Early ReportDissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin
Introduction
For more than 30 years, vancomycin has been a reliable treatment for gram-positive bacterial infection. In Japan, injectable forms of vancomycin were introduced in 1991, and have been used exclusively for methicillin-resistant Staphylococcus aureus (MRSA) infection. Nevertheless, the mortality rate due to MRSA infection changed little with the introduction of vancomycin in Japan.1 According to a 1995 nationwide survey of vancomycin efficacy, therapeutic failure occurred in 21·3% of 845 MRSA pneumonia cases, while MRSA infection persisted in as much as 35·8% of patients after therapy for lowerrespiratory-tract infections.2 In recent years, S aureus clinical isolates with resistance to teicoplanin, a glycopeptide antibiotic closely related to vancomycin, have been reported.3, 4, 5 S aureus produces resistant mutants more readily against teicoplanin than against vancomycin, and the resultant teicoplanin-resistant mutants are cross-resistant to vancomycin.6 However, teicoplanin has not yet been approved for clinical use in Japan. Thus, isolation of the first strain of MRSA resistant to vancomycin (VRSA), Mu50 (vancomycin minimum inhibitory concentration [MIC] 8 mg/L), from a Japanese surgical patient with a wound infection was unexpected.7
We suspected that Japanese MRSA strains, represented by clonotype II-A,8 had the potential to generate VRSA more readily than MRSA strains from other parts of the world. There has also been speculation that vancomycin therapeutic failure occurs in patients infected with MRSA strains susceptible to vancomycin MICs of 4 mg/L or less.9 We investigated the prevalence of vancomycin resistance in clinical MRSA isolates from Japanese hospitals.
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Bacterial strains
Mu50 (the first VRSA isolate) has been described previously.7 Mu3 was a clinical MRSA strain isolated in January, 1996, from a 64-year-old Japanese man who had MRSA pneumonia after an operation for primary lung cancer. Treatment with vancomycin (42 mg/Kg per day) for 12 days was ineffective and the pneumonia worsened during the last 4 days of therapy. The patient was then treated successfully with a 10-day course of ampicillin/sulbactam and arbekacin.7 Mu3 was isolated from purulent sputum
Hetero-VRSA strain Mu3
Figure 1 shows a comparison of the population analysis of Mu3 and Mu50 with vancomycin-susceptible MRSA H1 and S aureus FDA209P. 100% of Mu50 cells grew in 4 mg/L of vancomycin, and 0·001% of the population grew in the presence of 10 mg/L vancomycin. Mu3 was more susceptible to vancomycin than Mu50 as evidenced by the inhibition of 99·99% of the population by 4 mg/L of vancomycin. Nevertheless, Mu3 contained resistant subpopulations that grew in the presence of 5-9 mg/L vancomycin. Therefore,
Discussion
Vancomycin therapeutic failure in MRSA infection has been largely attributed to the poor health of patients with underlying diseases, malnutrition, post-surgery intubations, or decreased white-blood-cell counts. However, the role of reduced vancomycin susceptibility of MRSA isolates has not been investigated rigorously. We report a patient with pneumonia refractory to vancomycin caused by a MRSA strain, Mu3, with heterogeneous vancomycin resistance. Although Mu3 was susceptible to vancomycin
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