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Previous Article | Next Article 
Journal of Clinical Microbiology, April 1999, p. 1130-1136, Vol. 37, No. 4
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Antimicrobial Susceptibilities and Plasmid Contents
of Neisseria gonorrhoeae Isolates from Commercial
Sex Workers in Dhaka, Bangladesh: Emergence of High-Level
Resistance to Ciprofloxacin
Bahar Uddin
Bhuiyan,1
Motiur
Rahman,2,*
Mohammed
Ruhul Amin
Miah,3
Shamsun
Nahar,2
Nazrul
Islam,3
Monira
Ahmed,1
Kazi Masihur
Rahman,3 and
M. John
Albert2
Jahurul Islam Medical College Hospital,
Kishoregang,1 and International Centre
for Diarrhoeal Disease Research,
Bangladesh,2 and Institute of Post
Graduate Medicine & Research, Shahabag,3
Dhaka 1000, Bangladesh
Received 13 October 1998/Returned for modification 4 December
1998/Accepted 7 January 1999
 |
ABSTRACT |
Commercial sex workers (CSWs) serve as the most important reservoir
of sexually transmitted diseases (STD), including gonorrhea. Periodic
monitoring of the antimicrobial susceptibility profile of
Neisseria gonorrhoeae in a high-risk population provides
essential clues regarding the rapidly changing pattern of antimicrobial susceptibilities. A study concerning the prevalence of gonococcal infection among CSWs was conducted in Bangladesh. The isolates were
examined with regards to their antimicrobial susceptibility to, and the
MICs of, penicillin, tetracycline, ciprofloxacin, cefuroxime,
ceftriaxone, and spectinomycin by disk diffusion and agar dilution
methods. The total plasmid profile of the isolates was also analyzed.
Of the 224 CSWs, 94 (42%) were culture positive for N. gonorrhoeae. There was a good correlation between the results of
the disk diffusion and agar dilution methods. Some 66% of the isolates
were resistant to penicillin, and 34% were moderately susceptible to
penicillin. Among the resistant isolates, 23.4% were
penicillinase-producing N. gonorrhoeae (PPNG). 60.6% of
the isolates were resistant and 38.3% were moderately susceptible to
tetracycline, 17.5% were tetracycline-resistant N. gonorrhoeae, 11.7% were resistant and 26.6% had reduced
susceptibility to ciprofloxacin, 2.1% were resistant and 11.7% had
reduced susceptibility to cefuroxime, and 1% were resistant to
ceftriaxone. All PPNG isolates contained a 3.2-MDa African type of
plasmid, and a 24.2-MDa conjugative plasmid was present in 34.1% of
the isolates. Since quinolones such as ciprofloxacin are recommended as
the first line of therapy for gonorrhea, the emergence of significant
resistance to ciprofloxacin will limit the usefulness of this drug for
treatment of gonorrhea in Bangladesh.
| |
INTRODUCTION |
Despite a sharp decline in the
incidence of gonococcal infection in developed countries during the
last decade, gonorrhea remains one of the most common venereal diseases
in developing countries and a global health problem (7). The
problem is compounded by the development of resistance to
antimicrobials in N. gonorrhoeae, which is a result of both
wide dissemination of resistant clones and the emergence of strains
with novel resistance mechanisms (13). Periodic monitoring
of the antimicrobial susceptibility profile of N. gonorrhoeae strains prevalent in a high-risk group such as
commercial sex workers (CSWs) provides essential clues regarding
treatment options and emergence of drug resistance. CSWs sustain very
high rates of transmission of sexually transmitted diseases (STD);
among them, gonorrhea with multiple antibiotic resistance is
common (6). Gonococcal infection has been implicated in
facilitating human immunodeficiency virus (HIV) acquisition and
transmission (18). This is probably due to mucosal
inflammation, which provides greater access for HIV than that provided
by normal tissue, and the release of virus particles in semen is
significantly greater in HIV-infected patients with gonorrhea than
in patients without gonorrhea (31, 27).
Strategies for control of gonorrhea have relied on the use of highly
effective and, often, single-dose therapy administered at the time of
diagnosis. Penicillin has been used as the first-line therapy for
gonorrhea for over 40 years. Due to the appearance and the subsequent
increase in the prevalence of penicillinase-producing N. gonorrhoeae (PPNG) and to N. gonorrhoeae isolates with
chromosomally mediated resistance to penicillin and tetracycline
(CMRNGPT), the Centers for Disease Control, Atlanta, Ga.,
has advocated broad-spectrum cephalosporins or selected
fluoroquinolones, including ciprofloxacin and ofloxacin, as the
first-line therapies for uncomplicated gonorrhea (3-5, 16).
Ciprofloxacin is being used as the first-line therapy for uncomplicated
and suspected gonorrhea cases in Bangladesh. It is also included in
syndromic management in cases of suspected gonorrhea.
Since the introduction of fluoroquinolone for the treatment of
uncomplicated gonorrhea, ciprofloxacin has been used extensively in
Southeast Asia. However, gonococcal strains with reduced susceptibility to the fluoroquinolones have been reported in Asia (25, 6), the United Kingdom (10), North America (15), and
Europe (1).
Continuous surveillance of the epidemiology of gonococcal resistance,
based on type characterization, and detailed in vitro assessment of the
antimicrobial susceptibility of strains are imperative for treatment
and prevention (19). The prevalence of gonorrhea and
antimicrobial susceptibility of N. gonorrhoeae in a
high-risk population is not well documented in Bangladesh. The aim of
the present study was to examine the antimicrobial susceptibility and
plasmid profile of N. gonorrhoeae isolates from CSWs in
Dhaka, Bangladesh.
| |
MATERIALS AND METHODS |
Study population.
From June to November 1997, the prevalence
of gonorrhea among the CSWs in the city of Dhaka was studied. All CSWs
attending a rehabilitation center at Mirpur, Dhaka, for voluntary
rehabilitation under a government rehabilitation program were evaluated
for gonococcal infection. CSWs were recruited irrespective of symptoms
of STD. The only exclusion criterion for participation in the study was the use of antimicrobial agents in the preceding 2 weeks. Endocervical swabs from 224 consecutively seen CSWs were cultured for N. gonorrhoeae.
Isolation.
Endocervical swabs were streaked on modified
Thayer-Martin agar (BBL Microbiology Systems, Cockeysville, Md.). The
identity of the organism was confirmed by colony morphology, Gram
staining, oxidase and catalase tests, and the sugar fermentation test.
Isolates were further confirmed by PCR using primers which amplify a
390-bp region of the gonococcal cryptic plasmid (12).
Isolates were kept at 
70°C in Trypticase soy broth with 20%
glycerol until further studied.
-Lactamase test.
All penicillin-resistant isolates were
tested for -lactamase production by a paper acidometric method as
described earlier (32).
Disk diffusion.
Antimicrobial disks containing penicillin
(10 U/disk), tetracycline (30 µg/disk), ciprofloxacin (5 µg/disk),
ceftriaxone (30 µg/disk), cefuroxime (30 µg/disk) (all from Oxoid,
Hampshire, United Kingdom), and spectinomycin (100 µg/ml) (Becton
Dickinson, Cockeysville, Md.) were used for disk diffusion as described
earlier (16). Each test was done in triplicate, and the mean
value was determined.
MICs.
MICs of penicillin, tetracycline, spectinomycin,
ceftriaxone, cefuroxime, and ciprofloxacin were determined by an agar
dilution method as described earlier (22). Briefly, GC agar
base agar (BBL Microbiology Systems) supplemented with 1% IsoVitaleX
and twofold serial dilutions of antibiotics were used. Plates were inoculated with 104 CFU of bacteria and incubated in 5%
CO2 for 36 h. The end point was read as the lowest
concentration of antimicrobial agent giving complete inhibition of
growth. Five N. gonorrhoeae reference strains, WHO A to WHO
E, for which the MICs were known, were included for quality control in
each test. Each test was repeated three times. The antimicrobial
susceptibility was judged by breakpoint criteria defined by the
National Committee for Clinical Laboratory Standards (NCCLS)
(21). Twofold serial dilutions of antibiotics were used at
the following concentrations: penicillin (Sigma, St. Louis, Mo.), 0.03 to 64 µg/ml; tetracycline (Sigma), 0.03 to 64 µg/ml; ciprofloxacin
(Bayer, Hampshire, United Kingdom), 0.004 to 4 µg/ml; spectinomycin
(Upjohn, Puurs, Belgium), 2.0 to 128 µg/ml; cefuroxime (Sigma), 0.06 to 4 µg/ml; and ceftriaxone (Sigma), 0.004 to 0.5 µg/ml.
Plasmid analysis.
Isolates were grown overnight at 37°C in
5% CO2 on GC agar base with 1% Kellogg's supplement. The
plasmid DNA was extracted by the rapid alkaline lysis method
(2). The plasmid profile was determined by electrophoresis
at 50 V on a 0.7% agarose gel. The gel was stained with ethidium
bromide (0.5 µg/ml) and visualized by UV light transillumination.
Phenotypic characterization.
The criteria used for
phenotypic characterization of N. gonorrhoeae based on
plasmid and chromosomally mediated resistance to penicillin and
tetracycline are shown in Table 1
(26).
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TABLE 1.
Phenotypic categories of N. gonorrhoeae based
on plasmid and chromosomally mediated resistance to penicillin and
tetracycline (n = 94)
|
|
Correlation of MIC and inhibition zone.
The correlation of
the MIC to the zone of inhibition and the correlation coefficient were
calculated by the method of least squares, with the zone diameter as
the independent variable (x axis) and the MICs as the
dependent variable (y axis).
| |
RESULTS |
Among the endocervical swabs cultured from 224 consecutively seen
CSWs, 94 (42%) were culture positive for N. gonorrhoeae. We
examined the antimicrobial susceptibility of the isolates to penicillin, tetracycline, ciprofloxacin, cefuroxime, ceftriaxone, and
spectinomycin as well as the MICs of these antimicrobials for the
isolates by using disk diffusion and agar dilution methods. The MICs at
which 50 and 90% of the isolates were inhibited (MIC50s and MIC90s, respectively) were determined, and the range of
MICs of each antibiotic is shown in Table
2.
On the basis of susceptibility criteria established by NCCLS, the
overall susceptibilities of the isolates were determined and are shown
in Fig. 1. Among the isolates, 62 (66%)
were resistant (MIC, 
2 µg/ml) to penicillin, including 22 (23%)
PPNG isolates for which the penicillin MICs were 8 to 16 µg/ml (Fig.
1a); 57 (60.6%) were resistant (MIC, 2 µg/ml) to tetracycline,
including 10 (10.6%) tetracycline-resistant N. gonorrhoeae
(TRNG) isolates for which the tetracycline MICs were 16 µg/ml (Fig.
1b); and 11 (11.7%) were resistant (MIC, 1.0 µg/ml) and 25 (26.6%) had reduced susceptibility (MIC, 0.125 to 0.5 µg/ml) to
ciprofloxacin (Fig. 1c). Two (1.2%) isolates were resistant (MIC, 4
µg/ml) and 11 (11.7%) isolates were moderately susceptible (MIC, 2 µg/ml) to cefuroxime (Fig. 1d), whereas 1 (1%) was resistant to
ceftriaxone (MIC, 0.5 µg/ml) (Fig. 1f). This isolate had
concomitant resistance to cefuroxime. All isolates were susceptible to
spectinomycin (Fig. 1e).
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FIG. 1.
Distribution of MICs of penicillin (a), tetracycline
(b), ciprofloxacin (c), cefuroxime (d), spectinomycin (e), and
ceftriaxone (f) for N. gonorrhoeae isolates. Symbols:
 , susceptible;
 , moderately susceptible or
strains with reduced susceptibility;  , resistant. The
breakpoint criteria used for assessing the susceptibility were those
recommended previously (21, 22).
|
|
Seven (63.6%) ciprofloxacin-resistant isolates and 15 (25.9%)
ciprofloxacin-susceptible isolates belonged to the
CMRNGPT; 9 (81.8%)
ciprofloxacin-resistant isolates had chromosomally mediated
resistance to penicillin and/or tetracycline; 12 (48%) of the isolates
with reduced susceptibility were PPNG.
The correlation between MIC and zone diameter is shown in Fig.
2. For cefuroxime (Fig. 2c) and
ceftriaxone (Fig. 2d), the zone diameters of inhibition of the isolates
were correctly interpreted as belonging to the susceptible,
intermediately susceptible, and resistant categories corresponding to
the MIC interpretive breakpoints. All isolates were correctly
identified as susceptible to spectinomycin when the MIC interpretive
breakpoint of 128 µg/ml was applied (Fig. 2f). From results for
penicillin (Fig. 2a), tetracycline (Fig. 2b), and ciprofloxacin (Fig.
2e), most of the isolates could be identified as belonging to a single
susceptibility category. However, for some isolates, the use of neither
MIC limits nor zone diameter for susceptibility categories could
reproducibly identify isolates as belonging to any single category,
since the ranges of the MICs for these isolates were broad.
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FIG. 2.
Scattergram of MICs (y axis) and mean zone
diameter of inhibition (x axis) around disks of penicillin
(10 U) (a), tetracycline (30 µg/disk) (b), cefuroxime (30 µg/disk)
(c), ceftriaxone (30 µg/disk) (d), ciprofloxacin (5 µg/disk) (e),
and spectinomycin (100 µg/disk) (f) for 94 clinical isolates of
N. gonorrhoeae. The solid vertical and horizontal lines
indicate the criteria recommended by the NCCLS for the interpretation
of the susceptible categories for these agents by disk diffusion and
MICs.
|
|
Based on plasmid and chromosomally mediated resistance to penicillin
and tetracycline, the isolates were phenotypically categorized into
seven different groups (Table 1). The susceptibility patterns of the
different phenotypic categories of N. gonorrhoeae to
ciprofloxacin were further analyzed (Table
3).
The plasmid profiles of all isolates were analyzed (Table
4). All isolates harbored a 2.6-MDa
cryptic plasmid; 22 (23.4%) of the isolates were PPNG, and all of them
contained a 3.2-MDa African type PPNG plasmid; 10 (10.6%) of the
isolates were TRNG and contained a 25.2-MDa TRNG plasmid. A conjugative
plasmid was present in 34.1% of the isolates (36.3% in the PPNG
isolates and 32.2% in the others).
| |
DISCUSSION |
Gonorrhea remains a major cause of morbidity in sexually active
individuals, and most of the cases are projected to occur in countries
of the Southeast Asia region (7, 28). The control of
gonococcal infection is important considering the high incidence of
acute infections, complications, and sequelae and the role of
gonorrhoeae in facilitating HIV acquisition and transmission. N. gonorrhoeae isolates have consistently developed resistance to the
antimicrobial agents used for treatment of gonorrhea. Antimicrobial resistance in N. gonorrhoeae has become a major global
public health concern. Since the introduction of sulfonamides in the 1930s, N. gonorrhoeae isolates have developed resistance to
many of the antibiotics used in the treatment of gonococcal infections. There has been a remarkable increase in antimicrobial resistance among
N. gonorrhoeae isolates in many developing countries in recent years (23).
In many western countries, the incidence of gonorrhea has declined
since the mid-1970s; during the past year, however, evidence that the
incidence of gonorrhea is on the increase again in these countries, as
in the developing countries, has emerged. The focal nature of the
increased incidence suggests the need for geographically targeted interventions.
In developing countries where the prevalence of bacterial STD remains
high and laboratory facilities are limited, the World Health
Organization has recommended that a syndromic approach based on
clinical symptoms and signs be used and the Centers for Disease Control
have recommended a first-line therapeutic regimen based on
fluoroquinolones and cephalosporin. Resistance to fluoroquinolone in
neisseriae occurs as a result of point mutations in the DNA gyrase
(gyrA) gene and the topoisomerase IV (parC) gene.
High-level quinolone resistance indicates adaptive mutations of
N. gonorrhoeae under selective antibiotic pressure. N. gonorrhoeae has rapidly developed resistance to most antimicrobial
agents and, most recently, to quinolones used in treatment of the
diseases. Inappropriate therapy due to self-medication and poor
compliance is common among patients with gonorrhea, and these are the
factors that enhance the development of resistance. Fluoroquinolones
have been recently recommended for the primary treatment of
uncomplicated gonorrhea in areas where multiresistant strains are
common, such as Southeast Asia and central Africa. As a consequence of
the large-scale use of this group of antimicrobials in areas where
over-the-counter availability of drugs without prescription is common,
a substantial increase of resistant strains may occur. The appearance
of a significant number of resistant isolates (11.7% resistant and
26.6% with reduced susceptibility) in our study indicates that
CSWs in Bangladesh are exposed to fluoroquinolones and that
resistance has developed under selective antibiotic pressure. The fact
that the isolates in this study were collected randomly from the CSWs
in the city of Dhaka suggests that they are reasonably representative
of gonococcal strains in the CSWs.
Ciprofloxacin resistance among gonococci was found to be 1.3% in the
United States (8) and 10% in Hong Kong and the Philippines (17). Resistance to ciprofloxacin is chromosomally mediated, affects all the members of the fluoroquinolone group of antibiotics, and is apparently incremental (30). Of the 11 resistant
isolates in the present study, 9 (82%) had chromosomally mediated
resistance to penicillin and/or tetracycline, indicating that
ciprofloxacin-resistant strains are more prevalent in isolates having
chromosomally mediated resistance to penicillin and tetracycline. A
similar pattern has also been reported earlier in the United States and
Thailand (8, 17). The frequent appearance of elevated
ciprofloxacin MICs for strains with chromosomally mediated resistance
to penicillin and tetracycline remains unexplained because the
mechanism of ciprofloxacin resistance is different from those of
penicillin and tetracycline.
Resistance to penicillin and tetracycline is either chromosomally
mediated or plasmid mediated. Chromosomally mediated resistance to
penicillin is a low-level resistance and the result of the additive
effect of mutations at multiple loci, including penA, mtr, and penB (29), while
plasmid-mediated resistance is due to PPNG (the 3.2-MDa African type or
the 4.4-MDa Asian type) encoding a TEM-1 type -lactamase. The
high-level penicillin resistance observed in our study may be due to a
consequence of penicillin therapy for unrelated illnesses or
self-medication by CSWs with penicillin or penicillin congeners.
Self-medication among sex workers in the Philippines has been shown to
play a major role in the development of antimicrobial resistance, and a
similar practice is also common in Bangladesh (11). Plasmid
analysis showed that all PPNG isolates contained a 3.2-MDa African type of plasmid. Transfer of a penicillinase plasmid can occur between the
N. gonorrhoeae strains by conjugation, but it requires the presence of a 24.5-MDa conjugative plasmid in the donor to mobilize the
transfer (20). About one-third of the isolates we studied harbored a 24.5-MDa conjugative plasmid, and an equal number of PPNG
isolates also had this plasmid.
High-level plasmid-mediated resistance to tetracycline is due to
acquisition of the tetM determinant by the conjugative
plasmid (24.5 MDa) of N. gonorrhoeae, resulting in a
25.2-MDa plasmid (9). This plasmid is self-mobilizable and
can move between N. gonorrhoeae strains and other genera.
Tetracycline-resistant N. gonorrhoeae isolates are likely to
spread more quickly than PPNG isolates because of the presence of the
tetM plasmid in other flora found in the genital tract that
may act as a reservoir. Approximately 60% of the isolates were
tetracycline resistant, which indicates selective pressure
resulting from its use for STD and other illnesses.
The extended-spectrum cephalosporin (cefuroxime) and the broad-spectrum
cephalosporin (ceftriaxone) demonstrate very high levels of activity
against these gonococcal isolates, showing 86.1 and 98.9%
susceptibility, respectively. Of two isolates for which the cefuroxime
MIC was 4 µg/ml, one was resistant to ceftriaxone (MIC, 0.5 µg/ml)
by the in vitro test. We do not know the clinical significance of these
isolates and whether infections caused by these strains would fail to
respond to the currently recommended treatment with those drugs.
However, a therapeutic index (ratio of peak serum concentration to MIC)
of 3:1 to 4:1 has been recommended for reliable cure of gonococcal
urethritis (14), and a 500-mg intramuscular dose produces a
peak serum concentration of 42 to 45 µg/ml with a half-life in serum
of 6.0 to 8.3 h (24). Gonococcal isolates for which the
ceftriaxone MIC was 0.5 µg/ml and those for which the cefuroxime MIC
was 4 µg/ml have been reported in the United States and Thailand,
respectively (8, 17). All the isolates in the present study
were susceptible to spectinomycin (MIC, 
32 µg/ml), which remains a
valuable alternative.
There is a need for a simple and reliable routine susceptibility test
for gonococci for both epidemiological surveillance and for patient
management. A standardized disk diffusion test gives reproducible
results and is easy to perform by routine laboratories. Interpretive
MIC breakpoints for gonococcal susceptibility categories have been
based on single-dose treatment for most drugs, and these limits are
accordingly lower than those for other bacteria. The results of the
disk diffusion test for most of the isolates tested in this study were
in agreement with MIC breakpoints for gonococcal susceptibility categories.
The data presented here indicate that N. gonorrhoeae strains
resistant to the commonly used antimicrobial agents have increased, and
consequently penicillin and tetracycline can no longer be recommended
for the treatment of gonorrhea. Ciprofloxacin may soon approach the end
of its utility as a first-line drug for treatment of gonorrhea in
Bangladesh, where 11.7% of N. gonorrhoeae isolates are
currently resistant.
| |
ACKNOWLEDGMENTS |
Our research was funded by the Institute of Post Graduate
Medicine and Research and the International Centre for Diarrhoeal Disease Research, Bangladesh, which is supported by countries and
agencies that share its concern for the health problems of developing
countries. Current donors providing unrestricted support include the
aid agencies of the governments of Australia, Bangladesh, Belgium,
Canada, Saudi Arabia, Sweden, Switzerland, the United Kingdom, and the
United States and international organizations including the United
Nations Children's Fund (UNICEF). One fellowship, to Bahar Uddin
Bhuiyan from Jahurul Islam Medical College Hospital, is gratefully acknowledged.
We are grateful to Joseph Bogaerts and Anowar Hossain for their cooperation.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratory
Sciences Division, ICDDR,B, GPO Box-128, Dhaka-1000, Bangladesh. Phone: 880-2-871751-60. Fax: 880-2-872529. E-mail:
motiur{at}icddrb.org.
| |
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Abstract
Introduction
