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Journal of Clinical Microbiology, October 2000, p. 3879-3881, Vol. 38, No. 10
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Vancomycin-Intermediate Staphylococcus
aureus in Korea
Mi-Na
Kim,1,*
Chik Hyun
Pai,1
Jun Hee
Woo,2
Ji So
Ryu,2 and
Keiichi
Hiramatsu3
Department of Clinical
Pathology1 and Department of Internal
Medicine (Infectious Diseases),2 University
of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea,
and Department of Bacteriology, Juntendo University, Tokyo,
Japan3
Received 18 February 2000/Returned for modification 19 April
2000/Accepted 18 July 2000
 |
ABSTRACT |
Recent reports on some methicillin-resistant Staphylococcus
aureus (MRSA) with reduced susceptibility to vancomycin have been a major concern in Korea because of the widespread use of vancomycin due to a high prevalence of MRSA in the country. We describe a 45-year-old man with long-standing pelvic abscess due to MRSA. In spite
of vancomycin and teicoplanin treatment for a long period of time, the
patient died from MRSA sepsis. The blood culture isolate of MRSA
exhibited reduced susceptibility to vancomycin (MIC, 8 µg/ml). This
is the first report of a vancomycin-intermediate S. aureus
case from Korea.
| |
TEXT |
Case report.
A 45-year-old man from a Seoul suburb who had
sigmoid colon cancer was admitted to Asan Medical Center in April 1997. The patient had signs of liver metastasis and bowel perforation on abdominopelvic computerized tomography and was discharged with a
scheduling for chemotherapy after diagnostic workup. He was readmitted
10 days later due to fever, chills, and an abdominal mass; his blood
culture grew Bacteroides uniformis, and fever continued
spiking above 38°C in spite of antibiotic therapy with amikacin,
ceftizoxime, and metronidazole for 2 weeks. He had a transverse loop
colostomy at hospital day (HD) 19; a huge tumor mass was adhered to the
abdominal wall in the sigmoid colon, but no evidence of a perforation
of the sigmoid colon or abscesses was found during the operation.
However, follow-up computerized tomography revealed clearly a pelvic
abscess, for which a pigtail catheter was inserted at HD 30, and the
purulent drainage grew methicillin-resistant Staphylococcus
aureus (MRSA) and then MRSA and Escherichia coli on
four separate occasions until HD 69. The MRSA isolates were resistant
to ciprofloxacin, clindamycin, erythromycin, gentamicin, and
tetracycline but susceptible to rifampin, cotrimoxazole, and vancomycin
(MIC; 
2 µg/ml) in MicroScan PosCombo 6 (Dade-Behring, West Sacramento, Calif.). The patient was
treated with vancomycin (2 g per day) for 8 days, followed by
teicoplanin (200 mg per day) for 30 days in combination with
ciprofloxacin and metronidazole. C-reactive protein was 3.8 mg/dl, and
leukocyte counts ranged from 11,800 to 38,200/µl with 82 to 98%
neutrophils. When he was discharged at HD 94, fever had subsided for a
week, C-reactive protein was 1.6 mg/dl, and the pigtail catheter
was withdrawn. During that admission, he had received palliative
chemotherapy with flucytosine-cisplatin and flucytosine-palladium
regimens consecutively. However, 2 weeks later he was readmitted
for the third time via the Emergency Department on 8 August 1997; he
was septic and revealed an abdominal mass 20 cm in diameter. The blood culture grew MRSA, which showed the same antibiogram as previous isolates, but the vancomycin MIC was now 4 µg/ml by MicroScan. He was
treated with vancomycin, ciprofloxacin, and metronidazole but expired 2 weeks later.
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FIG. 1.
Population analysis for resistant subpopulations of
AMC11094 and Mu50. The curves are comparable.
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|
Laboratory investigation.
With the report of the first
vancomycin-intermediate S. aureus (VISA) from Japan followed
by similar reports from the United States (1, 4, 10, 11), we
at Asan Medical Center (AMC) begun to look for VISA in clinical
isolates. All S. aureus strains isolated during the 8-month
period from January to August 1999 were screened for VISA and
heterogeneous VISA using brain heart infusion agar containing 4 µg of vancomycin per ml (BHI-V4) (5). Ten microliters of
each bacterial suspension (McFarland 0.5) was inoculated on BHI-V4 and
incubated at 37°C for 48 h. Vancomycin-susceptible MRSA
strain H1 and heterogeneous-VISA strain Mu3 were used as controls
(5). Strains forming one or more colonies on BHI-V4 within
48 h of incubation were tested for MICs and population analysis
for vancomycin (5). Of 4,483 S. aureus strains
screened, 58 strains, all of which were MRSA, grew on BHI-V4, but no
VISA strains were identified; the MIC for all was less than 4 µg/ml. Subsequently, we tested an additional 60 MRSA strains which had been
isolated from blood cultures during 1997-1998 and stored at 
70°C.
One of those strains, AMC11094, grew confluently on BHI-V4 after
24 h of incubation. Susceptibility tests were performed by the
National Committee for Clinical Laboratory Standards (NCCLS) broth
microdilution method using cation-adjusted Mueller-Hinton broth
(8). The MICs for strain AMC11094 were as follows:
vancomycin, 8 µg/ml; teicoplanin, 16 µg/ml; oxacillin, >128
µg/ml; clinidamycin, >128 µg/ml; erythromycin, >128
µg/ml; ciprofloxacin, 64 µg/ml; rifampin, 0.006 µg/ml;
gentamicin, 0.5 µg/ml; and quinupristin-dalfopristin, 0.5 µg/ml.
The MICs of vancomycin and teicoplanin by E-test were also 8 and 16 µg/ml, respectively. A population analysis was performed by spreading
100 µl of the starting cell suspension (McFarland 0.5) and its serial
diluents onto BHI agar plates containing 1 to 15 µg of vancomycin per
ml in 1-µg/ml increments and counting the number of colonies after
24 h of incubation at 35°C (5); AMC11094 was
indistinguishable from Mu50 (Fig. 1), the first VISA strain reported by
Hiramatsu et al. (4). PCRs for the enterococcal vancomycin
resistance genes vanA, vanB,
vanC1, and vanC2/3
(7) were all negative. Transmission electron microscopy
showed that the cell wall of AMC11094 was two or three times thicker
than that of Mu3 (3, 9) and S. aureus ATCC 25923 (Fig. 2). In addition, pulsed-field gel
electrophoresis (PFGE) of SmaI-restricted chromosomal DNA
(M. N. Kim, J. S. Park, J. S. Jeong, J. S. Choi, and C. H. Pai, Abst. 38th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. K-125, p. 538, 1998) revealed that AMC11094 differed
from Mu50 and Mu3 by more than 10 bands (Fig.
3).
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FIG. 2.
AMC11094 (c) shows rough, thick cell walls compared to
ATCC25923 (a) and Mu3 (b). All of them were grown overnight on a blood
agar plate. Bars, 200 nm.
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|
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FIG. 3.
Patterns of SmaI-digested DNA of S. aureus isolates on PFGE. Lane S, phage lambda size standards; lane
1, Mu50 (Japanese VISA); lane 2, Mu3 (Japanese heterogenous-VISA); lane
3, AMC11094. Note that the PFGE pattern of AMC11094 differs from those
of Mu50 and Mu3 by more than 10 bands.
|
|
Discussion.
As in the previous reports of VISA (3, 4, 10,
11), the patient had been treated with vancomycin and teicoplanin for a long time before the resistant strain emerged, and the resistance in AMC11094 was also associated with an increase in the cell wall, while an enterococcal vancomycin resistance gene was not
detected. In PFGE analysis, AMC11094 was different from Mu50, as
were U.S. isolates of VISA (11, 13). Although all isolates
from the United States, Japan, and Korea have a thickened cell wall,
which suggested sequestration of vancomycin as a common mechanism of resistance (3), they do not represent a single clone of MRSA that has disseminated. Those findings suggested that VISA has emerged
by cellular modification under antibiotic pressure rather than by
acquisition of a resistance gene from other strains, such as
vancomycin-resistant enterococci, or by international transmission of
resistant clones, as shown for drug-resistant Streptococcus pneumoniae (12).
When AMC11094 was first isolated from the patient's blood culture, the
strain was considered susceptible to vancomycin because
routine
susceptibility testing showed a MIC of vancomycin of 4
µg/ml. In the
U.S. VISA case, for which the MIC of vancomycin
was 4 µg/ml by
MicroScan but 8 µg/ml by NCCLS broth microdilution
method
(
13). MRSA with a vancomycin MIC of 4 µg/ml by commercial
susceptibility test should be investigated further, as the recent
NCCLS
guideline has recommended (
9).
Vancomycin is one of the most frequently prescribed antimicrobial
agents in tertiary-care hospitals in Korea (continuous quality
improvement of antibiotic use, Asan Medical Center, 1998; unpublished
data), because of a high prevalence of MRSA, especially in nosocomial
infections (
2,
6). The emergence of
S. aureus
with an intermediate
resistance to vancomycin in a Korean university
hospital is a
warning to us that VISA may soon become a global problem
unless
antimicrobial agents are used more prudently. The clinical
laboratory
should identify and report strains with reduced
susceptibility
to vancomycin, including VISA, promptly for appropriate
treatment
of patients and start implementing infection control
precautions
to prevent the spread of
resistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Clinical Pathology, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea. Phone: 82-2-2224-4511. Fax: 82-2-478-0884. E-mail: mnkim{at}www.amc.seoul.kr.
| |
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Journal of Clinical Microbiology, October 2000, p. 3879-3881, Vol. 38, No. 10
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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