality in burn patients.
      Biopsy is required to conclusively stage the depth of invasion, with culture being required to identify infecting species.
      • Schofield C.M.
      • Murray C.K.
      • Horvath E.E.
      • et al.
      Correlation of culture with histopathology in fungal burn wound colonization and infection.
      Histopathologic depth of invasion by fungal filaments has been used to guide surgical strategies for local resection or amputation. Recent work is promising for the utility of molecular methods for in situ diagnosis of invasive fungal infection from biopsy specimens.
      • Farmer A.R.
      • Murray C.K.
      • Driscoll I.R.
      • et al.
      Combat-related Pythium aphanidermatum invasive wound infection: case report and discussion of utility of molecular diagnostics.
      Increased use of topical anti-infectives with broad-spectrum activity against common bacterial pathogens along with early excision and grafting led to an overall decrease in systemic infections in the 1970s. However, gram-positive and gram-negative organisms remain the most common bacterial causes of infection in those with burn injury. In addition, topical agents effective against invasive fungal pathogens are unavailable at present. This is problematic because increased mortality has been associated with invasive fungal wound infection in those with burns covering >30% of TBSA. Appropriate anti-infective therapy should therefore be a priority in the management of infectious complications in burn patients. However, anti-infective dose selection is difficult given the highly abnormal physiologic features of burn patients, which can greatly affect the pharmacokinetic (PK) disposition of these agents.

      Burn Injury Effects On Anti-Infective Pk Properties

      Approximately 80% of patients have thermal burns that cover <20% TBSA.
      2015 National Burn Repository
      Report of Data From 2005–2014.
      Patients with TBSA >20% are at risk for developing burn shock that requires resuscitation.
      • Herndon D.N.
      • Tompkins R.G.
      Support of the metabolic response to burn injury.
      This statistic is important because physiologic and metabolic derangements that affect anti-infective PK properties are most likely to occur in this population of burn patients. The hypermetabolic response to burn injury increases as the percentage of TBSA affected increases.
      • Herndon D.N.
      • Tompkins R.G.
      Support of the metabolic response to burn injury.
      As such, this article focuses on PK-pharmacodynamic (PD) anti-infective dosing in patients with burn injury of >20% TBSA.
      Physiologic response to severe burn injury can be divided into 2 stages. The ebb or resuscitative stage occurs within 12 hours of burn injury and may last 48 to 72 hours. It is characterized by increased capillary permeability and decreased interstitial oncotic pressure, leading to hypovolemia and edema in burned and nonburned tissue.
      • Bacomo F.K.
      • Chung K.K.
      A primer on burn resuscitation.
      In addition to the observed decrease in effective circulating blood volume, patients in this initial phase also have decreased myocardial contractility that has been correlated with increased circulation of cytokines, such as tumor necrosis factor-α, and diminished intracellular calcium.
      • Jeschke M.G.
      Postburn hypermetabolism: past, present, and future.
      The decrease in cardiac output during this burn shock phase results in decreased blood flow to organs and tissues. Burn resuscitation measures must be carefully implemented to increase effective circulating blood volume and increase tissue perfusion while minimizing excessive edema formation in burned and nonburned tissue that may lead to complications, such as pulmonary edema or compartment syndrome. During this transient first stage of severe burn injury, clinicians may expect prolonged drug distribution, a decrease in maximum serum concentrations, a delay in onset of action, and slower drug elimination.
      • Blanchet B.
      • Jullien V.
      • Vinsonneau C.
      • Tod M.
      Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients.
      The t1/2 may be markedly prolonged for those drugs that undergo renal excretion. Most infections occur after the first resuscitation stage. At the US Army Burn Center, the median time to positive bacterial cultures was 2 to 8 days (depending on the isolated pathogen) for those with combat-related injuries and 8 to 19 days for local civilians.
      • Keen 3rd, E.F.
      • Robinson B.J.
      • Hospenthal D.R.
      • et al.
      Incidence and bacteriology of burn infections at a military burn center.
      Because most infections will occur 48 hours after initial burn injury and anti-infective therapy often lasts ≥10 days, this review focuses on the PK properties of anti-infectives administered during the second stage of burn injury: the hypermetabolic or flow phase. Depressed metabolic variables in the first resuscitation stage of burn injury gradually increase within 2 to 5 days after injury to a state of hypermetabolism. This stage is characterized by hyperdynamic circulation, increased tissue perfusion, and hypoalbuminemia that results from significant increases in catecholamines, cortisol, glucagon, and prostaglandins.
      • Jeschke M.G.
      Postburn hypermetabolism: past, present, and future.
      This hypermetabolic and hyperinflammatory physiologic response may be sustained 1 to 3 years after initial burn injury.
      • Jeschke M.G.
      • Gauglitz G.G.
      • Kulp G.A.
      • et al.
      Long-term persistance of the pathophysiologic response to severe burn injury.
      The anti-infective PK properties in this hypermetabolic stage are affected in several ways. First, increased cardiac output will lead to faster drug distribution and time to Cmax. Second, enhanced blood flow to the liver and kidneys results in increased elimination or a shorter t1/2 than patients without burn injury. Consequently, larger doses and/or shorter dosing intervals may be required to avoid suboptimal antimicrobial treatment. Changes in volume of distribution are more complex and evolve over time. Early in this stage, increased synthesis of acute-phase proteins, such as α1-glycoprotein occurs, whereas serum albumin decreases because of burn wound loss during the resuscitation phase. As a result, an increased free fraction of albumin-bound acidic hydrophilic anti-infectives may be observed, and a decreased free fraction of basic anti-infectives occurs as a result of α1-glycoprotein binding.
      • Blanchet B.
      • Jullien V.
      • Vinsonneau C.
      • Tod M.
      Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients.
      Data for which protein-binding changes may be clinically relevant in altering anti-infective PK properties are currently limited to ceftriaxone, daptomycin, and ertapenem.
      • Ulldemolins M.
      • Roberts J.A.
      • Rello J.
      • et al.
      The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients.
      • Roberts J.A.
      • Pea F.
      • Lipman J.
      The clinical relevance of plasma protein binding changes.

      Anti-Infective Pk-Pd Targets

      The PK alterations observed in adults with severe burn injury affect dosing in different ways because the effectiveness of each anti-infective may be described in a unique way based on its PK-PD profile. The activity of anti-infectives against microorganisms may be predicted by comparing the agent’s PK disposition to the pathogen’s MIC, which is referred to as the PK-PD relationship. Three PK-PD relationships have been well described for several antimicrobial classes. These relationships include dosing anti-infectives to ensure that (1) free drug concentrations remain above the pathogen’s MIC for a specified percentage of time (fT>MIC) (eg, 70% fT>MIC for cephalosporins against P aeruginosa
      • Crandon J.L.
      • Bulik C.C.
      • Kuti J.L.
      • Nicolau D.P.
      Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa.
      ), (2) the ratio of maximum serum concentration to MIC exceeds a certain threshold (Cmax:MIC>10:1 for aminoglycosides against gram-negative pathogens
      • Moore R.D.
      • Lietman P.S.
      • Smith C.R.
      Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration.
      ), or (3) the ratio of the 24-hour AUC to exceeds a certain threshold (eg, AUC0–24:MIC >400:1 for vancomycin against S aureus
      • Song K.H.
      • Kim H.B.
      • Kim H.S.
      • et al.
      Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia.
      ). In most studies, researchers consider only free serum drug concentrations in determining the optimal PK-PD target because protein-bound drug is unable to inhibit pathogen growth.
      • Ulldemolins M.
      • Roberts J.A.
      • Rello J.
      • et al.
      The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients.
      In addition, PK-PD targets may vary, depending on the target pathogen. It is widely accepted that maximizing antimicrobial PD properties is essential for optimal treatment of bacterial infections and for reducing the risk of antimicrobial resistance.
      • Roberts J.A.
      • Abdul-Aziz M.H.
      • Lipman J.
      • et al.
      Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions.
      Increasing administration frequency and prolonging intravenous infusion times are appropriate strategies for optimizing the dose of those anti-infectives that use fT>MIC as a PK-PD target.
      • Roberts J.A.
      • Abdul-Aziz M.H.
      • Lipman J.
      • et al.
      Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions.
      These strategies are particularly important to overcome the more rapid drug elimination observed in patients in the hypermetabolic stage of severe burn injury. To maximize the PD properties of those anti-infectives that have a PK-PD target of Cmax:MIC, doses should be increased and may also have to be given more frequently to compensate for increased drug clearance. Finally, total daily doses of anti-infectives with AUC0–24:MIC as a PK-PD target should be increased to surmount subtherapeutic serum concentrations that occur in hypermetabolic burn patients compared with those without burn injury. The limiting factor with dose increases is risk of toxic effects.

      Anti-Infective Dosing Recommendations In Patients With Severe Burn Injury

      Methods Used to Develop Dosing Recommendations

      To make dosing recommendations that optimize PK-PD principles, we used the following methods. First, a PubMed search was performed by combining the MeSH terms burns and pharmacokinetics. Additional keywords used were the names of individual antibiotics. Only PK data obtained from patients with burn injury were included. PK data were excluded if patients had <20% TBSA burn, had serum concentrations measured within 48 hours of initial burn injury, or had an estimated creatinine clearance <50 ml/min. Population PK studies were preferably used to estimate mean Vd and t1/2. However, in the absence of published population PK studies, PK data for individual anti-infectives were combined from multiple studies to estimate means (SDs) of Vd and t1/2 (Table I). Finally, PD analyses were performed using 10,000-patient Monte Carlo simulations. This method uses PK variability observed in burn patients and MIC data to determine the probability of reaching predefined PK-PD targets. Anti-infective PK-PD targets were selected based on published clinical data. Although the PK data used in these models were derived from patients with burn injury, clinical PK-PD targets have not yet been confirmed in a burn population. The probability of target attainment (PTA) was defined as the likelihood that an anti-infective dosing regimen would achieve a specific PK-PD target at the single highest susceptible MIC (Table II). Cumulative fraction of response (CFR) was also calculated for each specific anti-infective dosing regimen after PTAs were determined (Table II). CFR was defined as the population PTA given a specific dose and a distribution of MICs. Antibiotic and antifungal steady-state concentration-time profiles were simulated using mean PK values identified from our literature search and were assumed to follow a log-normal distribution. The fraction of unbound or free drug followed a uniform distribution over the specified ranges. For CFR calculations, percentage of MIC distributions were created using European Committee on Antimicrobial Susceptibility Testing (EUCAST) data. Estimated creatinine clearance remains the most important factor in determining the PK disposition for antibiotics that undergo significant renal elimination. All antibiotic dosing regimens in Table II assume patients have normal or augmented renal clearance. Recommendations were capped at maximum doses, and toxicity data for higher doses were presented in the text where available.
      Table IAntibiotic and antifungal pharmacokinetic parameters used in Monte Carlo simulations and general characteristics of burn patients included in studies.
      Anti-infectiveProtein Binding, %Vd, Lt½, hTBSA Burn, %CrCl, mL/minReferences
      AmikacinNA36.6 (7.2)3.8 (1.4)27–38120–170
      • Conil J.M.
      • Georges B.
      • Breden A.
      • et al.
      Increased amikacin dosage requirements in burn patients receiving a once-daily regimen.
      ,
      • Akers K.S.
      • Cota J.M.
      • Frei C.R.
      • et al.
      Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration.
      Aztreonam5619.4 (2.9)2.7 (2.6)22–75100–140
      • Steele A.N.
      • Grimsrud K.N.
      • Sen S.
      • et al.
      Gap analysis of pharmacokinetics and pharmacodynamics in burn patients: a review.
      ,
      • Friedrich L.V.
      • White R.L.
      • Kays M.B.
      • et al.
      Aztreonam pharmacokinetics in burn patients.
      Cefepime2025.9 (3.6)2.4 (1.4)25–4590–135
      • Janicke D.M.
      • Cafarell R.F.
      • Parker S.W.
      • et al.
      Pharmacokinetics of aztreonam in patients with gram-negative infections.
      ,
      • Bonapace C.R.
      • White R.L.
      • Friedrich L.V.
      • et al.
      Pharmacokinetics of cefepime in patients with thermal burn injury.
      ,
      • Sampol E.
      • Jacquet A.
      • Viggiano M.
      • et al.
      Plasma, urine and skin pharmacokinetics of cefepime in burns patients.
      Ceftazidime1020.4 (2.5)4.6 (2.0)25–4095–140
      • Sampol E.
      • Jacquet A.
      • Viggiano M.
      • et al.
      Plasma, urine and skin pharmacokinetics of cefepime in burns patients.
      ,
      • Conil J.M.
      • Georges B.
      • Lavit M.
      • et al.
      Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance.
      ,
      • Dailly E.
      • Pannier M.
      • Jolliet P.
      • Bourin M.
      Population pharmacokinetics of ceftazidime in burn patients.
      ,
      • Conil J.M.
      • Georges B.
      • Lavit M.
      • et al.
      A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation.
      CiprofloxacinNA129 (33)4.5 (3.9)25–5575–160
      • Conil J.M.
      • Georges B.
      • Ravat F.
      • et al.
      Ceftazidime dosage recommendations in burn patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations.
      ,
      • Varela J.E.
      • Cohn S.M.
      • Brown M.
      • et al.
      Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries.
      ,
      • Lesne-Hulin A.
      • Bourget P.
      • Ravat F.
      • et al.
      Clinical pharmacokinetics of ciprofloxacin in patients with major burns.
      ColistinNA81.1 (9.7)6.7 (2.0)30–7070–200
      • Garrelts J.C.
      • Jost G.
      • Kowalsky S.F.
      • et al.
      Ciprofloxacin pharmacokinetics in burn patients.
      ,
      • Bode-Boger S.M.
      • Schopp B.
      • Troger U.
      • et al.
      Intravenous colistin in a patient with serious burns and borderline syndrome: the benefits of therapeutic drug monitoring.
      ,
      • Lee J.
      • Han S.
      • Jeon S.
      • et al.
      Population pharmacokinetic analysis of colistin in burn patients.
      DaptomycinNA12.6 (3.5)7.8 (4.0)18–5079–208
      • Mohr 3rd, J.F.
      • Ostrosky-Zeichner L.
      • Wainright D.J.
      • et al.
      Pharmacokinetic evaluation of single-dose intravenous daptomycin in patients with thermal burn injury.
      Ertapenem8994.2 (7.8)4.3 (1.4)23–6097–193
      • Akers K.S.
      • Rowan M.P.
      • Niece K.L.
      • et al.
      Colistin pharmacokinetics in burn patients during continuous venovenous hemofiltration.
      Fluconazole1259.9 (13.6)22.4 (6.7)40–6080–160
      • Patterson T.F.
      • Thompson 3rd, G.R.
      • Denning D.W.
      • et al.
      Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America.
      ,
      • Han S.
      • Kim J.
      • Yim H.
      • et al.
      Population pharmacokinetic analysis of fluconazole to predict therapeutic outcome in burn patients with Candida infection.
      ,
      • Pittrow L.
      • Penk A.
      Special pharmacokinetics of fluconazole in septic, obese and burn patients.
      Imipenem-cilastatin2051.9 (21.1)1.8 (2.0)25–4570–150
      • Dailly E.
      • Arnould J.F.
      • Fraissinet F.
      • et al.
      Pharmacokinetics of ertapenem in burns patients.
      ,
      • Dailly E.
      • Kergueris M.F.
      • Pannier M.
      • et al.
      Population pharmacokinetics of imipenem in burn patients.
      ,
      • Gomez D.S.
      • Sanches-Giraud C.
      • Silva Jr., C.V.
      • et al.
      Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.
      Levofloxacin3070.0 (21.0)8.2 (2.4)30–6870–160
      • Fournier A.
      • Eggimann P.
      • Pagani J.L.
      • et al.
      Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients.
      LinezolidNA50.8 (16.8)2.1 (1.0)20–80NA
      • Lovering A.M.
      • Le Floch R.
      • Hovsepian L.
      • et al.
      Pharmacokinetic evaluation of linezolid in patients with major thermal injuries.
      Meropenem224.4 (4.1)1.1 (1.4)20–5070–150
      • Gomez D.S.
      • Sanches-Giraud C.
      • Silva Jr., C.V.
      • et al.
      Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.
      ,
      • Kiser T.H.
      • Hoody D.W.
      • Obritsch M.D.
      • et al.
      Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury.
      Micafungin99.819.5 (5.9)11.4 (4.1)35–8075–200
      • Sasaki J.
      • Yamanouchi S.
      • Sato Y.
      • et al.
      Penetration of micafungin into the burn eschar in patients with severe burns.
      ,
      • Asensio M.J.
      • Sanchez M.
      • Galvan B.
      • et al.
      Micafungin at a standard dosage of 100 mg/day achieves adequate plasma exposure in critically ill patients with severe burn injuries.
      Piperacillin-tazobactam3036.8 (19.7)1.9 (0.7)20–50100–160
      • Jeon S.
      • Han S.
      • Lee J.
      • et al.
      Population pharmacokinetic analysis of piperacillin in burn patients.
      ,
      • Bourget P.
      • Lesne-Hulin A.
      • Le Reveille R.
      • et al.
      Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection.
      TobramycinNA26.5 (14.8)4.2 (0.4)20–6080–200
      • Bracco D.
      • Landry C.
      • Dubois M.J.
      • Eggimann P.
      Pharmacokinetic variability of extended interval tobramycin in burn patients.
      ,
      • Vella D.
      • Walker S.A.
      • Walker S.E.
      • et al.
      Determination of tobramycin pharmacokinetics in burn patients to evaluate the potential utility of once-daily dosing in this population.
      VancomycinNA50.9 (11.9)3.8 (1.1)40–60120–140
      • Carter B.L.
      • Damer K.M.
      • Walroth T.A.
      • et al.
      A Systematic review of vancomycin dosing and monitoring in burn patients.
      ,
      • Akers K.S.
      • Cota J.M.
      • Chung K.K.
      • et al.
      Serum vancomycin levels resulting from continuous or intermittent infusion in critically ill burn patients with or without continuous renal replacement therapy.
      CrCl = creatinine clearance; NA = not applicable; TBSA = total body surface area.
      All values are expressed as mean (SD).
      Table IIRecommended dosing regimens, PTA based on CLSI MIC susceptibility breakpoints, and CFR based on EUCAST MIC distributions.
      Anti-infective Dosing Regimen
      For those with estimated creatinine clearance >70 ml/min and severe burn injury covering >20% TBSA.
      Infusion Time, hPTA, %CFR, %Target PathogenPTA MIC, mg/LPK-PD Target
      Amikacin, 20 mg/kg × 11.0
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      Pseudomonas aeruginosa16AUC0–24:MIC >150:1
      Aztreonam
       2 g q8h4.09699P aeruginosa850% fT>MIC
       2 g q6h0.59297P aeruginosa850% fT>MIC
       2 g q8h0.58091P aeruginosa850% fT>MIC
      Cefepime
       2 g q8h4.09496P aeruginosa860% fT>MIC
       2 g q8h0.57586P aeruginosa860% fT>MIC
      Ceftazidime
       2 g q8h3.09699P aeruginosa860% fT>MIC
       1 g q8h3.08898P aeruginosa860% fT>MIC
       2 g q8h0.58696P aeruginosa860% fT>MIC
      Ciprofloxacin
       400 mg q8h1.0
      Probability of target attainment <1%.
      75P aeruginosa1AUC0–24:MIC >125:1
       400 mg q8h1.0
      Probability of target attainment <1%.
      92Klebsiella pneumoniae1AUC0–24:MIC >125:1
      Colistin
       150 mg q12h
      Expressed as colistin base activity.
      0.5
      Probability of target attainment <1%.
      28P aeruginosa2AUC0–24:MIC >30:1
       150 mg q12h
      Expressed as colistin base activity.
      0.5
      Probability of target attainment <1%.
      23Acinetobacter species2AUC0–24:MIC >30:1
       150 mg q12h
      Expressed as colistin base activity.
      0.5
      Probability of target attainment <1%.
      7P aeruginosa2AUC0–24:MIC >60:1
       150 mg q12h
      Expressed as colistin base activity.
      0.5
      Probability of target attainment <1%.
      3Acinetobacter species2AUC0–24:MIC >60:1
      Daptomycin
       10 mg/kg q24h0.53296Staphylococcus aureus1AUC0–24:MIC >600:1
       750 mg q24h0.52493S aureus1AUC0–24:MIC >600:1
      Ertapenem
       1 g q24h0.5
      Probability of target attainment <1%.
      98K pneumoniae0.540% fT>MIC
       1 g q24h0.5
      Probability of target attainment <1%.
      78Enterobacter species0.540% fT>MIC
      Fluconazole
       400 mg q24h2.0100100Candida albicans2fAUC0–24:MIC >25:1
       800 mg q24h4.0
      Probability of target attainment <1%.
      81Candida species32fAUC0–24:MIC >25:1
       800 mg q24h4.0
      Probability of target attainment <1%.
      42Candida glabrata32fAUC0–24:MIC >25:1
      Imipenem-cilastatin
       1 g q6h0.59094P aeruginosa240% fT>MIC
       500 mg q6h0.57788P aeruginosa240% fT>MIC
      Levofloxacin
       750 mg q24h1.5
      Probability of target attainment <1%.
      71P aeruginosa2AUC0–24:MIC >125:1
      Levofloxacin
       750 mg q24h1.5
      Probability of target attainment <1%.
      87K pneumoniae2AUC0–24:MIC >125:1
      Linezolid
       600 mg q12h2.0
      Probability of target attainment <1%.
      7S aureus4AUC0–24:MIC >100:1
       600 mg q12h2.0
      Probability of target attainment <1%.
      24S aureus480% T>MIC
      Meropenem
       1 g q8h3.098100P aeruginosa240% fT>MIC
       2 g q8h0.58496P aeruginosa240% fT>MIC
       500 mg q6h0.57990P aeruginosa240% fT>MIC
      Micafungin
       150 mg q24h1.04880C albicans0.03
      MIC90 = 0.03 mg/L.
      AUC0–24:MIC >3000:1
       150 mg q24h1.0
      Probability of target attainment <1%.
      4Candida parapsilosis2AUC0–24:MIC >285:1
      Piperacillin-tazobactam
       4.5 g q6h4.08794P aeruginosa1650% fT>MIC
       4.5 g q8h4.08192P aeruginosa1650% fT>MIC
       4.5 g q6h0.58091P aeruginosa1650% fT>MIC
      Tobramycin, 10 mg/kg × 11.0
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      P aeruginosa2AUC0–24:MIC >150:1
      Vancomycin, 20 mg/kg q8h2.0
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      S aureus2AUC0–24:MIC >400:1
      CLSI = Clinical and Laboratory Standards Institute; CFR = cumulative fraction of response; EUCAST = European Committee on Antimicrobial Susceptibility Testing; fT>MIC = free drug concentrations above the pathogen’s MIC for a specified percentage of time; PD = pharmacodynamic; PK = pharmacokinetic; PTA = probability of target attainment.
      low asterisk For those with estimated creatinine clearance >70 ml/min and severe burn injury covering >20% TBSA.
      Not calculated given wide PK variability; recommend therapeutic drug monitoring.
      Probability of target attainment <1%.
      § Expressed as colistin base activity.
      || MIC90 = 0.03 mg/L.

      β-lactam Dosing Recommendations

      Piperacillin-tazobactam is the only penicillin antibiotic for which sufficient PK data have been published to determine dosing recommendations in a burn population.
      • Jeon S.
      • Han S.
      • Lee J.
      • et al.
      Population pharmacokinetic analysis of piperacillin in burn patients.
      • Bourget P.
      • Lesne-Hulin A.
      • Le Reveille R.
      • et al.
      Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection.
      The PK-PD parameter associated with maximum bactericidal activity and improved clinical outcomes for β-lactams is fT>MIC. Optimizing the PK-PD profile of these antibiotics can be achieved by increasing the frequency of administration and/or prolonging intravenous infusion times. According to in vitro, animal, and clinical PK-PD studies in nonburn populations, penicillin antibiotics should be dosed to ensure 50% fT>MIC.
      • Jeon S.
      • Han S.
      • Lee J.
      • et al.
      Population pharmacokinetic analysis of piperacillin in burn patients.
      Given that empiric piperacillin-tazobactam in patients with burn injury is often used for its antipseudomonal activity, we considered doses to be optimized if unbound piperacillin serum concentrations remained above the P aeruginosa MIC for >50% of the dosing interval. According to EUCAST MIC distributions, approximately 15% of wild-type P aeruginosa isolates have MICs of 16 mg/L. As a result, CFRs exceed 90% for standard infusion piperacillin-tazobactam given at 4.5 g every 6 hours. However, infusion times must be prolonged to 4 hours to ensure close to 90% PTA for those isolates with MICs of 16 mg/L (Table II).
      One published study confirms the utility of continuous IV infusion oxacillin given as 12 g during 24 hours for burn wound cellulitis; however, PK assessments were not performed.
      • Schuster K.M.
      • Wilson D.
      • Schulman C.I.
      • et al.
      Continuous-infusion oxacillin for the treatment of burn wound cellulitis.
      Another group of investigators reported using increased ampicillin-sulbactam doses of 4 g of ampicillin and 2 g of sulbactam given intravenously every 6 hours as preferred treatment for burn patients with A baumannii infection to overcome poor outcomes associated with lower doses.
      • Cawley M.J.
      • Suh C.
      • Lee S.
      • Ackerman B.H.
      Nontraditional dosing of ampicillin-sulbactam for multidrug-resistant Acinetobacter baumannii meningitis.
      However, PK information is unavailable, and further guidance on dosing in nonburn populations is sparse. Therefore, it is unclear whether these regimens achieve the 50% fT>MIC PK-PD target.
      The antipseudomonal cephalosporin antibiotics ceftazidime and cefepime are the only agents in this class for which extensive PK data are available in patients with burn injury.
      • MacVane S.H.
      • Kuti J.L.
      • Nicolau D.P.
      Clinical pharmacodynamics of antipseudomonal cephalosporins in patients with ventilator-associated pneumonia.
      • Rhodes N.J.
      • Kuti J.L.
      • Nicolau D.P.
      • et al.
      Defining clinical exposures of cefepime for gram-negative bloodstream infections that are associated with improved survival.
      Favorable clinical outcomes have been documented with 60% fT>MIC in critically ill patients.
      • Crandon J.L.
      • Bulik C.C.
      • Kuti J.L.
      • Nicolau D.P.
      Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa.
      • MacVane S.H.
      • Kuti J.L.
      • Nicolau D.P.
      Clinical pharmacodynamics of antipseudomonal cephalosporins in patients with ventilator-associated pneumonia.
      • Rhodes N.J.
      • Kuti J.L.
      • Nicolau D.P.
      • et al.
      Defining clinical exposures of cefepime for gram-negative bloodstream infections that are associated with improved survival.
      As such, we recommend doses that would result in unbound serum concentrations exceeding the susceptibility breakpoint of 8 mg/L for the aforementioned time interval. More than 20% of P aeruginosa isolates have cefepime MICs of 8 mg/L. Although the CFR for maximum dose standard infusion cefepime is approximately 86%, infusion times must be prolonged to 4 hours to exceed 90% CFR and exceed 90% PTA when for P aeruginosa isolates with MICs of 8 mg/L. High-dose cefepime administration must also be balanced with the increased risk for neurotoxicity that has been observed when troughs exceed 22 mg/L.
      • Doh K.
      • Woo H.
      • Hur J.
      • et al.
      Population pharmacokinetics of meropenem in burn patients.
      According to our modeling, approximately 15% of patients receiving this dose would achieve troughs slightly above this threshold (mean, 25.6 mg/L) (data not shown). Similar recommendations are made for prolonging ceftazidime infusions to 3 hours to meet the 60% fT>MIC target for MICs at 8 mg/L (Table II).
      Of the carbapenems, population PK studies in patients with burn injury are available for imipenem and meropenem, whereas a single burn PK study evaluating ertapenem is available. Carbapenem PK-PD targets have been extensively studied, and animal models suggest that bactericidal activity is achieved at 40% fT>MIC.
      • Nicolau D.P.
      Pharmacokinetic and pharmacodynamic properties of meropenem.
      A significant predictor of microbiologic success in patients with lower respiratory tract infections was observed with a carbapenem PK-PD target of approximately 50% fT>MIC.
      • Li C.
      • Du X.
      • Kuti J.L.
      • Nicolau D.P.
      Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections.
      Again, these PK-PD targets have not yet been confirmed in burn populations. Despite this limitation, doses resulting in free imipenem and meropenem concentrations that remained above the Pseudomonas susceptibility breakpoint of 2 mg/L >40% of the time were considered optimal. Imipenem doses of 1 g given every 6 hours at standard infusion rates resulted in PTAs and CFRs >90% (Table II). Approximately 70% of wild-type P aeruginosa isolates have meropenem MICs of ≤0.5 mg/L. As a result, meropenem CFRs were ≥88% when dosed at 1 g every 8 hours infused for 30 minutes (data not shown) or 500 mg every 6 hours. However, prolonged infusions during 3 hours are required to treat those burn patients infected with pathogens who have an MIC of 2 mg/L (Table II). For ertapenem, free serum PK properties were compared with the MIC distributions for K pneumoniae and Enterobacter species because ertapenem lacks clinically relevant activity against Pseudomonas. The only recommended dose of ertapenem in patients with normal kidney function is 1 g administered intravenously for 30 minutes given every 24 hours. This dose resulted in high CFR for K pneumoniae but only a 78% CFR for Enterobacter species (Table II).
      A single study evaluated the PK properties of the monobactam aztreonam in patients with burn injury.
      • Bourget P.
      • Lesne-Hulin A.
      • Le Reveille R.
      • et al.
      Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection.
      Most investigators have used 50% fT>MIC as the PK-PD target for aztreonam. However, in a post hoc evaluation of 3 clinical trials, the probability of clinical cure increased when the aztreonam AUC0–24:MIC ratio exceeded 184:1.
      • Smith P.F.
      • Ballow C.H.
      • Booker B.M.
      • et al.
      Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients.
      Clinicians may consider aztreonam useful to treat Pseudomonas infections in those with severe penicillin allergies. Therefore, aztreonam doses were recommended if unbound serum concentrations exceeded the MIC for >50% of the dosing interval. Extended infusion doses of 2 g every 8 hours or standard infusion doses of 2 g every 6 hours are recommended for the 20% of P aeruginosa isolates with elevated aztreonam MICs of 8 mg/L (Table II).

      Fluoroquinolone Dosing Recommendations

      Dosing recommendations for the fluoroquinolones were derived using data from 3 ciprofloxacin and 1 levofloxacin burn PK studies. The PK-PD parameter associated with improved clinical outcomes for fluoroquinolones is AUC0–24:MIC, and optimized dosing can be achieved by maximizing the total daily dose administered. Favorable clinical response has been achieved when fluoroquinolone AUC0–24:MIC ratio is >125:1 for gram-negative infections in critically ill nonburn patients.
      • Peloquin C.A.
      • Cumbo T.J.
      • Nix D.E.
      • et al.
      Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections: impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication.
      • Forrest A.
      • Nix D.E.
      • Ballow C.H.
      • et al.
      Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.
      One study found an optimized PK-PD target of AUC0–24:MIC >250:1 for patients with Enterobacteriaceae bacteremia.
      • Zelenitsky S.A.
      • Ariano R.E.
      Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection.
      The MIC susceptibility breakpoint against Pseudomonas is 1 mg/L for ciprofloxacin and 2 mg/L for levofloxacin. However, maximum doses of these fluoroquinolones are unlikely to achieve an AUC0–24:MIC >125:1 when MICs are this high. In addition, these agents have 70% to 75% CFRs when accounting for wild-type P aeruginosa isolates that often have elevated fluoroquinolone MICs. Empiric maximum dose fluoroquinolone use for Enterobacteriaceae, such as K pneumoniae, has much higher CFRs (Table II). Published PK data for moxifloxacin and gemifloxacin in patients with severe burn injury are unavailable, but these specific fluoroquinolone agents are less likely to be used empirically because both lack activity against Pseudomonas aeruginosa.

      Aminoglycoside Dosing Recommendations

      The PK disposition of tobramycin and amikacin in patients with burn injury has been well described. Traditionally, aminoglycosides have been dosed to achieve a Cmax:MIC >10:1 based on older PD studies in which investigators lacked robust serum sampling data.
      • Moore R.D.
      • Lietman P.S.
      • Smith C.R.
      Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration.
      • Kashuba A.D.
      • Nafziger A.N.
      • Drusano G.L.
      • Bertino Jr, J.S.
      Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria.
      Contemporary aminoglycoside PK-PD data, derived from nonburn medical and surgical patients, suggest that there is a 90% probability of patients becoming afebrile by day 7 when aminoglycosides are dosed such that AUC0–24:MIC is >156:1.
      • Drusano G.L.
      • Ambrose P.G.
      • Bhavnani S.M.
      • et al.
      Back to the future: using aminoglycosides again and how to dose them optimally.
      One of the benefits of aminoglycoside use in patients with thermal burn injury is that therapeutic drug monitoring is readily available. A number of studies have found that patients with severe burn injury have large aminoglycoside Vd, which requires higher doses to achieve an adequate peak concentration. Furthermore, these patients may have much faster renal aminoglycoside clearance, placing patients who receive once-daily regimens at risk for prolonged periods where aminoglycoside concentrations fall below the MIC of the infecting pathogen.
      • Conil J.M.
      • Georges B.
      • Breden A.
      • et al.
      Increased amikacin dosage requirements in burn patients receiving a once-daily regimen.
      • Akers K.S.
      • Cota J.M.
      • Frei C.R.
      • et al.
      Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration.
      • Bracco D.
      • Landry C.
      • Dubois M.J.
      • Eggimann P.
      Pharmacokinetic variability of extended interval tobramycin in burn patients.
      • Vella D.
      • Walker S.A.
      • Walker S.E.
      • et al.
      Determination of tobramycin pharmacokinetics in burn patients to evaluate the potential utility of once-daily dosing in this population.
      Given this information and our published experience, we recommend that a single dose of 10 mg/kg of tobramycin or 20 mg/kg of amikacin be given followed by 2 postdistributional levels taken 2 and 8 to 10 hours after the start of the infusion in patient with burn injury and normal or augmented renal clearance. Subsequent aminoglycoside doses should be determined by patient-specific PK estimations derived from therapeutic drug monitoring. The Cmax may be accurately calculated and the AUC0–24 may be roughly estimated using these levels. Care must be taken to avoid using once-daily aminoglycoside monotherapy regimens where serum concentrations fall below the limit of detection for periods >10 to 12 hours. In patients with burn injury, once-daily tobramycin and amikacin doses recommended here are unlikely to reach AUC0–24 >600, a threshold at which the likelihood of nephrotoxicity increases significantly, especially when given concurrently with vancomycin.
      • Drusano G.L.
      • Ambrose P.G.
      • Bhavnani S.M.
      • et al.
      Back to the future: using aminoglycosides again and how to dose them optimally.
      In addition, the rate of aminoglycoside nephrotoxicity can be further reduced by limiting the duration of exposure.

      Dosing Recommendations for Antibiotics with Activity Against Methicillin-resistant S aureus

      Specific antibiotics that have activity against methicillin-resistant S aureus and for which PK data are available in patients with severe burn injury include daptomycin, linezolid, and vancomycin. Improved clinical outcomes in nonburn patients with serious methicillin-resistant S aureus infections has been documented as the vancomycin AUC0–24:MIC ratio is >400:1.
      • Men P.
      • Li H.B.
      • Zhai S.D.
      • Zhao R.S.
      Association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness: a systematic review and meta-analysis.
      Like aminoglycosides, therapeutic drug monitoring for vancomycin is readily available and should be used to optimize dosing in a patient-specific manner. Higher total daily doses of 40 to 70 mg/kg are likely required to optimize vancomycin PK-PD properties in patients with severe burn injury and normal or augmented renal clearance.
      • Carter B.L.
      • Damer K.M.
      • Walroth T.A.
      • et al.
      A Systematic review of vancomycin dosing and monitoring in burn patients.
      Patients with steady-state vancomycin troughs of 15 to 20 mg/L will have an AUC0–24 >360 to 480 mg∙h/L and meet the AUC0–24 target when vancomycin MICs are 1 mg/L. Continuous infusion vancomycin may be considered to more easily calculate AUC0–24 by multiplying steady-state plateau levels by 24 hours.
      • Akers K.S.
      • Cota J.M.
      • Chung K.K.
      • et al.
      Serum vancomycin levels resulting from continuous or intermittent infusion in critically ill burn patients with or without continuous renal replacement therapy.
      These recommendations must also be balanced with the risk of vancomycin-induced nephrotoxicity, which is usually reversible on discontinuation.
      The AUC0–24:MIC ratio is the best predictor of daptomycin activity against S aureus. Although one study suggests that an AUC0–24:MIC of <666:1 was associated with poor outcomes, this has not yet been validated by other investigators and has not been confirmed in a burn population.
      • Falcone M.
      • Russo A.
      • Cassetta M.I.
      • et al.
      Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary?.
      One PK study of daptomycin in patients with severe burn injury is available and suggests that the daptomycin AUC0–24 is 50% lower than what is observed in healthy volunteers.
      • Kullar R.
      • Casapao A.M.
      • Davis S.L.
      • et al.
      A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis.
      On the basis of the results of this single study, daptomycin dosed at 12 mg/kg of weight once daily in those with severe burn injury should produce levels similar to that of a 6-mg/kg dose. A number of studies confirm the tolerability of daptomycin doses of >8 mg/kg given once daily.
      • Kullar R.
      • Casapao A.M.
      • Davis S.L.
      • et al.
      A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis.
      • Casapao A.M.
      • Kullar R.
      • Davis S.L.
      • et al.
      Multicenter study of high-dose daptomycin for treatment of enterococcal infections.
      • Seaton R.A.
      • Gonzalez-Ruiz A.
      • Cleveland K.O.
      • et al.
      Real-world daptomycin use across wide geographical regions: results from a pooled analysis of CORE and EU-CORE.
      According to our PK-PD analysis, daptomycin doses given at 10 mg/kg once daily have CFRs >90% given the distribution of low MICs of wild-type S aureus isolates. A fixed empiric daptomycin dose of 750 mg given once daily may also be used to achieve similar CFRs with weight-based dosing.
      • Falcone M.
      • Russo A.
      • Venditti M.
      • et al.
      Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia.
      This study also confirmed that the probability of achieving daptomycin trough concentrations in excess of 24.3 mg/L (a level associated with skeletal muscle toxicity) using this 750-mg fixed-dosing schedule was approximately 1.3%.
      • Falcone M.
      • Russo A.
      • Venditti M.
      • et al.
      Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia.
      No patients in our model achieved a trough >24.3 mg/L (data not shown); therefore, daptomycin-induced skeletal muscle toxic effects would be unlikely to occur with these recommendations. Alternative agents would be recommended in those patients infected with S aureus isolates having MICs of 1 mg/L given the low daptomycin PTA.
      Linezolid should be dosed to achieve an AUC0–24:MIC >80 to 100:1 for improved clinical outcomes.
      • Rayner C.R.
      • Forrest A.
      • Meagher A.K.
      • et al.
      Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme.
      Alternatively, this PD index was also correlated with achieving 80% fT>MIC using the only recommended linezolid dosing regimen of 600 mg IV every 12 hours. In the only published study available, linezolid AUC0–24 decreased by 50% in those with severe burn injury compared with nonburn patients.
      • Lovering A.M.
      • Le Floch R.
      • Hovsepian L.
      • et al.
      Pharmacokinetic evaluation of linezolid in patients with major thermal injuries.
      Although this finding would suggest increasing total daily linezolid doses by 2-fold, published studies evaluating these high doses are unavailable. Standard doses of linezolid result in low CFRs in patients with burn injury (Table II). Data regarding linezolid doses of 600 mg given 3 times a day is restricted to limited case reports.
      • Lopez-Garcia B.
      • Luque S.
      • Roberts J.A.
      • Grau S.
      Pharmacokinetics and preliminary safety of high dose linezolid for the treatment of Gram-positive bacterial infections.
      However, according to our PD modeling, doses at this level would also result in CFRs <50% (data not shown). According to toxicodynamic models that have yet to be confirmed in clinical settings, <5% of patients would be predicted to develop thrombocytopenia if 1200 mg of linezolid given every 12 hours was given for 5 days followed by standard dosing.
      • Boak L.M.
      • Rayner C.R.
      • Grayson M.L.
      • et al.
      Clinical population pharmacokinetics and toxicodynamics of linezolid.
      Thrombocytopenia development was even less likely to occur according to this mathematical model in those with baseline platelet counts >400 × 109/L. High-dose linezolid must first be evaluated in large numbers of patients before these doses can be recommended in burn patients to overcome low likelihood of achieving PK-PD targets with current recommended doses.

      Colistin

      The PK profile of colistin in burn patients has been of great recent interest given the increase of multidrug-resistant pathogens.
      • Keen 3rd, E.F.
      • Robinson B.J.
      • Hospenthal D.R.
      • et al.
      Prevalence of multidrug-resistant organisms recovered at a military burn center.
      However, colistin PK-PD properties are still under investigation. Currently, only in vitro and animal data are available to guide PK-PD target selection.
      • Bergen P.J.
      • Bulitta J.B.
      • Forrest A.
      • et al.
      Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model.
      • Dudhani R.V.
      • Turnidge J.D.
      • Coulthard K.
      • et al.
      Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models.
      • Dudhani R.V.
      • Turnidge J.D.
      • Nation R.L.
      • Li J.
      fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models.
      These data suggest stasis or a 1-log reduction in bacterial burden when colistin dosing results in an AUC0–24:MIC ratio >30:1 or 60:1. Using information from a population PK study of colistin in patients with thermal burn injury, it is unlikely that current maximum recommended colistin doses of 150 mg of colistin base activity given every 12 hours would achieve therapeutic concentrations, assuming these PK-PD targets are accurate (Table II). Higher doses may predispose patients to an excessive nephrotoxicity risk. As such, colistin monotherapy is not recommended for patients with burn injury and normal or augmented renal clearance and may only be of use in the unlikely situation in which pathogen MICs are ≤0.5 mg/L. Furthermore, colistin is administered as the inactive prodrug colistin methanesulfonate (also known as colistimethate), which is converted to active colistin in vivo. The complicated and highly variable conversion to colistin (polymyxin E) makes accurate and predictable PK studies difficult. As such, clinicians may prefer polymyxin B over colistin therapy for multidrug-resistant pathogen treatment because polymyxin B is not a prodrug, does not require conversion in vivo to the active agent, and thus has a more predictable PK profile. Unfortunately, the PK disposition of polymyxin B in patients with severe burn injury has not yet been characterized.

      Antifungal Agents

      As noted previously, invasive fungal infections are of particular concern in a burn population in which effective antifungal topical agents are unavailable and increased mortality has been associated with these infections.
      • Murray C.K.
      • Loo F.L.
      • Hospenthal D.R.
      • et al.
      Incidence of systemic fungal infection and related mortality following severe burns.
      • Horvath E.E.
      • Murray C.K.
      • Vaughan G.M.
      • et al.
      Fungal wound infection (not colonization) is independently associated with mortality in burn patients.
      • Fochtmann A.
      • Forstner C.
      • Hagmann M.
      • et al.
      Predisposing factors for candidemia in patients with major burns.
      • Ballard J.
      • Edelman L.
      • Saffle J.
      • et al.
      Positive fungal cultures in burn patients: a multicenter review.
      Descriptions of the PK disposition of other agents, such as amphotericin B, voriconazole, and posaconazole, in patients with thermal burn injury are limited to small case series.
      • Akers K.S.
      • Rowan M.P.
      • Niece K.L.
      • et al.
      Antifungal wound penetration of amphotericin and voriconazole in combat-related injuries: case report.
      • Sasaki J.
      • Matsumoto K.
      • Fujishima S.
      • et al.
      Pharmacokinetics of a polyene antifungal agent, liposomal amphotericin B (L-AMB), in a severely burned patient.
      • Ressaire Q.
      • Padoin C.
      • Chaouat M.
      • et al.
      Muscle diffusion of liposomal amphotericin B and posaconazole in critically ill burn patients receiving continuous hemodialysis.
      Therefore, standard doses of these antifungals should be given and therapeutic drug monitoring should be performed when available. Published recommendations suggest dosing voriconazole and posaconazole to maintain trough levels >1 mg/L for efficacy in invasive aspergillosis.
      • Patterson T.F.
      • Thompson 3rd, G.R.
      • Denning D.W.
      • et al.
      Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America.
      Currently, it is unclear whether these therapeutic drug monitoring goals are generalizable because these recommendations have not been validated in a burn population. Voriconazole trough targets should be <5 to 6 mg/L to decrease central nervous system adverse effects, which may include self-limiting drug-induced visual disturbances.
      • Patterson T.F.
      • Thompson 3rd, G.R.
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      • et al.
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      Voriconazole has nonlinear saturable PK properties. Therefore, disproportionate changes in serum concentrations may occur with small voriconazole dose changes. The most extensive antifungal PK data are available to guide fluconazole and micafungin dosing in a severe burn patient population.
      • Han S.
      • Kim J.
      • Yim H.
      • et al.
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      • et al.
      Penetration of micafungin into the burn eschar in patients with severe burns.
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      • et al.
      Micafungin at a standard dosage of 100 mg/day achieves adequate plasma exposure in critically ill patients with severe burn injuries.
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      • et al.
      Fluconazole pharmacokinetics in burn patients.
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      Achieving a ratio of the free AUC0–24:MIC (fAUC0–24:MIC) of >25 is predictive of triazole efficacy in animal models of invasive candidiasis.
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      • van Ogtrop M.
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      Consistent with these data, therapeutic success and decreased mortality in nonburn patients with candidemia treated with fluconazole have been observed when fAUC0–24:MIC ratios of approximately 10 to 55.
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      It is important to determine what Candida species are prevalent in the health care facility that cares for patients with severe burn injury. When considering all Candida species, including Candida glabrata for which non–fluconazole-susceptible isolates may exceed 15% to 20% in some institutions, 800 mg of fluconazole given every 24 hours results in an 81% CFR (Table II). For those burn units where C albicans is the most prevalent Candida species, empiric fluconazole as low as 400 mg given every 24 hours achieves therapeutic serum concentrations (Table II).
      Micafungin is an echinocandin antifungal drug that has concentration-dependent activity with prolonged postantifungal effects. As such, investigators observed a 1-log reduction in fungal burden in animal models of invasive candidiasis when the unbound fAUC0–24:MIC ratio of 10 to 20 was achieved.
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      Favorable clinical outcomes, including mycologic response in nonburn patients with invasive candidiasis, were documented when a total AUC0–24:MIC ratio of >3000 was achieved. A lower total AUC0–24:MIC ratio of >285 was proposed for Candida parapsillosis.
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      MIC distributions from a recent study were used for micafungin simulations because EUCAST data were unavailable.
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      Micafungin’s PK properties are altered in patients with severe burn injury, such that peaks are lower and clearance is faster.
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      Micafungin concentrations in the plasma and burn eschar of severely burned patients.
      It is difficult to recommend specific micafungin doses based on PK-PD target attainment for 2 reasons. First, >99.5% of micafungin is protein bound. As a result, binding changes as small as 0.5% significantly affect free drug calculations.
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      Second, 90% of C albicans MICs to micafungin are <0.03 mg/L.
      • Pfaller M.A.
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      Isavuconazole, micafungin, and 8 comparator antifungal agents׳ susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values.
      Two-fold changes at these low MICs also drastically change PK-PD target attainment values. Given these potential confounders, we observed an 80% CFR with 150 mg of micafungin given every 24 hours for C albicans. PK-PD target attainment is more difficult for C parapsilosis because of elevated echinocandin MICs. A dosage of 150 mg of micafungin given every 24 hours is approved by the US Food and Drug Administration based on large randomized clinical trials evaluating tolerability and efficacy.
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      Early evidence suggests that micafungin doses of up to 300 mg may also be well tolerated.
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      Safety and efficacy of intermittent intravenous administration of high-dose micafungin.
      Clinicians may consider micafungin doses >150 mg to increase probability of PK-PD target attainment. However, in the absence of more supportive data for high-dose micafungin and given the difficulty in conducting more precise PK-PD estimates for echinocandins, 150-mg doses of micafungin seem most appropriate at this time.

      Conclusion and Future Directions

      Advances in antibiotic and antifungal PK-PD properties to predict efficacy has revolutionized dose selection, particularly in patients at greatest risk for altered PK properties, such as those with severe burn injury. Several anti-infective regimens modeled using maximum recommended doses had unacceptable probabilities of achieving PK-PD targets. Notably, ciprofloxacin, levofloxacin, and colistin had very low likelihoods of reaching PK-PD thresholds for P aeruginosa—a common pathogen encountered in patients with burn injury. Ertapenem was unlikely to achieve PK-PD targets against Enterobacter infections. Linezolid had low probability of achieving therapeutic concentrations in patients with burn injury suspected of having S aureus infections. From an antifungal drug perspective, in burn centers where C glabrata is a common pathogen, fluconazole should be avoided for empiric use based on its very low PTA. The dosing recommendations given in this article are not exhaustive because gaps in PK information exist for a number of antibiotics and antifungal drugs. In addition, other investigators have noted that most PK studies conducted in a burn patient population are limited by small sample size, high intrapatient and interpatient variability, and diverse computational modeling.
      • Steele A.N.
      • Grimsrud K.N.
      • Sen S.
      • et al.
      Gap analysis of pharmacokinetics and pharmacodynamics in burn patients: a review.
      To standardize dosing recommendations in this article, it is important to reemphasize that several assumptions were fixed. The recommendations are based on those patients who present >48 hours after initial injury, with >20% TBSA burns, and with normal to augmented renal clearance. In those patients that fall outside these parameters, doses must be adjusted accordingly. In addition, although dosing recommendations were derived from PK data in patients with burn injury, the selected PK-PD targets were taken from studies in critically ill nonburn patient populations because these targets have not yet been confirmed in burn patients. Indeed, PK-PD targets may differ in patients with burns given the unique physiologic features of their injuries. Confirming the relevance of these targets in a burn population is an area of continued uncertainty and would be of great value in more accurately deriving anti-infective dosing recommendations.
      Given the difficulty in predicting PK-PD profiles in this highly variable patient population, it is recommended that therapeutic drug monitoring be used for all antibiotics for which serum concentration monitoring is readily available. Indeed, it appears that the future of individualized antibiotic dosing in patients with burn injury will be incumbent on the availability of real-time therapeutic drug monitoring for all available antibiotics and antifungal drugs so that clinicians will be able to use nearly real-time dose modification to optimize PK-PD properties, thereby increasing the probability of infection eradication.
      • Roberts J.A.
      • Abdul-Aziz M.H.
      • Lipman J.
      • et al.
      Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions.

      Conflicts of Interest

      The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the US Department of the Army, US Department of the Air Force, US Department of Defense, or the US government.
      Jason M. Cota has served on the speakers' bureau for Merck & Co., Inc. and on advisory panels for Allergan, Plc. All other authors confirm that they have not received support from industry or organizations that might have influenced this work.
      This work was not industry-sponsored and was not supported by funding from grants.
      Previous work has been supported by Defense Medical Research & Development Program (DMRDP) Military Infectious Disease Clinical Trial Award (MID-CTA) D_MIDCTA_I_12_J2_299.
      Jason M. Cota performed a literature search, collected data, created tables, wrote the first draft, and revised manuscript. Alireza FakhriRavari performed a literature search, interpreted data, and revised manuscript. Matthew P. Rowan interpreted data and revised manuscript. Kevin K. Chung interpreted data and revised manuscript. Clinton K. Murray interpreted data and revised manuscript. Kevin S. Akers performed a literature search, collected data, wrote a section of the manuscript, interpreted data, and revised manuscript.

      Acknowledgments

      This manuscript is dedicated to the memory of Dr. Matthew P. Rowan, Ph.D., killed on 30 July 2016.

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