Stability of the MICs of various antibiotics in different clonal populations of methicillin-resistant Staphylococcus aureus (1998)

Sir, We read with interest the recent report by Hiramatsu et al. of the first isolation of a strain of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin. To date, clinical isolates of S. aureus have been uniformly susceptible only to glycopeptide antibiotics which have consequently become the drugs of choice for the treatment of patients with MRSA infections. However, as vancomycin-resistant isolates of S. aureus are likely to become more widespread, alternative antibiotics with activities against MRSA are needed urgently. Although arbekacin and ampicillin/sulbactam were used successfully to eradicate the Japanese isolate, thereby demonstrating the efficacy of existing non-glycopeptide drugs, little is known about the stability of the MICs of alternative compounds over time. In order to assess this property in clonally related MRSA strains isolated in the Dusseldorf area, we determined the MICs of a broad range of antimicrobial agents for 125 such isolates recovered over a period of 3 years. The test isolates were selected from a collection of 489 MRSA strains from 183 different patients; the organisms had been referred to the Institute for Medical Microbiology and Virology, University Hospital Dusseldorf, between 1992 and 1995 by 11 regional hospitals. From these 489 strains, 183 were chosen for typing studies on the basis that they were the first isolates recovered from any site of a colonized or infected patient. All isolates were typed by pulsed-field gel electrophoresis (PFGE) which is regarded as the most discriminatory molecular technique for typing MRSA strains. This procedure identified 28 distinct MRSA types, of which the three most common were types 1, 2 and 3 (comprising 75, 38 and 12 isolates respectively); these have been shown to be the predominant PFGE types found in western Germany. Carriage of the mecA and coa genes by the 125 isolates belonging to the three PFGE types was confirmed with a multiplex PCR. Type 1 MRSA strains were isolated between July 1992 and June 1995 from 29 wards in five hospitals throughout the region. Those belonging to MRSA type 2 were isolated between November 1992 and April 1995 from 19 wards in three hospitals, while those belonging to MRSA type 3 were isolated between September 1994 and January 1995 from five wards in three hospitals. The MICs of 20 antimicrobial agents for the 125 strains belonging to PFGE types 1, 2 and 3 were determined by a microbroth dilution method recommended by the National Committee for Clinical Laboratory Standards (NCCLS); the inoculum was approximately 10 cfu/L. All of the isolates were resistant to penicillin (MICs 32 mg/L), ampicillin (MICs 32 mg/L), amoxycillin– clavulanate (MICs 32 mg/L), piperacillin–tazobactam (MICs 128 mg/L), oxacillin (MICs 64 mg/L), imipenem (MICs 16 mg/L), ceftriaxone (MICs 32 mg/L), gentamicin (MICs 16 mg/L), tetracycline (MICs 8 mg/L), rifampicin (MICs 2 mg/L), erythromycin (MICs 16 mg/L) and clindamycin (MICs 8 mg/L). The MICs of the remaining agents are shown in the Table. All of the isolates were susceptible to the glycopeptides, vancomycin and teicoplanin, the MICs of these agents remaining stable over the range 0.5–1 mg/L. Despite reports of the development of low-level vancomycin resistance in clinical isolates of coagulase-negative staphylococci and the first report of reduced susceptibility to vancomycin in S. aureus, no increase in the MICs of glycopeptides for MRSA strains isolated in Dusseldorf was observed. These antibiotics therefore remain the drugs of choice for patients with MRSA infections, both in the Dusseldorf area and, indeed, throughout western Germany where the same PFGE types predominate. The combination of quinupristin and dalfopristin (Synercid) was highly active against all of the MRSA isolates tested; moreover, the MICs were stable over the range 0.25–1 mg/L during the study period. As the combination is also active in vitro against strains exhibiting inducible MLS (macrolide, lincosamide and streptogramin-B) resistance, quinupristin and dalfopristin being poor inducers of the methylase (erm) genes, it shows promise as an alternative to the glycopeptides in patients with MRSA infections.