High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study).
ABSTRACT A total of 685 clinical Streptococcus pneumoniae isolates from patients with pneumococcal diseases were collected from 14 centers in 11 Asian countries from January 2000 to June 2001. The in vitro susceptibilities of the isolates to 14 antimicrobial agents were determined by the broth microdilution test. Among the isolates tested, 483 (52.4%) were not susceptible to penicillin, 23% were intermediate, and 29.4% were penicillin resistant (MICs >/= 2 mg/liter). Isolates from Vietnam showed the highest prevalence of penicillin resistance (71.4%), followed by those from Korea (54.8%), Hong Kong (43.2%), and Taiwan (38.6%). The penicillin MICs at which 90% of isolates are inhibited (MIC(90)s) were 4 mg/liter among isolates from Vietnam, Hong Kong, Korea, and Taiwan. The prevalence of erythromycin resistance was also very high in Vietnam (92.1%), Taiwan (86%), Korea (80.6%), Hong Kong (76.8%), and China (73.9%). The MIC(90)s of erythromycin were >32 mg/liter among isolates from Korea, Vietnam, China, Taiwan, Singapore, Malaysia, and Hong Kong. Isolates from Hong Kong showed the highest rate of ciprofloxacin resistance (11.8%), followed by isolates from Sri Lanka (9.5%), the Philippines (9.1%), and Korea (6.5%). Multilocus sequence typing showed that the spread of the Taiwan(19F) clone and the Spain(23F) clone could be one of the major reasons for the rapid increases in antimicrobial resistance among S. pneumoniae isolates in Asia. Data from the multinational surveillance study clearly documented distinctive increases in the prevalence rates and the levels of antimicrobial resistance among S. pneumoniae isolates in many Asian countries, which are among the highest in the world published to date.
- SourceAvailable from: muhealth.org[show abstract] [hide abstract]
ABSTRACT: Davidson, R Cavalcanti, R Brunton, JL Bast, DJ de Azavedo, JCS Kibsey, P Fleming, C Low, DENew England Journal of Medicine 04/2002; 346(10):747-50. · 51.66 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The genetic relatedness of French isolates of Streptococcus pneumoniae highly resistant to amoxicillin (MIC, >/=4 microg/ml, equal to or exceeding those of penicillin) was investigated by molecular fingerprinting. The results suggest that high-level resistance to amoxicillin has emerged within preexisting penicillin-resistant clones.Antimicrobial Agents and Chemotherapy 07/1999; 43(6):1480-3. · 4.57 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: To investigate the nasal carriage of antibiotic-resistant pneumococci by children, anterior nasal swabs were done for 4963 children <5 years old in 11 countries in Asia and the Middle East. In total, 1105 pneumococci isolates (carriage rate, 22.3%) were collected, 35.8% of which were found to be nonsusceptible to penicillin. Prevalence of penicillin nonsusceptibility was highest in Taiwan (91.3%), followed by Korea (85.8%), Sri Lanka (76.5%), and Vietnam (70.4%). Penicillin resistance was related to residence in urban areas, enrollment in day care, and a history of otitis media. The most common serogroups were 6 (21.5%), 23 (16.5%), and 19 (15.7%). The most common clone, as assessed by pulsed-field gel electrophoresis, was identical to the Spanish 23F clone and to strains of invasive isolates from adult patients. Data in this study documented the high rate of penicillin or multidrug resistance among isolates of pneumococci carried nasally in children in Asia and the Middle East and showed that this is due to the spread of a few predominant clones in the region.Clinical Infectious Diseases 05/2001; 32(10):1463-9. · 9.37 Impact Factor
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2004, p. 2101–2107
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 6
High Prevalence of Antimicrobial Resistance among Clinical
Streptococcus pneumoniae Isolates in Asia (an ANSORP Study)
Jae-Hoon Song,1,2* Sook-In Jung,3Kwan Soo Ko,2Na Young Kim,2Jun Seong Son,1
Hyun-Ha Chang,4Hyun Kyun Ki,1Won Sup Oh,1Ji Yoeun Suh,2Kyong Ran Peck,1
Nam Yong Lee,5Yonghong Yang,6Quan Lu,7Anan Chongthaleong,8
Cheng-Hsun Chiu,9M. K. Lalitha,10Jennifer Perera,11Ti Teow Yee,12
Gamini Kumarasinghe,12Farida Jamal,13Adeeba Kamarulzaman,14
Navaratnam Parasakthi,14Pham Hung Van,15Celia Carlos,16Thomas So,17
Tak Keung Ng,17and Atef Shibl18
Division of Infectious Diseases1and Department of Laboratory Medicine,5Samsung Medical Center, Sungkyunkwan University
School of Medicine, Asian-Pacific Research Foundation for Infectious Diseases,2and Kyungbook National University,4
Seoul, and Chonnam National University Hospital, Gwangju,3Korea; Beijing Children’s Hospital, Beijing,6Shanghai
Children’s Hospital, Shanghai,7and Princess Margaret Hospital, Hong Kong,17China; Chulalongkorn University,
Bangkok, Thailand8; Chang Gung Children’s Hospital, Taipei, Taiwan9; Christian Medical College, Vellore, India10;
University of Colombo, Colombo, Sri Lanka11; National University of Singapore, Singapore12; Universiti Putra
Malaysia13and University Malaya,14Kuala Lumpur, Malaysia; University of Medicine and Pharmacy,
Ho Chi Minh City, Vietnam15; Research Institute for Tropical Medicine, Manila, Philippines16;
and King Saud University, Riyadh, Saudi Arabia18
Received 3 November 2003/Returned for modification 21 January 2004/Accepted 5 February 2004
A total of 685 clinical Streptococcus pneumoniae isolates from patients with pneumococcal diseases were
collected from 14 centers in 11 Asian countries from January 2000 to June 2001. The in vitro susceptibilities
of the isolates to 14 antimicrobial agents were determined by the broth microdilution test. Among the isolates
tested, 483 (52.4%) were not susceptible to penicillin, 23% were intermediate, and 29.4% were penicillin resistant
(MICs > 2 mg/liter). Isolates from Vietnam showed the highest prevalence of penicillin resistance (71.4%),
followed by those from Korea (54.8%), Hong Kong (43.2%), and Taiwan (38.6%). The penicillin MICs at which
90% of isolates are inhibited (MIC90s) were 4 mg/liter among isolates from Vietnam, Hong Kong, Korea, and
Taiwan. The prevalence of erythromycin resistance was also very high in Vietnam (92.1%), Taiwan (86%),
Korea (80.6%), Hong Kong (76.8%), and China (73.9%). The MIC90s of erythromycin were >32 mg/liter among
isolates from Korea, Vietnam, China, Taiwan, Singapore, Malaysia, and Hong Kong. Isolates from Hong Kong
showed the highest rate of ciprofloxacin resistance (11.8%), followed by isolates from Sri Lanka (9.5%), the
Philippines (9.1%), and Korea (6.5%). Multilocus sequence typing showed that the spread of the Taiwan19F
clone and the Spain23Fclone could be one of the major reasons for the rapid increases in antimicrobial
resistance among S. pneumoniae isolates in Asia. Data from the multinational surveillance study clearly
documented distinctive increases in the prevalence rates and the levels of antimicrobial resistance among S.
pneumoniae isolates in many Asian countries, which are among the highest in the world published to date.
The global emergence of in vitro antimicrobial resistance in
Streptococcus pneumoniae has become a serious clinical con-
cern since the 1980s (1). During the past two decades, the rates
of resistance to penicillin, other beta-lactams, and non-beta-
lactam agents have been increasing rapidly in many parts of the
world. In particular, data on rates of pneumococcal resistance
from Asian countries at the end of the 1990s were alarming.
International surveillance studies conducted in 1996-1997 (29)
and 1998-1999 (18) in 11 Asian countries by the Asian Network
for Surveillance of Resistant Pathogens (ANSORP) docu-
mented very high prevalence rates of penicillin and erythro-
mycin resistance among S. pneumoniae clinical isolates and
nasal carriage isolates from Korea, Japan, Vietnam, Thailand,
Taiwan, and Sri Lanka, as well as the introduction and the
spread of the Spanish 23F penicillin-resistant clone in Asia.
The increasing prevalence of antimicrobial resistance among S.
pneumoniae isolates is associated with an increasing incidence
of invasive pneumococcal diseases in children (23), as well as
clinical failures of antimicrobial treatment (6, 17, 19).
The present report describes the results of the third project
of surveillance for pneumococcal resistance among clinical S.
pneumoniae isolates collected from 14 centers in 11 countries
in Asia and the Middle East between 2000 and 2001 by the
ANSORP Study Group.
MATERIALS AND METHODS
The 14 study centers in 11 countries in Asia and the Middle East that make up
the ANSORP Study Group are listed in Acknowledgments. Clinical S. pneu-
moniae isolates were prospectively collected from patients with community-
acquired pneumococcal diseases at the 14 study centers from January 2000 to
June 2001. With the exception of lower respiratory tract specimens, all isolates
* Corresponding author. Mailing address: Division of Infectious
Diseases, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Asian-Pacific Research Foundation for Infectious Dis-
eases (ARFID), 50 Il-won dong, Kangnam-ku, Seoul 135-710, Korea.
Phone: 82-2-3410-0320. Fax: 82-2-3410-0328. E-mail: jhsong@smc
.samsung.co.kr or email@example.com.
were recovered from clinical specimens representative of normally sterile body
sites, such as blood, cerebrospinal fluid, ascitic fluid, pleural fluid, synovial fluid,
sinus aspirates, and middle ear aspirates. Pneumococcal isolates from lower
respiratory tract specimens were included only if S. pneumoniae was cultured
from adequate respiratory specimens from patients with clinical and radio-
graphic findings of pneumonia. Pneumococcal isolates from throat swab, nasal
swab, or nasopharyngeal aspirate specimens were excluded from the study. Nos-
ocomial infections caused by S. pneumoniae, which was defined as an infection
occurring 3 days after admission to a hospital, were not included in the study.
Isolates from study centers were transported to a central laboratory (Samsung
Medical Center, Seoul, Korea) in a transport tube containing 12 ml of semisolid
Ames transport medium with charcoal (Becton Dickinson, Sparks, Md.). Fol-
lowing storage at ?70°C, the isolates were thawed and subcultured onto blood
agar twice before susceptibility testing was performed.
In vitro susceptibility testing was performed by the broth microdilution test
according to guidelines of the National Committee for Clinical Laboratory Stan-
dards (NCCLS) (25). Fourteen antimicrobial agents were tested: penicillin,
amoxicillin-clavulanate, cefuroxime, ceftriaxone, erythromycin, azithromycin,
clarithromycin, clindamycin, ciprofloxacin, levofloxacin, moxifloxacin, gatifloxa-
cin, doxycycline, and trimethoprim-sulfamethoxazole. Interpretive criteria for
susceptibility were those indicated in NCCLS document M100-S13 (26). We used
two separate interpretive breakpoints for meningeal and nonmeningeal S. pneu-
moniae isolates to define ceftriaxone resistance: MICs of ?2 and ?4 mg/liter,
respectively. For the purpose of the study, ciprofloxacin MICs of ?4 mg/liter
were used to define the resistance category. S. pneumoniae ATCC 49619 was
used as a control strain in each set of tests. Multidrug-resistant (MDR) S.
pneumoniae was defined as a strain resistant to at least three of the antibiotic
All isolates were serotyped or serogrouped by the capsular Quellung method
with commercial antisera (Statens Seruminstitut, Copenhagen, Denmark), as
recommended by the manufacturer. Serotyping was performed only for sero-
groups 23, 19, and 6.
Sixty-eight randomly selected serotype 19A, 19F, and 23F pneumococcal iso-
lates were subjected to multilocus sequence typing (MLST) analysis. For MLST
analysis, fragments of the aroE, gdh, gki, recP, spi, xpt, and ddl genes were
obtained from chromosomal DNA by PCR and were directly sequenced with the
primers described previously (4). Allele profiles are shown as a series of seven
integers corresponding to the alleles at each of the loci, in the order aroE, gdh,
gki, recP, spi, xpt, and ddl. The allele profiles determined were compared with
data from the MLST website (www.mlst.net) and those for Pneumococcal Mo-
lecular Epidemiology Network clones (www.pneumo.com) (21). Isolates sharing
more than five identical loci were defined to be the same clonal complex (4, 7).
The BURST program was used to categorize the isolates into clonal complexes.
To analyze the risk factors for acquiring antibiotic-resistant S. pneumoniae,
epidemiologic and clinical information was obtained at the time of patient
enrollment the in the study. These factors included baseline demographic data
(age and sex), clinical information (antibiotic use within the previous 3 months
and underlying conditions), and others (serotype, specimen source, and resis-
tance to other antibiotics). Univariate and multivariate logistic regression anal-
yses were performed to evaluate the risk factors for acquiring antibiotic-resistant
A total of 685 isolates of S. pneumoniae which caused vari-
ous pneumococcal diseases were collected from 14 centers
from January 2000 to June 2001. The number of isolates varied
by center, according to the duration of collection (Table 1). Of
these, 243 (35.5%) were isolated from lower respiratory tract
specimens, 208 (30.4%) were isolated from blood cultures, 65
(9.5%) were isolated from middle ear aspirates, 56 (8.2%)
were isolated from cerebrospinal fluid, and 113 (16.5%) were
isolated from other sites. Of the 632 isolates for which the ages
of the patients were available, 264 (41.8%) were from patients
?5 years old, 54 (8.6%) were from patients between 5 and 15
years old, and 313 (49.6%) were from patients ?15 years old.
The results of in vitro susceptibility testing for penicillin and
beta-lactam agents are presented in Table 1. Of the 685 S.
pneumoniae isolates from Asia, 483 (52.4%) were not suscep-
TABLE 1. Susceptibilities to beta-lactams and erythromycin of pneumococcal isolates from 12 Asian countriesa
No. of isolates
0.0 ?0.03 ?0.03–0.5
0.0 0.12 ?0.03–8
1.3 ?0.25 ?0.015–0.5
14.3 22.2 8
0.25 ?0.03–0.25 21.3
0.0 0.25 ?0.03–0.5
aBreakpoints for I and R are according to the NCCLS guidelines.
2102SONG ET AL.ANTIMICROB. AGENTS CHEMOTHER.
tible to penicillin; 23% were penicillin intermediate (I; MICs ?
0.12 to 1 mg/liter), and 29.4% were penicillin resistant (R;
MICs ? 2 mg/liter) (Table 1). Prevalence rates of penicillin
nonsusceptibility varied widely by country, ranging from 7.8%
(Vellore, India) to 92% (Ho Chi Minh City, Vietnam). Isolates
from Vietnam showed the highest prevalence of penicillin non-
susceptibility (I, 20.6%; R, 71.4%) followed by those from Sri
Lanka (I, 71.4%; R, 14.3%), Hong Kong (I, 25.3%; R, 43.2%),
Korea (I, 9.7%; R, 54.8%), Taiwan (I, 24.6%; R, 38.6%), and
Thailand (I, 26.9%; R, 26.9%). The penicillin MIC at which
90% of isolates are inhibited (MIC90) was 4 mg/liter among
isolates from Vietnam, Hong Kong, Korea, and Taiwan, while
the MIC90s for isolates from India and the Philippines were
very low (0.03 and 0.25 mg/liter, respectively). If we compare
the prevalence rate of penicillin resistance among clinical
pathogens from this study with those among clinical isolates
(1996-1997) and carriage isolates (1998-1999) from previous
ANSORP studies, the rate of penicillin resistance has mark-
edly increased among isolates from Vietnam, China, Sri Lanka,
and Malaysia, while isolates from Korea, Taiwan, and Thailand
showed persistently high rates of penicillin resistance (Table
2). The level of penicillin resistance has also increased, espe-
cially among isolates from Vietnam, Hong Kong, Korea, and
Taiwan, as indicated by MIC90s of 4 mg/liter. Penicillin MICs
?4 mg/liter were found for 36.5% of pneumococcal isolates
from Vietnam, 25.8% of isolates from Korea, and 14.3% of
isolates from Hong Kong. The highest penicillin MIC was 8
mg/liter for isolates from Taiwan (three isolates), China (one
isolate), and Vietnam (one isolate). All cases caused by these
highly resistant strains were successfully treated with various
antimicrobial therapies. The rate of penicillin nonsusceptibility
was significantly higher in patients ?5 years of age (I, 23.1%;
R, 37.5%) than patients ?5 years of age (I, 23.1%; R, 26.6%)
(P ? 0.005). Pneumococcal isolates resistant to penicillin were
also resistant to other antimicrobial agents. Penicillin-resistant
isolates were resistant to amoxicillin-clavulanate (13.9%), ce-
furoxime (93.1%), ceftriaxone (7.9%), erythromycin (92.6%),
trimethoprim-sulfamethoxazole (89.1%), clindamycin (54.5%),
and ciprofloxacin (8.9%). Multivariate analyses showed that
age ?5 years (odds ratio [OR], 1.7; 95% confidence interval
[CI], 1.2 to 2.4; P ? 0.002), underlying pulmonary diseases
(OR, 2.0; 95% CI, 1.3 to 3.1; P ? 0.003), malignancy (OR, 2.3;
95% CI, 1.2 to 4.6; P ? 0.015), and steroid use (OR, 2.8; 95%
CI, 1.1 to 7.4; P ? 0.032) were independent risk factors for
penicillin resistance among pneumococcal isolates. The overall
rate of amoxicillin-clavulanate resistance (I and R) was 7.9%;
only 4.4% of isolates were resistant. The rates of ceftriaxone
resistance were 0.9% among nonmeningeal isolates (MICs ? 4
mg/liter) and 4.1% among meningeal isolates (MICs ? 2 mg/
liter). Although the prevalence rates of amoxicillin and ceftri-
axone resistance were not high, we found strains highly resis-
cephalosporins (ceftriaxone MICs ? 8 mg/liter) among isolates
from Vietnam (n ? 13), China (n ? 6), Hong Kong (n ? 3),
Korea (n ? 3), Taiwan (n ? 1), and Malaysia (n ? 1).
A total of 376 (54.9%) isolates were not susceptible to eryth-
romycin; 1.8% were intermediate, and 53.1% were resistant.
Very high rates of erythromycin resistance (MICs ? 1 mg/liter)
were observed in Vietnam (92.1%), Taiwan (86%), Korea
(80.6%), Hong Kong (76.8%), and China (73.9%). On the
other hand, erythromycin resistance was relatively not preva-
lent in India (1.3%), Saudi Arabia (10.3%), and Sri Lanka
(16.7%). Of the erythromycin-resistant isolates, 217 (59.6%)
were clindamycin resistant and had the macrolide-lincosamide-
streptrogramin B (MLSB) phenotype. The MIC90s of erythro-
mycin were ?32 mg/liter for isolates from Korea, Vietnam,
China, Taiwan, Singapore, Malaysia, and Hong Kong. Most of
penicillin-resistant isolates (92.6%) were resistant to erythro-
mycin, while 23.9% of penicillin-susceptible isolates were also
resistant to erythromycin. The rate of erythromycin resistance
was significantly higher among isolates from patients younger
than age 5 years (OR, 3.1; 95% CI, 1.9 to 5.2; P ? 0.001) and
among isolates with penicillin resistance (OR, 15.4; 95% CI,
9.5 to 25; P ? 0.001).
Forty-one (6%) isolates were resistant to ciprofloxacin
(MICs ? 4 mg/liter) (Table 3). Isolates from Hong Kong
TABLE 2. Changing trend of penicillin nonsusceptibility among pneumococcal isolates from Asia
% Nonsusceptible strains (I/R)
(n ? 685)
(n ? 1,105)
(n ? 996)
(n ? 685)
(n ? 1,105)
(n ? 996)
aData are from reference 18.
bData are from reference 29.
cNA, not available.
VOL. 48, 2004 PNEUMOCOCCAL RESISTANCE IN ASIA2103
showed the highest rate of ciprofloxacin resistance (11.8%),
followed by isolates from Sri Lanka (9.5%), the Philippines
(9.1%), and Korea (6.5%). Isolates from Hong Kong also
showed higher rates of resistance to levofloxacin (8%), gati-
floxacin (8.3%), and moxifloxacin (1.8%) than isolates from
other Asian countries, where the prevalence of resistance to
these newer fluoroquinolones was extremely low at the time of
The overall rate of MDR S. pneumoniae, which was defined
as resistance to at least three classes of antibiotics, was 26.8%,
with 71.4% of the isolates from Vietnam, 44.9% of the isolates
from Hong Kong, 30.9% of the isolates from Taiwan, and
45.2% of the isolates from Korea being MDR. The most com-
mon pattern of MDR was resistance to penicillin, erythromy-
cin, and trimethoprim-sulfamethoxazole.
The most prevalent serogroups among the clinical pathogens
from Asia were 19, 23, 6, 14, and 9, which accounted for 65.6%
of all isolates (Table 4). Of the 271 isolates from children
younger than age 5 years, serotypes 19F (21.8%), 23F (14.7%),
14 (10%), 6B (6.6%), 9 (4.5%), 6A (3.2%), and 19A (3%) were
the most common ones. MLST analysis showed that most of
the isolates belonged to either the Taiwan19Fclone (30 iso-
lates) or the Spain23Fclone (33 isolates) (Table 5).
The results of this study indicate that the rates of antimicro-
bial resistance among S. pneumoniae isolates in Asia continue
to increase. Since this study was a continuation of multina-
tional surveillance projects that included two previous AN-
SORP studies, it could provide a unique opportunity to inves-
tigate the changing trend in resistance rates in Asia over a
5-year period. Previous ANSORP studies with clinical isolates
(1996-1997) (29) and nasal carriage isolates (1998-1999) (18)
have already revealed that many Asian countries had serious
problems with in vitro resistance to penicillin and non-beta-
lactam agents among S. pneumoniae isolates. Although direct
comparison may not be possible due to the different charac-
teristics of the isolates, resistance rates among pneumococcal
isolates in this study strongly suggest a substantial increase in
TABLE 3. Susceptibilities to fluoroquinolones of pneumococcal isolates from 12 Asian countriesa
Levofloxacin Moxifloxacin Gatifloxacin Ciprofloxacin
% I % R
% I% R
% I% R
90% Range 90%Range90% Range90% Range
?0.002–41.30.3 0.50.03–8 0.31.620.008–?326
aMIC breakpoints for individual fluoroquinolones are as follows: for levofloxacin, I ? 4 mg/liter and R ? 8 mg/liter; for moxifloxacin, I ? 2 mg/liter and R ? 4
mg/liter; for gatifloxacin, I ? 2 mg/liter and R ? 4 mg/liter; and for ciprofloxacin R ? 4 mg/liter.
TABLE 4. Serotype distributions of pneumococcal isolates in 11 Asian countries
No. of isolates
% of strains by serotype (adults/children)
Total346/265 1.6/1.40.1/0.00.3/0.011.5/10.3 0.8/0.38.4/6.3 2.1/1.12.5/4.14.7/5.32.4/2.1 1.1/0.10.9/1.122.0/9.5
2104 SONG ET AL.ANTIMICROB. AGENTS CHEMOTHER.
antimicrobial resistance among S. pneumoniae isolates in the
region. Resistance rates among study centers in each country
varied widely. For example, the rates of penicillin resistance
(MICs ? 2 mg/liter) ranged from 0% (India and Philippines)
to 71.4% (Vietnam), and the rates of resistance to non-beta-
lactam agents varied in a similar manner.
The increasing prevalence of penicillin resistance in Asia
was consistent with recent reports on the emergence of peni-
cillin resistance in Hong Kong (15), Taiwan (12), and Vietnam
(27). The most remarkable finding with regard to the penicillin
resistance in this study is an incredibly high prevalence of
penicillin resistance in Vietnam (Ho Chi Minh City). In a
university hospital in Ho Chi Minh City, 92% of clinical patho-
gens were not susceptible to penicillin and 71% of the isolates
were fully resistant to penicillin, with penicillin MICs of ?2
mg/liter. This is a very alarming increase in high-level penicillin
resistance within the past 5 years. Previous ANSORP studies
showed that 32.6% of clinical isolates in 1996-1997 and 12.2%
of carriage isolates in 1998-1999 were fully resistant to peni-
cillin in a university hospital in Ho Chi Minh City. Although
these data were obtained from one university hospital and are
for a relatively small number of isolates, the data strongly
suggest the rapid surge of penicillin resistance among pneu-
mococcal isolates in that area. Another important observation
in this study is a rapid increase in penicillin resistance in China
(Beijing and Shanghai) and Malaysia (Kuala Lumpur). The
overall rates of penicillin nonsusceptibility in Beijing and
Shanghai, China, were about 10% (mostly intermediate) in the
previous studies in 1996-1999 (18, 29), but the rate has in-
creased to 43% (rate of resistance, 23.4%) in this study. The
same trend was noted among isolates from Kuala Lumpur,
Not only the proportion of nonsusceptible strains but also
the level of penicillin resistance have continued to increase in
many Asian countries. In Vietnam, Hong Kong, Korea, Tai-
wan, China, and Malaysia, penicillin-resistant strains were
more common than penicillin-intermediate strains. In this
study, we found five strains (three from Taiwan and one each
from China and Vietnam) for which penicillin MICs were 8
mg/liter. Recently, pneumococci with high-level resistance to
amoxicillin (MICs ? 4 mg/liter) and/or extended-spectrum
cephalosporins (cefotaxime MICs ? 4 mg/liter) have been
identified in France (3) and Canada (20). We found 27 strains
(13 from Vietnam, 6 from China, 3 from Korea, 3 from Hong
Kong, and 1 each from Malaysia and Taiwan) for which amoxi-
cillin MICs were ?8 mg/liter and/or ceftriaxone MICs were ?8
mg/liter. The emergence of such strains is of particular concern
in the treatment of pneumococcal meningitis, because ceftri-
axone is an important component of the combination regimens
for pneumococcal meningitis.
As documented in previous reports (16), children younger
than age 5 years were more frequently infected with penicillin-
resistant strains. Frequent exposures to antimicrobial agents
and day care center attendance would be important risk factors
for the higher prevalence of penicillin resistance among iso-
lates from children (22).
The remarkable increases in the prevalence and the level of
macrolide resistance among clinical pathogens from Asia are
of particular concern. Reported rates of erythromycin resis-
tance in the Western Hemisphere were high in France
(58.1%), Spain (57.1%), and the eastern south-central parts of
the United States (47%) (8, 31; D. Felmingham and R. N.
Gruneberg, Abstr. 40th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 1790, 2000). However, macrolide resistance
was reported to be more prevalent in Asian countries than in
Western countries. Reports from Hong Kong and Taiwan
showed that 80 to 91% of pneumococcal isolates were resistant
to erythromycin (13, 14). According to the data from the
present study, the prevalence rates of macrolide resistance
were alarmingly high in Vietnam, Taiwan, South Korea, Hong
Kong, and China, where more than 70% of clinical pathogens
were fully resistant to erythromycin. Erythromycin resistance
in pneumococci is due to the modification of the drug-binding
site [which is regulated by the erm(B) gene], which is usually
associated with the MLSBphenotype and high-level resistance
to erythromycin, with MICs of ?64 mg/liter. Low-level eryth-
romycin resistance, with MICs of 1 to 32 mg/liter, is due to the
active efflux of the drug [which is regulated by the mef(A)
gene] (5). The efflux mechanism caused by the mef(A) gene is
predominant in macrolide-resistant pneumococci in North
America (28), while erm(B)-mediated ribosomal methylation
has been found in ?80% of erythromycin-resistant S. pneu-
moniae isolates in most European countries (9). On the basis
of the distributions of the MICs for erythromycin-resistant
strains and the rate of resistance to clindamycin in this study,
the MLSBphenotype is predominant in Korea, China, Taiwan,
Vietnam, and Hong Kong. Molecular characterization of macro-
lide-resistant strains from Asia showed that the erm(B) gene
was found in more than 50% of pneumococcal isolates either
singly or dually with the mef(A) gene in Korea, China, Viet-
nam, and Taiwan (30). Recently, clinical failures of macrolide
treatment for pneumococcal infections caused by macrolide-
resistant strains have been reported (19, 24). Given the wide-
spread emergence of high-level resistance to erythromycin
among pneumococci in Asia, as documented in this study, the
use of a single macrolide for the treatment of pneumococcal
diseases may result in the clinical failure of antimicrobial ther-
Data from this study also showed the present situation of
fluoroquinolone resistance among pneumococcal isolates in
TABLE 5. Results of MLST analysis
No. of isolates
Serotype Clonal complexb
Sri Lanka (2)
Hong Kong (14)
Total (68)2 37 2930 335
aThe number of isolates used in MLST analysis is shown in parentheses.
bClonal complex as defined by McGee et al. (21) and the Pneumococcal
Molecular Epidemiology Network (www.pneumo.com).
VOL. 48, 2004PNEUMOCOCCAL RESISTANCE IN ASIA 2105
Asia. Recently, Hong Kong investigators demonstrated the
high rates of resistance of S. pneumoniae isolates to various
fluoroquinolones (10) and the presence of the Spanish 23F
clone, which has acquired fluoroquinolone resistance while
circulating in Hong Kong (11). Our data confirmed a higher
rate of ciprofloxacin resistance among isolates from Hong
Kong than among isolates from other Asian countries. Al-
though the overall rates resistance to fluoroquinolones remain
low in most Asian countries, we found 12 strains of diverse
serotypes (7 from Hong Kong and 1 each from China, Taiwan,
India, Singapore, and Thailand) with high-level resistance to
ciprofloxacin (MICs ? 8 mg/liter). These strains were also
resistant to newer fluoroquinolones, such as moxifloxacin and
gatifloxacin. The emergence of these strains highly resistant to
fluoroquinolones will be a concern in the future with regard to
the treatment of pneumococcal pneumonia. Clinical failures of
levofloxacin for the treatment of pneumococcal pneumonia
have already been documented (2).
The serotype distributions among the clinical pathogens
from Asia showed that major serogroups were 19 (19F), 23
(23F), 6 (6B), 14, and 9, which are contained in the seven-
valent conjugate vaccine. Given the high prevalence of antibi-
otic-resistant S. pneumoniae in Asia, pneumococcal vaccina-
tion should be applied more widely in Asia.
The MLST analysis performed in this study showed that the
spread of specific resistant clones, such as the Taiwan19Fclone
and the Spain23Fclone, in Asia could be one of the major
reasons for the rapid increases in penicillin and macrolide
resistance as well as MDR in S. pneumoniae.
There may be some limitations in interpreting the data from
this study. Since pneumococcal isolates were collected from
one or two referral centers, mainly in urban areas of each
country, and the number of isolates was relatively few in some
centers, data from this study may not reflect the overall resis-
tance status in a whole country. On the basis of the information
from this study, further surveillance of pneumococcal resis-
tance with more isolates from more centers is strongly war-
ranted, especially in countries where resistance rates have
markedly increased. Also, we could not identify the direct
relationship between the amounts of antibiotics used or the
history of previous antibiotic use and the emergence of resis-
tance due to a lack of relevant information in many countries.
In conclusion, this multinational surveillance study con-
ducted by ANSORP clearly documents distinctive increases in
the prevalence rates and the levels of penicillin and macrolide
resistance in many Asian countries, which are among the high-
est in the world that have been published to date, as well as the
emergence of fluoroquinolone resistance in Hong Kong. The
injudicious use of antibiotics and the clonal spread of resistant
strains in Asia could be the major reasons for the rapid in-
creases in the rates of pneumococcal resistance in Asia. Con-
tinuous surveillance of antimicrobial resistance among pneu-
mococcal isolates as well as appropriate use of antibiotics and
pneumococcal vaccination is critically required in Asia.
This study was partly supported by Bayer Healthcare (Wuppertal,
Germany), Wyeth-Ayerst (Madison, N.J.), the Samsung Biomedical
Research Institute (SBRI C-A3-214-1), the Samsung Medical Center,
and the Asian Pacific Research Foundation for Infectious Diseases
(ARFID), Seoul, Korea.
We thank Jane Ambler, Hans-Otto Werling, Helmut Schepers, and
Eddie Power of Bayer Healthcare and Rob Cummins of Wyeth-Ayerst
for their sincere support.
Centers participating in the Asian Network for Surveillance of Re-
sistant Pathogens (ANSORP) are as follows: Samsung Medical Center,
Seoul, Korea (coordinating center); Beijing Children’s Hospital, Bei-
jing, China; Shanghai Children’s Hospital, Shanghai, China; Princess
Margaret Hospital, Hong Kong, China; Chulalongkorn University,
Bangkok, Thailand; Chang Gung Children’s Hospital, Taipei, Taiwan;
Christian Medical College, Vellore, India; University of Colombo,
Colombo, Sri Lanka; National University of Singapore, Singapore;
Universiti Putra Malaysia and University Malaya, Kuala Lumpur, Ma-
laysia; University of Medicine and Pharmacy, Ho Chi Minh City, Viet-
nam; Research Institute of Tropical Medicine, Manila, Philippines;
and King Saud University, Riyadh, Saudi Arabia.
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