Pharmacokinetics of Antimicrobials in Patients with Burn Wounds
Abstract & Commentary
By Catherine J. Hill, PharmD, is PGY1 Pharmacy Resident, Santa Clara Valley Medical Center, San Jose, CA.
Jessica C. Song, MA, PharmD, is Associate Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, is Associate Editor for Infectious Disease Alert.
Catherine Hill and Jessica Song report no financial relationships relevant to this field of study.
Patients with burn injuries are at high risk for major infections, given their impaired humoral and cellular immunity. Moreover, this patient population displays numerous physiologic alterations affecting organ function and drug metabolism. Pathological changes that occur after burn injury can be divided into two phases; the acute phase and the hypermetabolic phase.1-4 The acute phase occurs within the first 48 hours after thermal injury. During this phase, loss of protein rich fluid occurs as a result of increased capillary permeability.1,2 A decrease in cardiac output occurs as a result of hypovolemia, and this causes a decrease in oxygen delivery as well as a decrease in glomerular filtration rate (GFR).1,3,4 The hypermetabolic phase occurs more than 48 hours after thermal injury, assuming that adequate fluid replacement occurs. A doubling of the metabolic rate occurs gradually over several days and results in an increase in oxygen consumption, heat production, protein catabolism, and blood flow.2 Increasing blood flow culminates in an increase in GFR and liver blood flow, which affect clearance of numerous medications.1,3,4
The purpose of this review is to discuss the pharmacokinetic alterations of various antimicrobials likely to be used by burn patients that have been reported in the medical literature. In addition, dosing and level monitoring recommendations for vancomycin, gentamicin, and colistin will be highlighted in this review.
Pharmacokinetics
Therapeutic drug monitoring in burn patients relies on plasma drug concentrations, volume of distribution (Vd), absorption, metabolism, clearance (total, renal, non-renal), and half-life in order to predict the dosage necessary to produce maximum efficacy and minimal toxicity. Unfortunately, the altered physiologic state of burn patients, along with inter-individual variations in this population, cause the relevant pharmacokinetic parameters to change significantly.1
There is no one single factor that solely influences the pharmacokinetics of antimicrobial agents. Factors such as the size and depth of the burn, presence of sepsis, time since burn injury, as well as the age, serum protein level, and fluid status of the patient, can influence the pharmacokinetics of antimicrobial agents.1
Absorption of medication is affected in burn patients as a result of the change in blood flow, intestinal permeability,2 and dermal injury.3 Medications administered subcutaneously or intramuscularly during the acute phase display decreased extent of absorption, whereas increased absorption may be observed with percutaneous and oral administration of medications.3
The distribution of a medication depends on its chemical/pharmacokinetic properties, such as water solubility and protein binding. During the hypermetabolic phase, patients exhibit lower albumin levels and increased a-1 acid glycoprotein levels.1-4 Consequently, the extent of protein binding can be decreased for certain drugs, but increased with other medications. In general, an inverse relationship exists between the degree of protein binding and the fraction of free drug available to the tissues. Alterations in the fraction of free drug can result in significant changes in the dose of drug required to produce the same effect.
The Vd represents a key parameter in determining the loading dose of drugs that require rapid administration to achieve target unbound concentrations.2 Changes in protein binding, free fraction of drug, and fluid/electrolyte status can lead to significant changes in Vd.
During the hypermetabolic phase, phase II metabolism (conjugation of medications) appears to be unaffected, whereas phase I metabolism (metabolism by cytochrome P450 enzymes) may be decreased.3,4 The effect of the change in metabolism may be offset by the increase in the hepatic blood flow to the liver.
Burn patients display increased elimination of medications as a direct consequence of increased clearance, both renal and non-renal. During the hypermetabolic phase, elevated GFRs allow for enhanced drug delivery to the kidneys.2-4 The changes in drug delivery and possible increases in free drug can cause more of the drug to be cleared from the kidney. Moreover, increased non-renal clearance may be attributed to the loss of drug through wounds.3
Changes in Vd and clearance ultimately effect the half-life of the drug.2 Changes in half-life may necessitate a change in dosing frequency in order to maintain therapeutic concentrations.
Dosing of Antimicrobial
There is limited data regarding the pharmacokinetics of different antimicrobial agents in patients who have suffered a burn injury. Developing optimal antimicrobial therapeutic regimens for burn patients can pose a tremendous challenge to practitioners, given that the degree and type of burn injury varies with each patient. The published studies and case reports generally included 10 or fewer patients, and included patients with widely varying total body surface areas covered by the burns. Because of the numerous variables influencing the pharmacokinetics of antimicrobials in burn patients, individualization of antimicrobial therapy is critical for this patient population. Table 1 summarizes the most relevant case reports, studies, reviews, and recommendations for dosing modifications.2-10
Aminoglycosides represent the best studied antimicrobials in the setting of burn injuries. One study conducted by Zaske et al demonstrated the need for higher doses of gentamicin. Patients in this study required doses of 7.4-11.2 mg/kg/d of gentamicin compared to 3-5 mg/kg/d in non-burn patients.1,11 Increased mortality rates have been shown to be associated with gram negative septicemia,1 and rapid attainment of therapeutic aminoglycoside levels has been shown to improve outcomes.11 Weinbren proposed using a loading dose of 5 mg/kg of gentamicin and monitoring the peak level after the first dose, followed by a second level seven hours later.1 A seven-hour level below 1 µ/mL allowed for a repeat dose of 5 mg/kg; a level in excess of 1 µg/mL delayed the administration of a repeat 5 mg/kg dose until the level dropped below 1 µg/mL.1
Vancomycin levels may be decreased in patients with burn injuries. This phenomenon occurs as a result of increased drug clearance and shortened half life.4 Garrelts and Peterie reported that achievement of therapeutic Vancomycin concentrations required a dose increase of 78%.2 Total daily doses of vancomycin have ranged between 2-6 g/day, and may be divided in 6-8 hour dosing intervals.1,11 Continuous infusion of vancomycin has been suggested to maintain appropriate drug levels. However, while this regimen has been shown to be safe, it does not result in improved achievement rates of therapeutic levels over intermittent dosing.1 Therapeutic level monitoring of vancomycin will guide the necessity of an increase in dosage.
Clearance of beta-lactams is increased in burn patients.2 Routine level monitoring of this class of drugs does not occur in clinical practice and, as a result, dose adjustment of b-lactams should be based on the patient's response to treatment. Maximum doses should be used to compensate for increased drug clearance. Patients with impaired renal function should be dosed based on their creatinine clearances for those medications requiring renal dose adjustment.
At present, no pharmacokinetic studies of colistin in burn patients have been reported in the medical literature. However, since colistin undergoes renal elimination, a higher dose of colistin may be needed. David and Gill reported a case of potential subtherapeutic dosing of colistin in a patient with resistant Acinetobacter.12 The authors hypothesized that resistance to colistin developed as a result of subtherapeutic drug levels secondary to the increased clearance of colistin. The report concluded with the recommendation of checking colistin levels three to five days after the start of therapy, aiming for a peak level (drawn 30 minutes after infusion) of 10-15 mg/L.12
Conclusion
As a population, burn patients exhibit large inter- and intra-patient variability. As a result, the pharmacokinetics, as well as dose requirements of antimicrobials may be ever changing. Therapeutic drug monitoring helps to individualize therapy to the patient, as well as accommodate the patient's changing status. Aminoglycosides and vancomycin levels are commonly monitored; monitoring of colistin levels can be of benefit to patients with burn injury.
References
- Weinbren MJ. Pharmacokinetics of antibiotics in burn patients. J Antimicrob Chemother. 1999;44:319-327.
- Jaehde U, Sörgel F. Clinical pharmacokinetics in patients with burns. Clin Pharmacokinet. 1995;29:15-28.
- Bonate PL. Pathophysiology and pharmacokinetics following burn injury. Clin Pharmacokinet. 1990;18:118-130.
- Boucher BA, et al. Pharmacokinetics of systemically administered antibiotics in patients with thermal injury. Clin Infect Dis. 1992;14:458-463.
- Bonapace CR, et al. Pharmacokinetics of cefepime in patients with thermal burn injury. Antimicrob Agents Chemother. 1999;43:2848-2854.
- Bourget P, et al. Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection. Antimicrob Agents Chemother. 1996;40:139-145.
- Mohr JF 3rd, et al. Pharmacokinetic evaluation of single-dose intravenous daptomycin in patients with thermal burn injury. Antimicrob Agents Chemother. 2008;52:1891-1893.
- Kiser TH, et al. Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury. Antimicrob Agents Chemother. 2006;50:1937-1945.
- Boucher BA, et al. Fluconazole pharmacokinetics in burn patients. Antimicrob Agents Chemother. 1998;42:930-933.
- Pea F, et al. Antimicrobial therapy in critically ill patients. Clin Pharmacokinet. 2005;44:1009-1034.
- Bergman SJ, et al. Pharmacokinetic and pharmacodynamic aspects of antibiotic use in high-risk populations. Infect Dis Clin North Am. 2007;21:821-846.
- David MD, Gill MJ. Potential for underdosing and emergence of resistance in Acinetobacter baumannii during treatment with colistin. J Antimicrob Chemother. 2008;61:962-964.
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