Clinical Outcomes by Methicillin-Resistant Staphylococcus aureus Staphylococcal Cassette Chromosome mec Type: Isolates Recovered from a Phase IV Clinical Trial of Linezolid and Vancomycin for Complicated Skin and Skin Structure Infections

Abstract

Worldwide, Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is the most frequently identified pathogen causing complicated skin and skin structure infections (cSSSI). The increasing prevalence of MRSA isolates causing cSSSI is a significant therapeutic problem. MRSA isolates are classified according to the type of staphylococcal cassette chromosome mec (SCCmec), a mobile genetic element that harbors the mecA gene and other resistance determinants. In the United States, health care-associated MRSA (HA-MRSA) is associated with SCCmec types I, II, and III, and community-associated MRSA (CA-MRSA) is associated with SCCmec type IV. Most U.S. CA-MRSA isolates obtained from cSSSI carry the gene encoding Panton-Valentine leukocidin (PVL), a pore-forming exotoxin known to induce cell death by necrosis or apoptosis. At one medical center, SCCmec type II was associated with increased mortality compared with type IVa (33% versus 14%) (1). In these analyses, we sought to determine the impact of the MRSA SCCmec type on the outcome of patients with cSSSI treated with linezolid and vancomycin. Patients were treated with 600 mg linezolid orally or intravenously every 12 h or 15 mg/kg of body weight vancomycin intravenously every 12 h, with dose adjustment based on trough levels and creatinine clearance, for up to 28 days. A total of 465 MRSA isolates were identified from 2004 to 2007 (2). MRSA isolates were obtained by fine-needle aspiration, tissue biopsy, or collection of debridement tissue from patients with cSSSI. Isolates were identified by local laboratories using routine methods and sent to a central laboratory for confirmation of identification and susceptibility testing. MICs to study drugs were determined by broth microdilution according to Clinical and Laboratory Standards Institute guidelines. All isolates were submitted for SCCmec typing (I to IV) using a multiplex PCR strategy and were screened for PVL-encoding genes by multiplex PCR using PVL-specific primers as previously described (3). Clinical and microbiological outcomes were evaluated at 6 to 28 days after the last dose of a study drug. Clinical success was defined by resolution of clinical signs and symptoms of infection that were identified at baseline. Type IV (PVL positive), which corresponds to CA-MRSA, was the most common SCCmec type identified (n = 236). The clinical and microbiological outcomes by SCCmec type for linezolid and vancomycin are shown in Fig. ​Fig.11 and ​and2,2, respectively. The vancomycin clinical success rate for CA-MRSA isolates with a vancomycin MIC of 2 μg/ml as determined by broth microdilution was 50% (1 cure and 1 failure), and for HA-MRSA, it was 50% (5 cures and 5 failures). The distribution of vancomycin MICs by SCCmec type is shown in Table ​Table1.1. No MRSA isolate had a vancomycin MIC of >2 μg/ml. In the linezolid treatment group, no CA-MRSA and four HA-MRSA isolates had a vancomycin MIC of 2 μg/ml. The linezolid clinical success rate for these HA-MRSA isolates was 100%. The MIC90 values for linezolid and vancomycin were 2 μg/ml and 1 μg/ml, respectively. FIG. 1. Clinical success by MRSA SCCmec type. The differences and 95% confidence intervals (in parentheses) between linezolid and vancomycin were as follows: type I, 1% (25.3, −23.3); type II, 11% (31.0, −7.3); type III, ... FIG. 2. Microbiological success by MRSA SCCmec type. The differences and 95% confidence intervals (in parentheses) between linezolid and vancomycin were as follows: type I, 3% (29.3, −24.0); type II, 25% (46.2, 4.5); type III, ... TABLE 1. Distribution of vancomycin MICs by MRSA SCCmec type All isolates were screened for the presence of heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA) using the Etest macromethod as described by Wootton et al. (4). Overall, five isolates were characterized as hVISA; none were CA-MRSA. Three patients who received linezolid had successful clinical and microbiologic outcomes, while 1 of 2 patients who received vancomycin was assessed as a failure (Table ​(Table22). TABLE 2. SCCmec types, study drug MICs, and outcomes for hVISA isolates The clinical and microbiological outcomes were independent of SCCmec type for linezolid and vancomycin. No differences in mortality were noted between treatment groups by SCCmec type. These findings suggest that linezolid and vancomycin are clinically effective for the treatment of MRSA of all SCCmec types, both HA-MRSA SCCmec types I, II, and III and CA-MRSA SCCmec type IV, among patients with cSSSI.