GONORRHEA IS ONE OF the classical sexually transmitted diseases (STDs) with human as the only host for the causative agent, Neisseria gonorrhoeae. The estimated number of cases globally is 200 million every year. There are several problems in compilation of data, as clinical presentation is not specific enough and laboratory-based diagnosis is not attempted in many areas because of inadequate facilities, material, or personnel. Besides, there is a lack of reporting mechanism in developing countries. The prevalence rate of the disease varies greatly among countries in the developed and developing world, the highest being in south and southeast Asia, followed by sub-Saharan Africa and Latin America, where it continues to be a major public health problem.1 The Regional STD Teaching, Training and Research Centre at New Delhi showed an increasing trend from 14% to 19.4% between 1990 and 2001.2,3 Overall, it varies between 4.2% and 16.2% in the other STD clinics of the country. In Bangladesh, the incidence is around 35.5%.4 The success of the HIV Control Programme in Thailand has led to decline in gonorrhea by more than 80%.5
Emergence of resistance to antimicrobial agents has made the treatment of gonorrhea expensive and prolonged, as well as unpredictable. The organism acquires resistance by spontaneous mutation or it acquires new DNA via conjugation and transformation, and thus resistance may be chromosomal or extrachromosomal.6,7 A single organism can have both the mechanisms of resistance, and resistance to multiple antibiotics is often seen. Antimicrobial resistance against almost all the antimicrobial agents is spreading now in southeast Asian region (SEAR) countries.8–10 Surveillance was therefore considered mandatory to develop strategy and policy for proper therapy.
WHO recommended establishing a global surveillance program in 1978 and 1990.11,12 Gonococcal Antimicrobial Susceptibility Programme (GASP) became functional in SEAR in 1997. Two regional reference laboratories (RRL), 1 each in India and Thailand, were identified to provide technical and material support to 5 countries each of the regions. The Inter Regional Reference Laboratory, located at Sydney, Australia, provides technical support and organizes the external quality-assessment scheme for these 2 laboratories. Laboratories from India, Bangladesh, and Sri Lanka have participated in the program since its inception. Although isolated studies have been done in Sri Lanka to understand the susceptibility of N. gonorrhoeae strains towards penicillin, only in 1997 was a systematic monitoring system established with the introduction of GASP.
The present communication compares the current status of the antimicrobial susceptibility pattern of N. gonorrhoeae, isolated in different GASP focal-point laboratories, and also attempts to assess the trend of antimicrobial resistance of N. gonorrhoeae in 3 selected laboratories, based on the data presented by the in-charges of these laboratories in the WHO-SEAR intercountry consultative meeting conducted in December 2001 at RRL, Regional STD Teaching, Training and Research Centre, Vardhman Mahavir Medical College, and Safdarjung Hospital, New Delhi, India. The data could be used by the public health managers to change the national management guidelines, if necessary.
Materials and Methods
There are 10 functional focal point laboratories for GASP under RRL, New Delhi, 7 from India, and 3 from other countries (eg, Bangladesh, Sri Lanka, and Nepal). As the present communication describes the results reported from different focal-point laboratories, the study populations differed in each setup, as shown in Table 1. Standard methods for transport, isolation, presumptive and confirmatory identification, subculture, and storage were adopted by all the laboratories under GASP, according to the WHO manual.13 Antimicrobial susceptibility testing was carried out following either National Committee for Clinical Laboratory Standards (NCCLS) method14 or calibrated dichotomous sensitivity (CDS) technique,13 using high- and low-potency discs, respectively (Himedia Laboratories Ltd., India/Oxoid). All the laboratories used the same panel of antibiotics. The discs used in the 2 techniques were penicillin (10 and 0.5 IU), tetracycline (30 μg and 10 μg), ciprofloxacin (5 μg and 1 μg), ceftriaxone (30 μg and 0.5 μg), and spectinomycin (100 μg in both), respectively. For the NCCLS method, media used was GC agar base + hemoglobin/blood and Isovitalex/Vitamino growth supplement, and for the CDS technique, chocolate agar having Columbia agar base was used. The source of media components was either from BBL, now Becton Dickinson, Sparks, MD; or HiMedia. The interpretive criteria were according to CDS and NCCLS guidelines.13,14 The RRL at New Delhi compared the CDS technique with NCCLS in 50 strains of N. gonorrhoeae before adopting it for use. The results were in 98% agreement. WHO N. gonorrhoeae strains A to E were used as control strains. RRL, New Delhi, Bangladesh, and Sri Lanka received the control strains from WHO Neisseria Reference Laboratory, Sydney, Australia. These strains were distributed to focal-point laboratories in India. Interpretation of antimicrobial susceptibility and breakpoints for resistance were as reported earlier.13,14 β Lactamase testing for detection of penicillinase-producing N. gonorrhoeae (PPNG) was performed by a paper acidometric method in Bangladesh, Chennai, Nagpur, and by chromogenic cephalosporin method using nitrocefin freeze-dried powder (Oxoid) in RRL, New Delhi, and nitrocefin disc (BBL) in Maulana Azad Medical College (MAMC), New Delhi.
TRNGs were defined as plasmid-mediated tetracycline-resistant N. gonorrhoeae with tetracycline MIC ≥16 μg/mL. Chromosomally mediated resistant strains for tetracycline (TetR) were defined as non-TRNG with tetracycline MIC of ≥2 μg/mL.9 Presumptively, in the NCCLS technique,14 TRNGs were identified when the zone of inhibition (diameter) was ≤19 mm and in the CDS technique when the zone of inhibition (annular radius) was ≤1 mm.
The resistance patterns of consecutive isolates of N. gonorrhoeae in different focal-point laboratories in 2001 were summarized and compared. The trends of antimicrobial resistance in Sri Lanka, Bangladesh, and New Delhi (RRL), India, from 1996 to 2000 were also compared. Data for penicillin and tetracycline resistance from Bangladesh were available only from 1997 to 1999. Trend data were analyzed statistically using χ2 test, and P value was determined.
Current Status of Antimicrobial Resistance of N. gonorrhoeae in India
Table 2 summarizes and compares the resistance patterns of N. gonorrhoeae in 2001, as reported from 7 focal-point laboratories in India.
Resistance to this antibiotic continues to be a problem in India. Resistance was reported from all 7 laboratories but varied between 20% and 79%. PPNGs were reported from Delhi-MAMC (10%), Nagpur (13.5%), and RRL, New Delhi (26.8%).
Resistance to tetracycline was reported from all the laboratories except Chennai and Kolkata. In Pune (data communicated after the meeting) and Hyderabad, percent resistance was 97.2% and 45.6%, respectively. A total of 33.8% of strains were reported from Nagpur as TRNG. From both the laboratories in Delhi, percent of resistance varied from 7.4% to 10%.
Resistance to ciprofloxacin was reported from all the laboratories and varied considerably. Delhi (RRL 88.4% and MAMC 100%) and Hyderabad (57%) reported very high percent resistance.
The RRL, New Delhi, did not report any strain having reduced susceptibility to ceftriaxone. However, it was reported from 5 laboratories and varied between 5% and 20%. MAMC, Delhi, reported decreasing zone diameters from 50 mm to 40 mm (NCCLS) for this antibiotic.
No spectinomycin resistance was reported from India, so far.
Current Status of Antimicrobial Resistance of N. gonorrhoeae in Other SEAR Countries
Table 2 summarizes and compares the resistance patterns of N. gonorrhoeae, as reported from Bangladesh, Sri Lanka, and Nepal.
The resistance to penicillin and tetracycline continued to be a problem, and the isolates from FSWs had 33% resistance and 66% reduced susceptibility to penicillin and 57% resistance and 35% reduced susceptibility to tetracycline in 1999. High percent resistance (76%) against ciprofloxacin and reduced susceptibility to ceftriaxone, only in 1.5% of the isolates, were reported in 2000.
Resistance to penicillin and ciprofloxacin was reported to be 96.8% and 8.2%, respectively, in 2000. No resistance was reported against the other antibiotics.
The report was based only on 9 isolates in 2001 and showed 4 PPNGs, 4 TRNGs, and only 1 isolate resistant to ciprofloxacin. No resistance was reported to ceftriaxone and spectinomycin.
Antimicrobial Resistance Trends in 3 SEAR Countries
The trends of antimicrobial susceptibility of N. gonorrhoeae strains towards penicillin in the 3 SEAR countries are shown in Fig. 1a and the trends of PPNG in Figure 1b. In Sri Lanka, a highly significant (P < 0.001) rise in the percentage of chromosomally mediated resistance to penicillin from 37% in 1996 to 96.8% was observed in 2000. The rest of the strains were low sensitive. β Lactamase testing has been done since 1980. Since then, the percentage of β lactamase–positive strains gradually increased to 20% in 1989. However, with the withdrawal of penicillin as the first line of therapy, detection of PPNG strains decreased, and in 1995, no PPNG strains were isolated. During the past few years, the percentage of PPNG isolates was reported to increase to 10% to 15%. In Bangladesh, 65.0% resistance to penicillin was reported in 1997, which reduced to 33% (P < 0.001) in 1999, with highly significant (P < 0.001) increase in less-sensitive strains from 35% to 66% during the same period. However, the PPNG isolates rose from 10% in 1999 to 31% (P < 0.001) in 2000. In RRL, New Delhi, a very low level of chromosomal penicillin resistance was maintained till 1999, which increased significantly (P < 0.001) to 42.4% in 2000. A significant (P < 0.01) increasing trend was also observed in the percent of PPNG isolates from 3.4% in 1996 to 17.6% in 2000.
The trends of antimicrobial susceptibility of N. gonorrhoeae strains towards tetracycline in the 3 SEAR countries are shown in Figure 1c. In Sri Lanka, TRNG isolates were 13.5% in 1997, which reduced to 0% (P < 0.001) in 2000. In Bangladesh, between 1997 and 1999, tetracycline resistance varied from 57% to 72%, and the TRNG isolates increased significantly (P < 0.001) from 6.5% to 21%. In RRL, New Delhi, resistance was maintained between 1.7% and 12.3% from 1996 to 2000.
The trends of antimicrobial susceptibility of N. gonorrhoeae isolates towards ciprofloxacin in the 3 SEAR countries are shown in Figure 1d. In Sri Lanka, resistance to ciprofloxacin varied from 10.3% to 13.7% from 1996 to 1998 and showed a declining trend to 7.7% and 8.2% in 1999 and 2000, respectively. Monitoring of ciprofloxacin resistance from 1997 onward in Bangladesh had shown a highly significant (P < 0.001) increase in resistant strains from 9% in 1997 to 76% in 2000. A steady rise was observed in the percent resistance in the isolates from RRL, New Delhi, from 1996 to 1999, increasing significantly (P < 0.001) from 19.3% in 1999 to 76% in 2000.
No ceftriaxone less-susceptible strain was isolated till 2000 in Sri Lanka and at RRL, New Delhi, whereas Bangladesh reported reduced susceptibility to ceftriaxone from 1.0% in 1997 to 1.5% in 2000.
Spectinomycin resistance was not reported from these countries till the time of the meeting.
Penicillin was widely used for the treatment of gonorrhea for many years and is still being used in many countries. Appearance of chromosomal resistance produced a slow stepwise decline in penicillin sensitivity until clinically significant levels were reached.15
In the current report, different Indian laboratories showed varying penicillin resistance patterns and also fluctuating trends in some of them. Since 1990, use of penicillin for treatment of gonorrhea was discontinued in India, with the result that penicillin resistance (both chromosomal and plasmid mediated), as reported from New Delhi till 1999,8 was quite low. The resistance showed a steep rise to 42.4% and 66.7% in 2000 and 2001,3 respectively, along with increasing isolation of PPNGs. The low level of PPNGs, maintained during 1995 to 1999, could also be due to the widespread use of fluoroquinolones, which are able to cure strains of plasmids, as speculated earlier.16 However, the sudden rise in penicillin resistance, as well as PPNG, in the same laboratory in New Delhi,3 although difficult to explain, could be because of discontinuation of fluoroquinolones in the management of gonorrhea in this center. Penicillin resistance was also reported to be quite high in Hyderabad (79%) and Chennai (62.5%), whereas it was at a comparatively lower level (20% to 33%) in Kolkata, Nagpur, and Pune.
The alarming (96.8%) penicillin resistance reported from Sri Lanka in 2000 prompted the authorities to discontinue its use as the first line of treatment, and cefuroxime was reported to be in use, although a decline in the PPNG was earlier reported from the same city.10 In Bangladesh, a decreasing trend in penicillin resistance, along with a similar trend of PPNG isolates during 1997 to 1999, was reported. However, the subsequent rise in the incidence of PPNG isolates up to 2001 is a matter of concern.
PPNG, in particular, has the potential to spread rapidly within a community, increasing in Nigeria, for example, from 0% of isolates to 70% over a 5-year period.17 Ever since its first isolation18 in 1981, its prevalence in India has been variable. In 1999, Divekar and Gogte19 reported 94% of their isolates as PPNG, and 71% were Asian plasmids. In limited studies from Delhi20,21 also, presence of Asian plasmid could be confirmed. In other SEAR countries like Thailand,22 penicillin resistance was very high in 1997, with 17.8% of the isolates being PPNG, whereas in Indonesia,23 a high rate of PPNG without CMRNG was reported in 1998.
Wide variation in the prevalence of penicillin resistance in the same country could be due to its widespread availability, especially in subtherapeutic doses,24 as well as use of this antimicrobial as prophylaxis by CSWs25. However, the syndromic management being in use in the community, use of penicillin for therapy of STDs was limited during the period of study. In spite of this, the increasing resistance towards this antibiotic, as observed in India, could be due to the widespread use of penicillin derivatives in the treatment of unrelated illnesses. But reduction in penicillin resistance in gonococcal isolates from Bangladesh could be due to the discontinuation of the drug in treatment of many diseases, including gonorrhea. However, increase in the PPNG strains within the gonococcal isolates from the same city does not correlate with the above observation.
Tetracycline, a cheap and widely used antimicrobial, is an adjunct therapy for Chlamydia trachomatis in syndromic management of STDs, as well as in some other illnesses. High-level tetracycline resistance was first reported in 1985 from CDC Atlanta.26 In a study conducted in 1085 gonococcal isolates from prostitutes over a period of 30 months in Kinshasa, Zaire, 30% were TRNG.27 Tetracycline resistance was reported to be high in Indonesia in 1998 (100% with 94% TRNG)23 and Thailand in 1999 (55% with 7.9% TRNG).22 However, the resistance pattern reported in N. gonorrhoeae under GASP in different SEAR countries showed variable results. In spite of its frequent use, the prevalence of resistance is low in most of the focal-point laboratories in India, as well as in Sri Lanka. High percentage resistance was shown by only 3 centers in India (Hyderabad, Nagpur, and Pune, being adjacent states) and also from Dhaka, Bangladesh. Presence of TRNG was reported from Nagpur (33.8%) and Dhaka (21%). It is interesting to note that in Kolkata, which is the capital of West Bengal, and the adjacent Indian state of Bangladesh, the N. gonorrhoeae strains isolated from female CSWs did not show any tetracycline resistance.
Significant quinolone resistance, exclusively chromosomally mediated, has emerged in the WHO Western Pacific region28 and SEAR8 and has spread to many countries with a high burden of gonorrhea. Emergence may be accelerated by use of quinolones for treatment of other diseases, and rapid spread through domestic transmission seems to have occurred in Bangladesh, reporting a very high prevalence of resistance with treatment failure.29 Over a third of the isolates in 1997 here were QRNG.9 In contrast, ciprofloxacin resistance in Sri Lanka, already reported to have emerged,10 was observed to vary between 10.3% and 13.7% between 1996 and 1998 and declining to 8.2% in 2000. In other SEAR countries like Indonesia,23 the quinolone resistance was reported to be nil, while in Thailand30 it increased from 13.8% in 1998 to 25.4% in 1999. Self-prescribed prophylactic antimicrobial use and inconsistent condom use could be important factors in the continued emergence of gonococcal antimicrobial resistance in Philippines, reporting substantial increase in the proportion of N. gonorrhoeae, highly resistant to ciprofloxacin.31 Although low prevalence8 was reported earlier from Delhi, India, it has assumed an alarming proportion recently.3 The trend is also evident from Delhi (MAMC) and Hyderabad. In spite of the National AIDS Control Organisation (NACO) guidelines for management of gonorrhea with ciprofloxacin, the RRL, New Delhi, had to discontinue its use in 1996 because of treatment failure and has been using injectable ceftriaxone for the last few years to manage the clinical cases.
Very high level of activity of the broad spectrum cephalosporin (ie, ceftriaxone) against gonococci was observed in most of the laboratories. Reduced susceptibility towards ceftriaxone reported by some laboratories in India and neighboring countries should be considered with caution as this antimicrobial is used as a drug of choice in most of the centers for management of acute gonorrhea. It is important to correlate these observations with treatment efficacy. In countries like China,32 the Philippines,33 and Thailand,34N. gonorrhoeae strains having MIC ≥1 μg/mL for ceftriaxone have been reported. Two strains, isolated from one of the focal-point laboratories in India, showing reduced susceptibility towards ceftriaxone could not be confirmed at the RRL, New Delhi. The strains showed sensitive results following both NCCLS and CDS technique, but the zone sizes were close to cutoff (ie, 36 and 7 mm, 40 and 6 mm, respectively). Ceftriaxone less-sensitive strains (unconfirmed by MIC) from other laboratories were not received in RRL for confirmation. The results highlight the importance of quality assurance in the antimicrobial susceptibility techniques in different laboratories before deciding on antimicrobial policy of this important organism. Close monitoring of cephalosporin sensitivity is required, as recommended earlier from Western Pacific regional office experience.28
Spectinomycin resistance has not so far been reported from SEAR countries,16,18–20,22,23 although reports from the Philippines33 and China32 showed emergence of resistance to this antimicrobial.
To conclude, gonococcus has developed resistance to the older, as well as the newly introduced, agents, compromising the efficacy of individual case management and the control programs, highlighting the importance of the fact that the data should be generated in different parts of the globe, based on culture and antimicrobial susceptibility. Often the data are sketchy and based on single-point prevalence study, which does not indicate trend. The problem of inability to compare data from different areas arises because of use of different laboratory techniques for determining the antimicrobial susceptibility and absence of proper quality assurance in different laboratories, both internal and external. It is important that formulation of country-specific treatment guidelines for this disease be based on quality-assured antimicrobial susceptibility data collected by reference laboratories from different countries, under such programs as GASP, in order to follow the rationale recommended that a standard treatment regimen is expected to cure 95% or more of gonorrhea cases and an antibiotic should not be used when more than 5% are resistant to it.35 Once antibiotic resistance has emerged in a community and the treatment policy is not altered, the resistant strains become endemic, specially when CSWs, the high-frequency transmitters, have been infected.
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