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Original Study

Trends of Resistance to Antimicrobials Recommended Currently and in the Past for Management of Gonorrhea in the Apex STD Center in India and Comparison of Antimicrobial Resistance Profile Between 2002–2006 and 2007–2012

Bala, Manju MD; Singh, Vikram PhD; Bhargava, Aradhana MD; Ramesh, V MD

Author Information
Sexually Transmitted Diseases: April 2015 - Volume 42 - Issue 4 - p 218-222
doi: 10.1097/OLQ.0000000000000261

Gonorrhea infections are the second most common prevalent sexually transmitted bacterial infections causing considerable morbidity globally each year.1 Recent global estimates by the World Health Organization (WHO) suggest that of the estimated 106 million every year, most occurred in Southeast Asia, sub-Saharan Africa, and South and Central America. Gonococcal antimicrobial resistance (AMR) severely compromises control of gonococcal disease, preventing effective treatment for individuals, increasing the rate of morbidity and complications, and enhancing the transmission of HIV. Neisseria gonorrhoeae strains have developed a high level of resistance against all antimicrobial agents that have been introduced as first-line treatment of the infection. Decreased susceptibility or resistance to extended-spectrum cephalosporins (ESCs), currently recommended for treatment of uncomplicated gonococcal infections, has been documented in numerous countries worldwide including Asia, Africa, Australia, the United States, and Europe.2–9 In recent years, the extensively drug-resistant N. gonorrhoeae isolates, with ceftriaxone treatment failures, were reported posing an increasing problem in the management of gonorrhea.10–12

Antimicrobial resistance surveillance is recommended to guide therapy in individual patient, monitor AMR trends, and follow the emergence and spread of new resistant strains. Recognizing the need for ongoing surveillance of gonococcal AMR, the WHO established a surveillance program in different regions of the world known as the Gonococcal Antimicrobial Surveillance Program (GASP) in 1990.13 The Gonococcal Antimicrobial Surveillance Program has been effective in encouraging countries to develop appropriate infrastructure and methods for testing gonococcal isolates for antimicrobial susceptibility. Collation of GASP data assists national health administrations to base or amend their treatment policies. Regular monitoring of antimicrobial susceptibility is being carried out at this center since 1996 till date,4,14–19 and this center is functioning as the Regional Reference Laboratory for WHO GASP in the South-East Asia Region (SEAR) since 1999.20–22 Antimicrobial resistance trend data from India for the years 1996–1999, 2000–2001, and 2002–2006 have been reported earlier.4,14,15 In the present study, we analyzed the AMR profile and trends in resistance to antimicrobials used in the past and at present for treatment of gonorrhea over a 6-year period, 2007 to 2012, and compared the recent AMR data with published trends in 2002 to 2006.4

MATERIALS AND METHODS

Two hundred sixty-one N. gonorrhoeae isolates were collected from all male and female patients presenting with acute gonococcal urethritis and cervical discharge to the male and female STD clinic of Apex Regional STD Teaching, Training and Research Centre, Safdarjung Hospital, New Delhi, India, from January 2007 to December 2012. Isolates were from consecutive patients and nonrepetitive (1 per patient). Standard protocols were used for isolation and identification of N. gonorrhoeae.15,23

All isolates were tested for antimicrobial susceptibility using Oxoid antibiotic disks for penicillin, tetracycline, ciprofloxacin, spectinomycin, ESCs (ceftriaxone, cefpodoxime), and azithromycin by disk diffusion method using the Calibrated Dichotomous Sensitivity (CDS) technique.24,25 Cefixime testing was performed by the Clinical and Laboratory Standards Institute disk diffusion method using GC agar base with 1% isovitalex or vitamino growth supplement as interpretation criteria for cefixime by the CDS method is not available.26 Minimum inhibitory concentration (MIC) testing for the above antibiotics was performed by the Etest method (AB Biodisk, Solna, Sweden) on GC agar (Difco Laboratories, Detroit, MI) containing 1% vitamin growth supplement or isovitalex. The Etest was performed as specified in the manufacturer’s product package insert. All isolates were tested by the CDS technique and the Etest after first subculture, and no batch testing was performed. Susceptibility testing for cefpodoxime by the CDS method started in December 2009 and by Etest in November 2012. Cefixime testing by Etest started in January 2012. The strains were defined as susceptible, less susceptible, and resistant.24,26,27 The interpretive criteria for defining susceptibility category by the CDS technique and the Etest are depicted in Supplementary Table, http://links.lww.com/OLQ/A104.

N. gonorrhoeae isolates were tested for β-lactamase production by the chromogenic cephalosporin method using nitrocefin freeze-dried powder (Oxoid, Hampshire, UK) or a nitrocefin slide (Becton, Dickinson and Company, Sparks, MD). Preservation of clinical isolates and WHO reference strains was carried out by lyophilization and deep freezing at −70 °C.28

The χ2 test was applied for comparison of trend data, and P value was determined. P values less than 0.05 were considered statistically significant. The level of agreement between the CDS and Etest technique was calculated.25

Quality control was performed using the WHO reference strains (A–E and F–P) for disk diffusion technique and MIC testing. WHO GASP Regional Reference Laboratory for SEAR countries is participating in external quality assurance scheme (EQAS) of Gonococcal Antimicrobial Susceptibility Testing every year from the year 2000 conducted by Neisseria Reference Laboratory, WHO Collaborating Centre for STD and HIV, Department of Microbiology, The Prince of Wales Hospital, Sydney, Australia. Under this EQAS, 6 lyophilized quality assurance strains were received every year from the reference laboratory. The results of antimicrobial susceptibility testing of these strains were communicated, and feedback was received. The results of EQAS every year showed 100% agreement with the reference laboratory results, except that 1 strain each for ceftriaxone in 2002 and 2013 and 1 strain for penicillin in 2004 showed some disagreement of results. On repeat testing, 100% agreement was observed.

RESULTS

AMR Profile and Trends in 2007 to 2012

The status of antimicrobial susceptibility profile and trends of AMR for different antimicrobials between 2007 and 2012 are shown in Table 1. The susceptibility category for all the antibiotics, except cefixime, in Table 1 is based on the Etest MICs values, as the level of agreement between the CDS technique and the Etest was not 100%. The interpretive percentage agreement between the CDS and Etest method was found to be 96.2%, 95.4%, 98.5%, 100%, 98.5%, and 100% for penicillin, ciprofloxacin, ceftriaxone, azithromycin, tetracycline, and spectinomycin, respectively. During the study period, overall chromosomal and plasmid-mediated penicillin resistance was observed to be 53.3%, and most of the resistant strains produced β-lactamase (47.9%). The rate of chromosomally mediated resistance (CMR) to penicillin increased (χ2 = 0.29, P > 0.05) from 9.1% in 2007 to 13.2% in 2010, but it decreased (χ2 = 0.89, P > 0.05) to 7.3% in 2012. The frequency of penicillinase-producing N. gonorrhoeae (PPNG) rate increased significantly (χ2 = 7.04, P < 0.05) from 36.4% in 2007 to 65.4% in 2012.

TABLE 1
TABLE 1:
Year-Wise Antimicrobial Susceptibility Pattern ofN. gonorrhoeae Isolates From 2007 to 2012

For tetracycline, of 261 isolates, 66 (25.3%) and 195 (74.7%) were tetracycline-resistant N. gonorrhoeae (TRNG) and non-TRNG, respectively. Of 195 non-TRNG isolates, 12.3%, 30.6%, and 31.8% were CMR, less susceptible, and susceptible, respectively. Tetracycline-resistant N. gonorrhoeae isolates increased significantly (χ2 = 11.16, P = 0.0008) from 12.1% in 2007 to 51.9% in 2011. The rate of TRNG decreased insignificantly (χ2 = 2.78, P > 0.05) from 51.9% in 2011 to 32.7% in 2012.

During the overall study period, of 89.7% ciprofloxacin-resistant isolates, 42.1% had high-level resistance (HLR). Ciprofloxacin-resistant isolates including HLR increased significantly (χ2 = 8.69, P = 0.003) from 75.8% in 2007 to 96.3% in 2012. The rate of HLR isolates was 27.3% in 2007, which increased significantly (χ2 = 9.14, P = 0.002) to 63.2% in 2010 and decreased insignificantly to 52.7% (χ2 = 0.99, P = 0.31) in 2012.

The decreased susceptibility to ceftriaxone was found to be 1.8% in 2008, which increased significantly to 15.8% (χ2 = 6.58, P < 0.05) in 2010. However, it decreased subsequently in 2011 and 2012 to 11.1% and 1.8%, respectively, and its decrease was significant in 2012 (χ2 = 6.30, P < 0.05). All 11 isolates with decreased susceptibility to ceftriaxone during the study period were also having decreased susceptibility to cefixime and cefpodoxime. Of these 11 strains, 3 were also resistant to penicillin, tetracycline, and ciprofloxacin and 7 were resistant to penicillin and ciprofloxacin. None of these strains was resistant to azithromycin.

Susceptibility to spectinomycin did not change between 2007 and 2012, and no less susceptible and resistant strains were identified. Only 2%, 2.6%, and 3.6% were resistant to azithromycin in 2009, 2010, and 2012, respectively; all remaining isolates were susceptible.

Comparison of AMR Profile in 2007 to 2012 With 2002 to 2006

Comparison of antimicrobial susceptibility profile for various antibiotics between the 2 periods, that is. 2007 to 2012 and 2002 to 2006 are shown in Figure 1. In comparison of overall results between the 2 periods (2002–2006 and 2007–2012), PPNG increased significantly (χ2 = 50.72, P < 0.0001) from 21.2% to 47.9%. The frequency of TRNG strains was 13.6% in 2002 to 2006, which almost doubled (25.3%) in 2007 to 2012 (χ2 = 14.10, P = 0.0002). The resistance rate of ciprofloxacin increased significantly (P = 0.0001) from 78% in 2002 to 2006 to 89.7% in 2007 to 2012. Ciprofloxacin HLR strains were 25.9% in 2002 to 2006, and its increase was highly significant (χ2 = 18.62, P < 0.0001) to 42.1% in 2007 to 2012.

Figure 1
Figure 1:
Comparison of antimicrobial susceptibility profile ofN.gonorrhoeae isolates for different antibiotics in 2 periods.

An insignificant increase (χ2 = 1.78, P > 0.05) in decreased susceptibility to injectable third-generation cephalosporin and ceftriaxone was observed. This increased from 2.4% in 2002 to 2006 to 4.2% in 2007 to 2012. Antimicrobial resistance profile for oral third-generation cephalosporins cefixime and cefpodoxime could not be compared with 2002 to 2006 data because testing for cefixime and cefpodoxime started in May 2006 and December 2009, respectively. All isolates were susceptible to spectinomycin over both the periods, except for 1 isolate in 2002. Susceptibility testing for azithromycin started in November 2004, and 133 isolates were tested from November 2004 to December 2006. During this period, 1 (0.8%) isolate was resistant to azithromycin and azithromycin resistance increased insignificantly (χ2 = 0.43, P > 0.05) to 1.5% in 2007 to 2012.

DISCUSSION

The emergence of N. gonorrhoeae strains resistant to ESCs, the antibiotics used as the first-line treatment of uncomplicated gonococcal infections, is now a serious concern worldwide because it may lead to untreatable gonorrhea.10–12 The present study reported high rates of resistance to penicillin, tetracycline, and ciprofloxacin, previously recommended for treatment of gonorrhea. It also revealed decreased susceptibility to cephalosporins and resistance to azithromycin recommended currently as first-line drugs in syndromic management or in dual therapy in many countries. Comparisons of AMR profile of 2007 to 2012 with that of 2002 to 2006 (published)4 have documented the pattern of AMR in N. gonorrhoeae, highlighting the alarming increase in rates of resistance to many previously recommended antibiotics, although these antibiotics are no longer used for management of gonorrhea in India.

The percentage of resistance to penicillin increased considerably during the period of study and is coherent with reports from Kenya (65%), other centers in India (Pune 25%, Delhi All India Institute of Medical Sciences (AIIMS) 60.7%, Hyderabad 58.1%, Kolkata 78.9%, Nagpur 60%, Delhi Maulana Azad Medical College (MAMC) 100%), and SEAR countries such as Bhutan, Myanmar, Sri Lanka, Thailand (67–97%), and Ethiopia (94.4%).2,22,29 Throughout the study period, the contribution of PPNG isolates (47.9%) to overall penicillin resistance was higher as compared with N. gonorrhoeae isolates with chromosomally mediated penicillin resistance (5.4%). The findings are similar to those from Kenya, Thailand, South America, and the Caribbean.2,22,30 The reason for this consistency may be because of the mode of transfer of resistance determinants between N. gonorrhoeae isolates. β-Lactamase plasmid can be mobilized between N. gonorrhoeae isolates by the transfer plasmid. However, low levels of resistance to penicillin were reported from areas of remote Australia and some Pacific Islands, where penicillin is still in clinical use.6

The very high occurrence of tetracycline-resistant and less susceptible strains to the extent of 74.7% in this study is comparable with reports from other countries (Kenya 97%, Thailand 82%, Indonesia 100%, Ethiopia 92.6%,).2,22,29 Some exceptions were noted in the United States,5 where tetracycline resistance rates were only 22.5% and rates in South America and the Caribbean decreased from a level of 61.1% of isolates tested in 2001 to 21.8% in 2010.30 This high percentage of resistance to tetracycline indicates that this antibiotic is certainly not appropriate for gonorrhea treatment in India and other countries.

Ciprofloxacin resistance including HLR strains varied between 75.8% and 97.4% during the study period. Similarly, high rates of resistance to ciprofloxacin have been demonstrated in other centers in India (Hyderabad 35.5%, Chennai 52.4%, Kolkata 68.4%, Nagpur 80%, AIIMS Delhi 93.7%, Pune 100%) and SEAR countries (81%–100% in 2009–2012),22 Western Pacific Region (WPR) countries (29%–97%, 2010),6 countries in Latin America and Caribbean (1.6%–42.1%, 1997–2010),30 Kenya (9.5%–50%, 2007–2009),2 and European countries (42%–52%, 2006–2008).31 The increasing trend of PPNG, TRNG, and HLR to ciprofloxacin observed in India may reflect ongoing selective pressure produced by the use of these antibiotics to treat other infections.

Extended-spectrum cephalosporins are presently the drug of choice for the treatment of gonorrhea. Recent reports on gonorrhea treatment failures with extended spectrum cephalosporins has put a question mark on the prolonged existence of this class of antibiotics as a single-dose treatment of gonorrhea.8–11 Hence, dual therapy is recommended to address the potential emergence of gonococcal cephalosporin resistance as per recent Centers for Disease Control and Prevention and European treatment guidelines.32,33 Other countries have also implemented these guidelines. In our study, decreased susceptibility to 3 ESCs (ceftriaxone, cefixime, cefpodoxime) was observed to be 15.8% and 11.1% in 2010 and 2011. The decreased susceptibility to all 3 ESCs significantly decreased to 1.8% in 2012. In the United States, the percentage of isolates with elevated cefixime MICs increased from 0.1% in 2006 to 1.4% in 2010, but remained stable in 2011 to 2012. However, MIC breakpoints for ceftriaxone were 0.06 to 0.25 mg/L in the present study, and in the USA study, breakpoints were at least 0.125 mg/L for ceftriaxone and at least 0.25 mg/L for cefixime. It has been proposed that routine use of dual therapy and a higher dose of ceftriaxone cured infections more effectively and slowed the transmission of strains with reduced cefixime susceptibility.5 We have not received any reports of ceftriaxone or cefixime clinical treatment failures in India. Since ceftriaxone-resistant isolates were identified in Japan (2009), France (2010), and Spain (2011),10–12 a real threat now exists that extensively resistant strains of N. gonorrhoeae may emerge and spread worldwide. Enhanced surveillance for resistance against other antigonococcal agents is therefore warranted.

In this study, we observed no resistance to spectinomycin, except for 1 strain in 200216. No resistance was reported, even from the United States also in January 2006 to June 2012, from other centers in India in 2009 to 2012, and from Kenya in 2002 to 2009.2,5,22 Spectinomycin resistance has been reported sporadically and at low levels in Western Pacific Region, SEAR countries, and South America.6,22,34 Spectinomycin is an effective alternative drug of choice for the treatment of uncomplicated gonorrhea, especially in those patients who cannot tolerate cephalosporins. However, spectinomycin is not easily available in India and many other countries, and this is the most likely reason for its consistent susceptibility in most of the countries.

The results of our study indicate that N. gonorrhoeae isolates were highly susceptible (>95%) to azithromycin. It is important to monitor azithromycin resistance, particularly because the gonococcal population is frequently exposed to this drug, as it is recommended currently in the syndromic management (cefixime 400 mg + azithromycin 1 gm) for treating Chlamydia trachomatis coinfection. Syndromic management is recommended in India by National AIDS Control Organization guidelines to treat all cases diagnosed with urethral and cervical discharge syndrome. Because of over-the-counter availability of antibiotics in India and easily available syndromic management, a major challenge to monitoring AMR of N. gonorrhoeae was the substantial decline in capability of laboratories to perform essential gonorrhea culture techniques required for antibiotic susceptibility testing. Therefore, NACO has developed operational guidelines for 10 regional STI centers and 45 state reference centers for STIs in India. According to these guidelines, syndromic management in these 55 centers needs to be validated by etiological tests and antimicrobial susceptibility testing of N. gonorrhoeae, which is of global concern, and needs to be monitored on a regular basis. Linkage of these 55 centers is being established with WHO GASP so as to provide timely technical support to the sites concerned and the national program for modifying treatment protocols if required.35

To conclude, the increasing AMR pattern to a variety of antimicrobials of gonorrhea in developing countries like India will be without any doubt a rising serious public health crisis during the coming years and may possibly influence future treatment of gonorrhea, which will be more complicated. The surveillance data presented by this study will help to guide clinicians in India in the selection of appropriate antimicrobial treatment and to be able to update treatment recommendations so as to assist in disease control. This study did not include any pharyngeal and rectal N. gonorrhoeae isolates. It is important to study drug resistance in these isolates because pharyngeal and rectal infections are harder to treat than urogenital infection and represent an asymptomatic reservoir for infection and emergence of resistance. It has been reported that extensively drug-resistant N. gonorrhoeae strains were isolated from pharyngeal infection cases from different countries.10–12 The observations underscore the need for broader susceptibility surveillance studies in pharyngeal and rectal isolates to elucidate the pattern and extent of drug resistance in India.

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