Thursday, October 25, 2007

Antibiotic Selection for Infections Involving Methicillin-Resistant Staphylococcus aureus

Antibiotic Selection for Infections Involving Methicillin-Resistant Staphylococcus aureus

John G. Bartlett, MD

Choosing Appropriate Therapy for MRSA

The mainstay antibiotic for treatment of infections caused by MRSA has been vancomycin, a drug that was approved by the US Food and Drug administration (FDA) in 1956 but not used extensively until the last 20 years.[1] The escalating use of vancomycin is attributed to the increase in nosocomial infections caused by MRSA from 2% in 1974 to more than 50% in 2000.[1,21] Vancomycin is used mainly to treat patients with infections caused by MRSA, patients with infections caused by gram-positive bacteria in whom beta-lactam antibiotics are contraindicated, and patients with device- and catheter-associated infections.

Vancomycin has established efficacy and is currently recommended for endocarditic prophylaxis in penicillin-allergic patients undergoing invasive genitourinary or gastrointestinal procedures likely to result in transient bacteremia.[22] However, there are major concerns with the use of this drug. First, rapid infusion with vancomycin is associated with histamine release syndrome (red man syndrome), which usually can be corrected by slow infusion. However, 3% to 4% of patients appear to have true hypersensitivity reactions expressed as a maculopapular rash, and a small percentage have reversible marrow suppression.[21,23] Second, vancomycin is not available in an oral formulation for treatment of systemic infection, so patients are exposed to the risks and expenses of intravenous therapy. Third, some clinicians question the potency of vancomycin in selected settings because of slow clinical responses, clinical failures, and high rates of relapse.[24-28] Finally, many clinicians are concerned about the clinical significance of reduced susceptibility with VISA strains and the threat of vancomycin-resistant S aureus (VRSA).[17,18,29-31] Although the clinical significance of VISA is unclear,[16,29-31] the emergence of this organism alarmed those concerned about possibility of a vancomycin resistant strain. This became a reality in 2002, when the Centers for Disease Control and Prevention (CDC) published reports of 2 patients with infections caused by VRSA.[17,32] In both cases, the isolates contained the vanA gene of vancomycin resistance, presumably by transfer from vancomycin-resistant enterococci (VRE) at a co-infected site.

In April 2004, the CDC reported on the third documented clinical isolate of VRSA, which was obtained from a long-term care facility resident in New York.[33] On March 17, 2003, the isolate yielded S aureus, and laboratory tests indicated that it was resistant to vancomycin. Further testing revealed that the isolate contained both the mecA and vanA genes; however, the CDC states that the isolate appears unrelated epidemiologically to the 2 previously identified VRSA isolates. Although the New York isolate contained the vanA gene, the vancomycin MIC of the isolate appeared low when initially tested by an automated method. Vancomycin resistance was revealed using the broth microdilution reference method, a nonautomated testing technique. The CDC concluded that additional VRSA infections might have occurred but were undetected by laboratories using automated methods and recommends that potential VRSA isolates should be saved for confirmatory testing using nonautomated methods such as broth microdilution, agar dilution, or agar-gradient diffusion. The patient remains in a long-term care facility, and the New York State Department of Health continues to investigate this case

In the past 5 years, the FDA has approved 3 alternatives to vancomycin for treatment of infections caused by MRSA: quinupristin-dalfopristin, linezolid, and daptomycin. These agents have good in vitro activity against MRSA and most other clinically important gram-positive bacterial pathogens. A general comparison of these drugs is summarized in Table 3.

In addition, important advantages and disadvantages of these drugs include the following:

Quinupristin-dalfopristin is the first agent in the streptogramin class. It is indicated for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium bacteremia and complicated skin and skin structure infections caused by S aureus and S pyogenes.[34] Investigators conducted a randomized, open-label, controlled clinical trial comparing quinupristin-dalfopristin 7.5 mg/kg q12h IV (n=221) with cefazolin 1g q8h IV (n=222) in the treatment of complicated skin and skin structure infections caused by suspected or confirmed MRSA. One hundred thirteen patients (51%) and 120 patients (54%) in the quinupristin-dalfopristin and cefazolin groups, respectively, were found to be clinically evaluable. Of these patients, the success rate was 66% in the quinupristin-dalfopristin group and 64% in the cefazolin group. In another trial, quinupristin-dalfopristin 7.5 mg/kg q12h IV (n=229) was compared with oxacillin 2 g q6h IV (n=221). Of the 105 patients (46%) in the quinupristin-dalfopristin arm and the 106 patients (48%) in the cefazolin arm who were found to be clinically evaluable, the success rate was 50% for those taking quinupristin-dalfopristin and 52% for those on cefazolin therapy.

The drug has a curious sensitivity profile, with activity against vancomycin-resistant E faecium but not against Enterococcus faecalis. Quinupristin-dalfopristin has been associated with venous irritation, which can be avoided if the drug is infused through a central line, and also with high rates of injection site reactions and often debilitating myalgias.

Linezolid is the first drug in the oxazolidinone class and is available in both oral and parenteral formulations. The oral formulation is nearly 100% bioavailable and is thus interchangeable with the parenteral formulation.[35] Linezolid is indicated in the treatment of vancomycin-resistant E faecium infections, nosocomial pneumonia caused by S aureus (methicillin-susceptible and -resistant strains) of Streptococcus pneumoniae (penicillin-resistant strains), complicated skin and skin structure infections including diabetic foot infections without concomitant osteomyelitis caused by S aureus, S pyogenes, and S agalactiae, and community-acquired pneumonia caused by S pneumoniae or S aureus.

In a randomized, multicenter, double-blind, double-dummy trial, 400 patients received linezolid 600 mg IV q12h followed by 600 mg PO q12h, and 419 patients received oxacillin 2g IV q6h followed by dicloxacillin 500 mg PO q6h. Two hundred forty-five (61%) patients in the linezolid arm and 242 patients (58%) in the oxacillin-dicloxacillin arm were clinically evaluable.

Cure rates were 90% in the linezolid group and 85% in the oxacillin-dicloxacillin group. The most common adverse events are nausea, vomiting, diarrhea, and headache, and cases of linezolid resistance have been reported.

Daptomycin is the most recent addition and represents a new class of antibiotics. Clinical trials showed good results in skin and soft tissue infections.[36] Adult patients with clinically documented complicated skin and skin structure infections were enrolled in 2 randomized, multinational, multicenter, investigator-blinded studies. One study was conducted primarily in the United States and South Africa, and the other was conducted at non-US sites only. A total of 534 patients received daptomycin 4 mg/kg IV q24h and 558 patients received the comparator drug, which consisted of either vancomycin 1 g q12h or a semisynthetic penicillin (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 4-12 g IV per day). In the first study, clinical success rates in the clinically evaluable population were 76% (158/208) in the daptomycin group and 77% (158/206) in the comparator group. In the second study, clinical success rates in the clinically evaluable population were 89% (214/238) in patients taking daptomycin and 91% (226/250) in those treated with comparator drugs.

However, the failure rate of daptomycin was excessive in a controlled trial for community-acquired pneumonia. This observation is thought to be attributable to relatively poor penetration into epithelial lining fluid in the lung. Some authorities conclude that daptomycin may have a therapeutic niche with endocarditis caused by MRSA or VRE because of results in an animal model.[37] The most common adverse events include gastrointestinal disorders, general disorders (ie, injection site reactions, fever), and nervous system disorders.


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