Treatment of infection in burns

organism (MDRO’s). The aminoglycosides and in particular, gentamicin, were historically the antibiotics of choice in the treatment of gram-negative infections. The synergistic activity with penicillinaseresistant penicillins and vancomycin in the treatment of staphylococcal infections further standardized its premier status before the advent of newer extended-spectrum penicillins, the fourth generation cephalosporins, the monobactams, the carbapenems and the quinolones. However, some gram-negative bacteria encountered in the burn unit are now resistant to all the aforementioned antibiotic classes and must now be treated with an old drug class, the polymixins.

Polymyxins are amphipathic molecules that interact with the lipopolysaccharide in the bacterial outer membrane; insertion of the antibiotic into the membrane disrupts it and releases lipopolysaccharide into the surrounding milieu. They also have potent antiendotoxic properties and antibacterial activity against P. aeruginosa and many of the Enterobacteriaceae [34].

Colistin, or polymyxin E, is a multicomponent polypeptide antibiotic comprised mainly of colistins A and B. It became available for clinical use in the 1960s. There are two forms of colistin available: Colistin sulfate for oral and topical use and colistimethate sodium for parenteral use [35]. Based on the studies of Storm et al., the polymyxins are bacteriostatic at low concentrations and bactericidal at high concentrations [36].

In early studies, Evans et al. and Nord and Hoeprich reported that at concentrations of 0.01 mcM/ mL, polymyxin B sulfate was bactericidal for 88% of the P. aeruginosa strains [35, 37]. Full bactericidal activity against P. aeruginosa is not seen until the colistin concentration reaches 0.1 mcM/mL [35].

In susceptibility testing performed at the Galveston Shriners Hospital from 2005 to 2008, A. baumannii=haemlyticus, E. cloacae, E. coli, and K. pneumoniae all showed 100% susceptibility to colistin and polymyxin B, whereas P. aeruginosa showed 96% and 99% susceptibility to colistin and polymyxin B, respectively.

Nephrotoxicity and neurotoxicity are the most common adverse effects of colistin. Close monitoring of the dose-dependent nephrotoxicity and central nervous system toxicity associated with its systemic use therefore is necessary [38].

To investigate whether the use of colistin can moderate multi-resistant infections, and to elucidate whether it is associated with a greater number of adverse effects or a higher mortality rate in burn patients, Branski et al. reviewed 398 severely burned patients (burns >40% total body surface area [TBSA]) admitted to the Galveston Shriners Hospital between 2000 and 2006 who did not contract multi-drug- resistant gram-negative organisms during their hospital course and received the standard antibiotic regimen – vancomycin and piperacillin/tazobactam – served as controls (piperacillin/tazobactam; n=280) [38].

The treatment group consisted of patients who, during their acute hospital stay, developed infections with multi-drug-resistant gram-negative pathogens and were treated with vancomycin and colistin for at least three days (colistin; n=118). Colistin was given at a mean dose of 4.4±0.9 mg/kg divided into three (or, in rare cases, two) doses over 24h. Patients who required colistin therapy had a significantly larger average total and full-thickness burn than patients treated with piperacillin/tazobactam and vancomycin, and the mortality rate was significantly higher in the colistin group (p > 0.05). However, there was no significant difference between the colistin and piperacillin/ tazobactam groups in the incidence of neurotoxicity, hepatic toxicity, or nephrotoxicity. The authors concluded that Colistin is a safe and efficacious antimicrobial therapy without a marked incidence of toxic side effects. The higher mortality rate in the colistin group at the Galveston Shriners Hospital indicates that multi-resistant organisms are aggressive and a major contributor to burn-related death. The significantly larger burns in the colistin group certainly are the main reason for this finding. This study indicates that treatment of the pediatric burn population with colistin can be safe, as it did not increase the overall incidence of adverse effects. However, colistin should be used only under close monitoring of renal function [38].

Treatment of yeast and fungal infections

The five classes of systemic antifungal medications include the polyenes, the azoles, nucleosides, echinocandin, and allylamine. Thus there are 4 potential

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target sites in the fungal cell for the antifungal drugs to act. The allylamine antifungal, terbinafine, which is used primarily for management of dermatophytosis and onchomycosis, and ketoconazole which has been replaced by newer, less toxic triazole drugs will not be discussed.

The Polyenes (Amphotericin B)

Amphotericin B, an amphoteric polyene macrolide, is an antifungal antibiotic. Conventional IV amphotericin N is used for the treatment of potentially lifethreatening fungal infections including aspergillosis, North American blastomycosis, systemic candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and zygomycosis [32].

Amphotericin B usually is fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms. Amphotericin B exerts its antifungal activity principally by binding to sterols (e. g. ergosterol) in the fungal cell membrane. As a result of this binding, the cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs. Cell death occurs in part as a result of permeability changes, but other mechanisms also may contribute to the in vivo antifungal effects of amphotericin B against some fungi [32]. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e. g. bacteria).

Binding to sterols in mammalian cells (such as certain kidney cells and erythrocytes) may account for some of the toxicities reported with conventional amphotericin B therapy. Nephrotoxicity is the major dose-limiting side effect reported with conventional IV amphotericin B and occurs to some degree in the majority of patients receiving the drug. Adverse renal effects include decreased renal function and renal function abnormalities such as azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis [32]. Increased BUN and serum creatinine concentrations and decreased creatinine clearance, glomerular filtration rate, and renal plasma flow occur in most patients receiving conventional IV amphotericin.

Acute infusion reactions consisting of fever, shaking, chills, hypotension, anorexia, nausea, vom-

iting, headache, dyspnea, and tachypnea may occur 1–3 hours after initiating of IV infusions of conventional IV amphotericin B or other formulations such as amphotericin B cholesteryl sulfate, amphotericin B lipid complex, and amphotericin B liposomal. Acetaminophen, meperidine, antihistamines (e. g. diphenhydramine), or corticosteroids have been used for the treatment or prevention of these acute infusion reactions.

Azole antifungals

The azole antifungals consist of the triazole antifungal oral and intravenous drugs, fluconazole, itraconazole and voriconazole and the imidazole oral drug, ketoconazole. These antifungal agents act by interfering with cytochrome P450 activity, decreasing ergosterol synthesis (the principal sterol in the fungal cell membrane), and inhibiting cell membrane formation [26].

The triazole antifungal drugs can be distinguished by differences in their spectrum of activity. Fluconazole is generally active in vitro against Candida albicans, many of the non-albicans Candida species, and C. neoformans. However it is not generally active against Candida krusei or Aspergillus species [26]. Itraconazole also has excellent anti-Candi- da activity, is more effective in vitro than fluconazole against the endemic fungi, H. capsulatum, S. schenckii, and B dermatitidis and has fungistatic activity against Aspergillus [26]. Voriconazole has up to 60fold lower minimum inhibitory concentrations for Candida species (including resistant strains) than fluconazole, is fungicidal for Aspergillus and has some activity against Fusarium species and Scedosporium apiospermum [26]. None of the triazoles are active against the Zygomycetes.

In general, azole drugs are better tolerated than the amphotericin B formulations. Side effects of fluconazole, which are uncommon, include rash and elevations in liver function test results. In patients who receive prolonged courses of high-dose therapy, reversible alopecia and dry lips can occur. Potential side effects of itraconazole include peripheral edema, exacerbation of congestive heart failure (caused by a negative inotropic effect), hypokalemia, or rash [26]. Reported toxicities of voriconazole include elevations in liver function test results, rash,

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