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The combination of vancomycin and beta-lactam antibiotic synergistically is known to act on vancomycin-susceptible Staphylococcus aureus (VSSA). But some MRSA with the antagonism in the combination of vancomycin and beta-lactam antibiotic was identified in Japan. We called the MRSA "beta-lactam antibiotic-induced vancomycin-resistant MRSA (BIVR)", to distinguish it from hetero-VISA. The percentage of hetero-VISA isolated in Japan that Hiramatsu et al. reported in The Lancet in 1997 was that of "candidate-hetero-VISA" because it did not satisfy the criteria for detection of hetero-VISA that they proposed. Therefore, except for Mu3, a strictly defined hetero-VISA strain has never been detected in Japan. However, BIVR is certainly detectable in Japan. We performed a retrospective study of BIVR in 189 MRSA strains isolated from blood between 1978 and 1999 at the same institution. To performed a retrospective study, 189 MRSA strains were divided such as 1978-1984 (45strains), 1985-1989 (45strains), 1990-1994 (49strains), 1995-1999 (50strains). MIC90 of anti-MRSA drugs according to above chronological transition were 2, 2, 2, 1 as vancomycin, 2, 1, 1, 1 as teicoplanin, and 8, 8, 1, 1 microgram/mL as arbekacin, respectively, and then the detection rate of BIVR was 2.2, 2.2, 6.1, 10.4%, respectively. The BIVR detection rate in MRSA isolated from blood at 14 institutions was 14.8% (12/81) in 1999-2002, and that of non-blood was 4.6% (42/905) (p < 0.001; chi 2-t examination). Of particular importance is that the percentage of BIVR isolated from blood is higher than that from non-blood, and the detection rate of BIVR from blood increases annually.

Fuminori Sakai1, Hideaki Hanaki2, Kazunari Barada4, Yuriko Hirao1, Takashi Inamatsu5, Taiji Nakae2, Keisuke Sunakawa31Laboratory of Infectious Diseases, Graduate School of Infection Control Sciences, 2Research Center for Anti-Infectious Drugs, Kitasato Institute, 3Department of Research Project Studies, Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan; 4Department of Pharmacy, General Ota Hospital, Society of Health Insurance of Fuji Heavy Industries Ltd, Gunma, Japan; 5Department of Infectious Diseases, Tokyo Metropolitan Geriatric Hospital, Tokyo, JapanAbstract: We analyzed 218 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from the septicemia patients in a geriatric hospital for 25 years. These strains were classified into 11 major DNA types, A through K, and 27 minor types. The strains belonging to group A and B isolated before 1990 were susceptible to imipenem (IPM), fluoroquinolone, and most other antibiotics tested, except that they were markedly resistant to gentamicin. Strains mostly isolated in 1985 and thereafter were classified into group C through K, and they were mainly resistant to IPM, fluoroquinolones, and clindamycin. Analysis of the MRSA marker gene, staphylococcal cassette chromosome mec (SCCmec), of these strains revealed that the strains in groups A and B had mainly type IV and type I, respectively, and that strains in groups C through J had mainly type II. These results suggested that the strains holding type II SCCmec were resistant to IPM, fluoroquinolone, and clindamycin and they were dominant-resistant type after late 1980s. The antibiotic resistance profiles of MRSA dramatically changed during late 1980s, and these were correlated with the SCCmec types. The lesson from this study would be that consistent execution of surveillance study is needed to update the resistant profiles.Keywords: methicillin-resistant Staphylococcus aureus, DNA typing, antibiotic resistance, survey, geriatric hospital

We investigated trends of beta-lactam antibiotic susceptibility in a total of 218 strains of blood-borne methicillin-resistant Staphylococcus aureus (MRSA) isolated from 1978 through 2002 at a middle-size geriatric hospital in Tokyo; the strains were classified by the MRSA marker, staphylococcal cassette chromosome mec (SCCmec). The minimum growth inhibitory concentration (MIC) of cloxacillin at which 50% of the strains were inhibited (MIC50) was 2 microg/ml in the strains isolated in 1978-1984 and 32 to 64 microg/ml in the strains isolated subsequently. Similarly, the MIC50 values of cefazolin and imipenem in the 1978-1984 isolates were 16 andor=0.25 microg/ml, respectively, and those in the strains isolated subsequently were 128 and 16 to 32 microg/ml, respectively. These results indicated that the MRSA strains isolated after 1985 had gained high-level resistance to beta-lactam antibiotics. The type of SCCmec was investigated by polymerase chain reaction (PCR). We observed an elevated frequency of type II SCCmec, from about 15% in the strains isolated in 1978-1984 to about 50% in the 1985-1989 isolates, and the frequency reached and remained at about 90% subsequently. These results imply that the high-level beta-lactam antibiotic resistance of the MRSA strains isolated after 1985 is most likely due to the increased integration of type II SCCmec.

It is generally accepted that methicillin-resistant Staphylococcus aureus (MRSA) is also resistant to aminoglycoside antibiotics. We investigated trends of gentamicin and arbekacin susceptibilities and the prevalence of the genes encoding aminoglycoside-modifying enzymes (AMEs) for a total of 218 strains of MRSA isolated from blood specimens obtained from 1978 through 2002 in one hospital. The minimum inhibitory concentrations of gentamicin at which 50% of the strains were inhibited (MIC(50)) wereor =128 and 32 microg/ml for isolates obtained from 1978 to 1984 and from 1985 to 1989, respectively, and 0.5 microg/ml for isolates obtained from 1990 to 2002. The MIC(90) of gentamicin was consistentlyor =128 microg/ml. Investigation of the occurrence of AME revealed that the MIC(50) of gentamicin was highly correlated with the presence of aac(6')/aph(2'') encoding aminoglycoside acetyl/phosphotransferase. The MIC(50) of arbekacin was 2 microg/ml for strains isolated in 1978-1984 and/=0.5 microg/ml for strains isolated from 1985 to 2002. The MIC(90) of arbekacin was 8 microg/ml for the strains isolated in 1978-1989 and 1 to 2 microg/ml for strains isolated in 1990-2002. Though it has been established that AAC(6')/APH(2'') modifies arbekacin, the trend of arbekacin resistance was not necessarily consistent with the presence of this enzyme. However, the prevalence of both aac(6')/aph(2'') and aph(3')-III in the strains isolated from 1978 through 2002 was correlated with the MIC(90) values of arbekacin. Thus, it is most likely that APH(3')-III, in addition to AAC(6')/APH(2''), is somehow involved in arbekacin resistance in S. aureus. Our results imply that gentamicin- and arbekacin-resistant MRSAs have consistently decreased for the past 25 years and that this finding is, most likely, attributable to the declining prevalence of genes encoding for AMEs.

We could not detect hetero-vancomycin-intermediate resistant Staphylococcus aureus (hetero-VISA), according to the definition of hetero-VISA, from the clinical isolates of 140 methicillin-resistant S. aureus (MRSA) strains. However, 15 beta-lactam antibiotic-induced vancomycin-resistant MRSA (BIVR) strains were detected from the same strains. We screened 1882 MRSA clinical isolates obtained in 2002 from 21 institutes throughout Japan. The detection rate of blood-isolated BIVR was 12.6% (19/151), and that of nonblood-isolated BIVR was 4.9% (85/1731; P0.001; chi2 test). Uridine-diphosphate-N-acetylmuramyl-L: -alanyl-D: -isoglutamyl-L: -lysine, used as the peptidoglycan material of S. aureus, showed the same results as beta-lactam antibiotics in BIVR.