Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin

doi:10.1016/S0140-6736(97)07324-8

The Lancet

Volume 350, Issue 9092, 6 December 1997, Pages 1670-1673

https://doi.org/10.1016/S0140-6736(97)07324-8 Get rights and content

Summary

Background

Since the discovery of the vancomycin-resistant Staphylococcus aureus (VRSA) strain Mu50 (minimum inhibitory concentration [MIC] 8 mg/L), there has been concern about the potential spread of such strains throughout Japanese hospitals. Two important questions need to be answered: (1) what is the prevalence of VRSA, and (2) by what mechanism does vancomycin resistance occur.

Methods

The vancomycin susceptibilities of three methicillin-resistant S aureus (MRSA) strains (Mu50, Mu3, and H1) and the methicillin-susceptible S aureus type strain FDA209P were compared by MIC determinations and population analysis. Mu3 (MIC 3 mg/L) was isolated from the sputum of a patient with pneumonia after surgery who had failed vancomycin therapy. H1 (MIC 2 mg/L), which is a representative vancomycin-susceptible MRSA strain, was isolated from a patient with pneumonia who responded favourably to vancomycin therapy. Subclones of Mu3 with increased resistance against vancomycin were selected with serial concentrations of vancomycin and their MICs were determined. The prevalence of VRSA and Mu3-like strains in Japanese hospitals was estimated by population analysis from 1149 clinical MRSA isolates obtained from 203 hospitals throughout Japan. The genetic traits of the Mu3 and Mu50 strains were compared with clonotypes of MRSA from around the world.

Findings

Mu3 and Mu50 had an identical pulsed-field gel electrophoresis banding pattern. When grown in a drug-free medium, Mu3 produced subpopulation of cells with varying degrees of vancomycin resistance, thus demonstrating natural heterogeneity, or variability, in susceptibility to vancomycin. In the presence of vancomycin, Mu3 produced subclones with resistance roughly proportional to the concentrations of vancomycin used. Selection of Mu3 with 8 mg/L or more of vancomycin gave rise to subclones with vancomycin resistance equal to that of Mu50 (MIC 8 mg/L) at a frequency of 1/1000000. During screening of Japanese MRSA strains, no strain of VRSA additional to Mu50 was found. The prevalence of MRSA isolates heterogeneously resistant to vancomycin was 20% in Juntendo University Hospital, 9·3% in the other seven university hospitals, and 1·3% in non-university hospitals or clinics.

Interpretation

Heterogeneously resistant VRSA is a preliminary stage that allows development into VRSA upon exposure to vancomycin. Heterogeneously resistant VRSA was found in hospitals throughout Japan. This finding could explain, at least partly, the frequent therapeutic failure of MRSA infection with vancomycin in Japan.

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.

Section snippets

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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Early ReportDissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Bacterial strains

Hetero-VRSA strain Mu3

Discussion

J Infect Chemother

J Infect Chemother

Therapeutic strategy for MRSA infections

Clinical summary of intravenous use of vancomycin hydrochloride for severe infection caused by methicillin-resistant Staphylococcus aureus

Jpn J Chemother

Emergence of teicoplanin resistance during therapy of Staphylococcus aureus endocarditis

J Infect Dis

Failure of teicoplanin therapy in two neutropenic patients with staphylococcal septicaemia who recovered after administration of vancomycin

Eur J Clin Microbiol Infect Dis

Decreased teicoplanin susceptibility of methicillin-resistant strains of Staphylococcus aureus

J Infect Dis

Teicoplanin selects for Staphylococcus aureus that is resistant to vancomycin

Clin Infect Dis

Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility

Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, fourth edition: approved standard, M7-A4

Molecular evolution of MRSA

Microbiol Immunol

Tests for bactericidal effects of antimicrobial agents: technical performance and clinical relevance

Clin Microbiol Rev

Early Report
Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin