Emerging Infections in Burns

Pharmacologic treatment

Therapy for S. aureus has been challenged by the development of drug resistance. The first resistant isolate was recovered only two years after the introduction of penicillin in 1944 [24]; a similar two-year period elapsed between the introduction of the semisynthetic penicillin, methicillin and the emergence of the first MRSA [25]. Guggenheim et al. calculated the decline of susceptibility of S. aureus to broad-spectrum first-line drugs, such as ciprofloxacin or penicillinase-stable penicillins (oxacillin or methicillin) over the past 20 years [19]. Vancomycin alone or in conjunction with other antibiotics generally has been considered the treatment of choice for infections caused by MRSA. Even though vancomycin is used only as a last resort in treating MRSA infections, resistance recently has developed to this agent also. Vancomycin-intermediate susceptible S. aureus (VISA) was isolated in 1997 and has since appeared as analogous strains in numerous countries [26].

At this time, no antibiotic class is uniformly effective against S. aureus [26]. The continuously emerging resistance against existing drugs underscores the importance of the development of new antibiotics. New classes of agents have been developed, including inhibitors of protein synthesis such as oxazolidinones (linezolid) and streptogramins (quinupristin/dalfopristin); tigecycline; a bactericidal drug that acts on the cell membrane (daptomycin); and an inhibitor of peptidoglycan synthesis in cell walls (dalbavancin) [27].

In an internal study performed in 2005 at the Galveston Shriners Hospital, only 31% of S. aureus burn wound isolates and none of the S. epidermidis and S. haemolyticus isolates were sensitive to oxacillin [9]. Other antibiotics, such as cotrimoxazole, netilmicin, and rifampin, have, however, retained surprisingly high levels of efficiency. Clindamycin has remained effective, with susceptibility rates exceeding 90% [9]. This susceptibility pattern is consistent with community-acquired MRSA (CA-MRSA).

Prevention

The transmission of MRSA and other infectious agents can be reduced by applying standard infection control measures of hand washing and barrier nursing, efficient cleaning and decontamination of hospital equipment, and actions such as mechanical scrubbing and periodic use of strong disinfectants [9]. In an MRSA-colonized or -infected patient, current recommendations call for patient-dedicated equipment, cohort nursing, regular changes of intravascular catheters, and hydrotherapy [16]. Finally, treatment of infection rather than mere colonization is a major prevention strategy against emergence of more resistant S. aureus [23].

Recent developments

Appropriate infection control practices remain the most important components of the fight against MRSA. A recent study from Rhode Island Hospital showed that it is necessary to screen both patients and health care workers for MRSA, as unrecognized infection in health care workers may function as a reservoir that could impair other control measures [28]. Dansby et al. recently reported that an epidemic of MRSA continued at the Parkland Hospital Burn Unit despite prompt rigorous isolation of identified patients and largely negative personnel cultures [29]. It was only after a renovation that allowed door closure during dressing changes that a sustained decrease in MRSA cases occurred. The authors concluded that rigorous infection control measures, paired with logistic burn unit considerations, are paramount to battle the increasing occurrence of MRSA [29].

Wibbenmeyer et al. examined an outbreak of infection with USA300, a CA-MRSA strain, at the University of Iowa Burn Center [13]. This strain is found in a variety of skin and soft tissue infections, particularly in younger patients. The outbreak caused numerous simultaneous MRSA abscesses. A comparison with a control group, not affected by the aforementioned strain, revealed that infected patients were more likely to have been hospitalized or to have had an operation in the six months before they were hospitalized. The authors concluded that burn patients may be at particular risk for numerous abscesses with USA300. They again stressed that contact precautions and appropriate training of all burn care providers are key to lowering infection rates [13].

Pharmacologic treatment

Aminoglycosides, in particular gentamicin, were historically the antibiotics of choice for the treatment of gram-negative infections. The synergistic activity with penicillinase-resistant penicillins and vancomycin in the treatment of staphylococcal infections standardized their premier status before the advent of newer extended-spectrum penicillins, fourth-generation cephalosporins, monobactams, carbapenems, and quinolones [9]. In a study conducted at the Galveston Shriners Hospital, aztreonam was more effective than amikacin and piperacillin (58.4% vs. 45.8%, respectively) against Enterobacteriaceae. Pseudomonas aeruginosa remained susceptible to aztreonam and piperacillin in 90% of cases, whereas it was resistant to aminoglycosides in 79% of cases [36]. When choosing an antimicrobial drug for a suspected P. aeruginosa burn infection, therefore, aztreonam and piperacillin are now considered the first-line agents [36] at our facility.

Treatment of multi-resistant pathogens

Some strains of P. aeruginosa and Acinetobacter now encountered in burn units are resistant to all the aforementioned antibiotic classes. Over the last 20 years, an increase in resistance of P. aeruginosa to reserve antibiotics such as ceftazidime, and a dramatic decrease in susceptibility of Acinetobacter spp. to ceftazidime and ciprofloxacin, has developed [19]. Meropenem has been identified as an important reserve antibiotic to which most P. aeruginosa and Acinetobacter are susceptible [19], but resistance to the carbapenems has developed [37–39]. A study at eight centers in the United States found that 15% of P. aeruginosa isolates recovered from burn ICUs were resistant to ceftazidime and 20% were resistant to imipenem [40]. Pseudomonas isolates with resistance to ciprofloxacin also have been reported [41]. Outbreaks of P. aeruginosa resistant to most available beta-lactams, aminoglycosides, and fluoroquinolones have been reported in burn units, neurosurgical ICUs, and cancer centers and among patients with cystic fibrosis [42].

For the treatment of emerging multiresistant Pseudomonas and Acinetobacter at the Galveston Shriners Hospital, we were forced to re-introduce an old drug class, the polymyxins. 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 [9]. 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 [43].

According to Storm et al., the polymyxins are bacteriostatic at low concentrations and bactericidal at high concentrations [44]. In early studies, Evans et al. and Nord and Hoeprich reported that at a concentration of 0.01 mcM/mL, polymyxin B sulfate was bactericidal for 88% of the P. aeruginosa strains [42,45]. Full bactericidal activity against P. aeruginosa is not seen until the colistin concentration reaches 0.1 mcM/mL [42]. 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.

Dosing of polymyxins must be altered in patients with renal impairment, as the kidney is their principal route of elimination [43]. Distribution into pleural fluid, joints, and cerebrospinal fluid is poor [42]. 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. When colistin is given to animals or humans, it binds, via free amino acid groups, to negatively charged phospholipids in tissues. Kunin and Bugg showed that binding is greatest to kidney and brain tissues, followed by liver, muscle, and lung [46,47]. After repeated doses, the drug accumulates in tissues to concentrations four to five times higher than the peak serum concentrations and persists for at least five to seven days [46,47]. Drug removal by dialysis can be difficult because of the extensive tissue binding.

Colistin in severely burned pediatric patients: A six-year review

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, we reviewed patients treated at the Galveston Shriners Hospital (previously unreported data). Three hundred ninety-eight patients with burns exceeding 40% TBSA admitted to our hospital between January 2000 and April 2006 were included. Patients who did not contract multi-drug-resistant gram-negative organisms during their hospital courses and received our standard antibiotic regimen—vancomycin and piperacillin/tazobactam—served as controls (piperacillin/tazobactam group; n = 280)(Table 1). The treatment group consisted of burn patients who, during their acute hospital stays, developed infections with multidrug-resistant P. aeruginosa/fluorescence/putida, A. baumannii, E. coli, or K. pneumoniae and who were treated with vancomycin and colistin for at least three days (colistin group; 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 24 h. The primary outcome measures were death; neuronal complications (defined by neuropathies, dizziness, vertigo, apnea, altered mental status, or neuromuscular blockade); hepatic complications (defined by elevated liver enzyme concentrations); and renal dysfunction (defined as an increase in the serum creatinine concentration to more than 50% above the baseline value or a decline in function necessitating renal replacement therapy).

Patients who had multi-resistant gram-negative infections and required colistin therapy had a significantly larger average total and full-thickness burn than patients treated with piperacillin/tazobactam and vancomycin (p < 0.05; Table 2). There was no significant difference between the colistin and piperacillin/tazobactam groups in the incidence of neurotoxicity, hepatic toxicity, or nephrotoxicity (Table 3). However, the mortality rate was significantly higher in the colistin group (p < 0.05; Table 3).

Our data indicate that contracting multi-resistant gram-negative infection causes a higher mortality rate in burn patients than does infection caused by susceptible organisms. Colistin is a safe and efficacious antimicrobial therapy without a marked incidence of in toxic side effects. In a recent review article on the re-emergence of colistin as the antibiotic of choice for multidrug-resistant bacterial infections, Li et al. suggested that the toxicity observed in studies from the 1960s and 1970s may have been caused by a lack of understanding of the drug's pharmacokinetics and toxicodynamics [43]. Most of the studies were performed in pediatric patients who suffered from cystic fibrosis-associated pneumonia caused by multi-drug-resistant organisms. However, recent findings show that close monitoring of renal function and, in patients with kidney failure, measurement of drug concentrations enables avoidance of toxicity [43].

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.

Fungal pathogens

Candida spp. are the fungal pathogens most commonly encountered in the burn patient. Features identified as independent risk factors for disseminated candidiasis in ICU patients are multiple or prolonged courses of antimicrobial treatment, central intravascular catheters, renal dysfunction and hemodialysis, and Candida spp. found in a culture other than blood [64].

Non-albicans Candida spp, such as C. tropicalis, C. parapsilosis, C. krusei, and C. glabrata are the other most commonly isolated species responsible for surgical infections [63]. Particularly virulent fungal organisms include Aspergillus, Fusarium, and Mucormycosis, as summarized in Table 4. At the Galveston Shriners Hospital, Candida albicans, other Candida spp., and Fusarium are the fungal pathogens isolated most frequently (Fig. 3).

Various specialized culture media are used to grow and identify fungal organisms. Several weeks often are required to receive laboratory confirmation and drug sensitivity reports for specific isolates [9]. Microscopic analysis of tissue biopsies provides an alternative diagnostic method. However, correlation between histopathology samples and burn culture identification appears inconsistent in determining fungal infection [62]. This report highlighted the fact that histopathology study alone often was inadequate in distinguishing fungal colonization from infection and emphasized the importance of sending concurrent samples for culture as well as histopathology study in order to identify species and guide therapy [62].

Pharmacologic treatment

The features and therapies for some of the most common fungal organisms encountered in burn patients are summarized in Table 4. Of note, azoles and echinocandins are efficacious and less toxic than amphotericin B for the treatment of patients with candidemia [65]. Although they are better tolerated, there is no evidence that lipid formulations of amphotericin B are superior to amphotericin B deoxycholate for the treatment of candidemia [65]. Voriconazole improved survival and resulted in fewer severe side effects than amphotericin B deoxycholate in the treatment of invasive aspergillosis. However, transient visual disturbances are common [66].

In patients with severe sepsis or septic shock, empirical antifungal therapy should not be given on a routine basis, although it may be justified in patients at high risk for invasive candidiasis, given the fact that fungal infections account for only 5% of these infections [65].

The enhanced efficacy and reduced toxicity of newer drugs offers an improvement in the treatment of serious fungal infections. However, further studies are required to develop and enhance management guidelines for fungal infections in the burn care setting.