Low Prevalence of Ciprofloxacin-Resistant Neisseria gonorrhoeae in Nuuk, Greenland

Pedersen, Michael Lynge MD, PhD*†; Clausen-Dichow, Pernille MD; Poulsen, Peter; Nyborg, Hanne RN; Jensen, Jørgen Skov MD, PhD, DMedSci§

Sexually Transmitted Diseases:
doi: 10.1097/01.OLQ.0000430780.79488.0f

Abstract: During a 35-day period, 32 isolates of Neisseria gonorrhoeae strains were collected by culture from patients with positive nucleic acid amplification test results in Nuuk, Greenland, where ciprofloxacin is the preferred treatment. All isolates were quinolone susceptible, suggesting that resistance is rare. Sampling patients for culture before treatment may prove useful in reestablishing surveillance.

In Brief

Antimicrobial susceptibility testing is lacking in Greenland because of nucleic acid amplification test for Neisseria gonorrhoeae, but ciprofloxacin has remained the recommended treatment. A survey suggested that quinolone resistance is rare and proposed a method for surveillance.

Author Information

From the *Greenland Center for Health Research, Nuuk, Greenland; ‡Queen Ingrid Hospital, Nuuk, Greenland; †Queen Ingrid Health Care Centre, Nuuk, Greenland; and §Statens Serum Institut, Copenhagen, Denmark

Competing interest: None declared.

Correspondence: Michael Lynge Pedersen, MD, PhD, Queen Ingrid Health Care Center, Box 3333, 3900 Nuuk, Greenland. E-mail: milp@peqqik.gl.

Received for publication January 10, 2013; and accepted April 11, 2013.

Article Outline

For decades, sexually transmitted infections including infections with Neisseria gonorrhoeae have been highly prevalent in Greenland.1–3 Thus, in 2009, a total of 1105 cases of gonorrhoea were reported, corresponding to 2589 cases per 100,000 inhabitants3 compared with only 8.9 cases per 100,000 inhabitants in Denmark in 2011.4

Previously, the diagnosis of gonorrhoea in Greenland was based on microscopy and culture of N. gonorrhoeae. However, since 2005, diagnosis of gonorrhoea has been performed with nucleic acid amplification tests (NAATs) by stand displacement amplification (Becton Dickinson ProbeTec). Testing for gonorrhoea has been performed on urine samples since January 2011 and is offered to all attendees at the Health Care Center, leading to an increase in the number of tests performed. Thus, all inhabitants in Nuuk with or without symptoms can have a free test whenever they want to without any further examinations. Patients with a positive urine test result are offered treatment with a single 500-mg oral dose of ciprofloxacin. Culture has not been widely performed in Greenland in recent years and has been totally lacking from the end of 2010, and thus, the current level of antimicrobial resistance among N. gonorrhoeae strains is unknown. In most parts of the world, ciprofloxacin-resistant N. gonorrhoeae strains have emerged, and in a 2009 European survey of gonococcal resistance among 1366 strains collected from 17 countries, 63% of all N. gonorrhoeae strains were resistant to ciprofloxacin.5 Thus, both American and European treatment guidelines have discouraged treatment with ciprofloxacin without isolation and antimicrobial susceptibility testing.6,7 Instead, treatment with an intramuscular injection of ceftriaxone is recommended. However, even this treatment is challenged because resistant N. gonorrhoeae strains have developed8 and N. gonorrhoeae may become difficult to treat in the future.9 As a consequence, the most updated guidelines now suggest a combination of ceftriaxone and azithromycin.10

Thus, a clinical practice of treating gonorrhoea in a community with a high prevalence with single-dose ciprofloxacin without monitoring for resistant strains may be very risky because resistant N. gonorrhoeae strains may develop or be introduced in Greenland.

An initiative at Queen Ingrid’s Health Care Center in Nuuk to address this problem was taken in autumn 2011. The aim of the initiative was to test the present level of ciprofloxacin resistance among strains of N. gonorrhoeae circulating in Nuuk, Greenland, and, further, to test if a clinical management that includes isolation by culture and monitoring of antimicrobial susceptibility is feasible.

Queen Ingrid Health Care Centre is the only primary health clinic in Nuuk and serves all 16,000 inhabitants in Nuuk with free health care service. The center is physically connected with the Queen Ingrid Hospital and shares facilities such as laboratory, x-ray, and so on. The Queen Ingrid Hospital also serves as a central hospital for all Greenland.

Patients attending the Health Care Centre who had a N. gonorrhoeae NAAT-positive urine sample (ProbeTec ET analyzed on a Viper automated platform; Becton, Dickinson and Company, Sparks, MD) in a 35-day period in November and December 2011 were invited to participate. At return after a positive NAAT test result, they were offered a N. gonorrhoeae culture test with subsequent ciprofloxacin susceptibility testing in addition to immediate treatment with ciprofloxacin 500 mg given as a single oral dose.

Samples for N. gonorrhoeae culture were taken from the urethra in men and from the cervix in women with a charcoal-impregnated swab and transported in Stuart transport medium to the Central Laboratory at Queen Ingrid Hospital. Isolation of N. gonorrhoeae was performed on chocolate-agar plates containing selective antibiotics (lincomycin, polymyxin B, trimetroprim, and amphotericin B). Identification of N. gonorrhoeae strains was performed on gram-negative, oxidase-positive diplococci using Minibact-N (Statens Serum Institut, Copenhagen, Denmark). Ciprofloxacin susceptibility testing was performed with Etest (AB Biodisk, Solna, Sweden) on chocolate-agar plates without antibiotics. World Health Organization reference strains G, K, M, O, and P were used for quality control and showed ciprofloxacin minimal inhibitory concentrations (MICs) within accepted ranges. Strains with an MIC for ciprofloxacin of 0.032 mg/L or less were considered susceptible. Antimicrobial susceptibility to other drugs was not determined, and because of practical issues, the N. gonorrhoeae strains were not stored for supplementary workup. No test of cure was performed because this is not routine practice in Greenland.

Variables were described using medians and quartiles (Q1–Q3). Medians were compared using Mann-Whitney test. A P value of 0.05 was used as level of significance. Estimates were calculated with 95% confidence intervals (CIs).

A total of 74 patients were identified with a N. gonorrhoeae NAAT-positive urine sample. The men (n = 36) had a median age of 26 (Q1–Q3, 21–33) years, which was higher than that among the women (n = 38) who had a median age of 21 (Q1–Q3, 18–24) years (P = 0.020).

Ninety-five percent (70/74) received standard treatment with oral ciprofloxacin for N. gonorrhoeae infection. No contact was established with 3 cases, whereas 1 person was only in transit in Nuuk and was encouraged to seek medical care at home. In total, 25 cases were not examined with culture because of the following: lack of contact (3), traveling (4), treatment in the hospital in relation to abortion (4), previous treatment in the clinic (3) or at other clinics (1), unwillingness to participate (1), lack of health care personal (3), contact established after the end of study period (3), and unknown reasons (3).

Thus, 66% (49/74) of all cases were tested for N. gonorrhoeae by culture, and N. gonorrhoeae strains were isolated from 65% (32/49) of these cases. In 75% (21/28) of men and 52% (11/21) of women, N. gonorrhoeae was successfully isolated (P = 0.100).

All 32 N. gonorrhoeae strains were susceptible to ciprofloxacin (95% CI, 0%–12%), with MICs below 0.005 mg/L (range, <0.002–0.004 mg/L).

This initiative demonstrated that the N. gonorrhoeae strains circulating in Nuuk Greenland have remained ciprofloxacin susceptible. Furthermore, a feasible way of monitoring for antimicrobial resistance in N. gonorrhoeae was demonstrated and could be implementable because 66% of all patients with an N. gonorrhoeae NAAT-positive urine sample participated in the additional testing.

The major strength of this study is that all cases of N. gonorrhoeae in Nuuk are diagnosed at the Central Laboratory of Queen Ingrid Hospital. Thus, all patients in the primary health care system in Nuuk are included in the study.

The main limitation of the study is the relatively low number of cases. Although all N. gonorrhoeae isolates were susceptible to ciprofloxacin, our estimate is not very accurate because the upper limit of the 95% CI is as high as 12%. However, we can conclude that the prevalence of resistant N. gonorrhoeae stains in Nuuk is much lower than the 50% to 75% reported from most places in Europe.5 Another limitation is that 34% of the patients with a positive urine NAAT result were not included in the study. Thus, the existence of resistant N. gonorrhoeae in this group cannot be excluded, but the patients were excluded for very different reasons and a systematic bias is therefore unlikely.

Although Greenland is an island and geographically isolated from populations in the rest of the world, daily international flights connect the population in Greenland with the population in Denmark. In addition, international flights connect Nuuk with Iceland. Although, travel between towns and settlements in Greenland is limited to flight or boat, the towns cannot be seen as totally isolated cities. Domestic traveling to visit relatives, for education, to work, and so on, is routine throughout the year. It is thus quite surprising that the N. gonorrhoeae strains isolated in Greenland seem to be so different from N. gonorrhoeae strains in, for example, Denmark. It is difficult to imagine that the N. gonorrhoeae strains circulating in Greenland should represent only local transmission of 1 or a few clonal strains as a relatively large proportion of Greenlandic youth study abroad, in particular in Denmark, where the ciprofloxacin resistance level is as high as 62% in 2011.4 Import of a ciprofloxacin-resistant strain was reported in a survey of strains collected already in 1998 to 1999,11 but apparently, this has not led to a significant spread. Unfortunately, the N. gonorrhoeae strains were not stored for supplementary analysis of susceptibility to other antimicrobials or sequence-based typing.12

In conclusion, the prevalence of ciprofloxacin-resistant N. gonorrhoeae strains in Nuuk, Greenland, seems to be low. However, this has to be evaluated in a study with power to estimate the prevalence with more accuracy and where supplementary analysis of susceptibility to other antimicrobials and sequence-based typing of the N. gonorrhoeae strains can be performed.

A feasible way of monitoring for antimicrobial resistance in N. gonorrhoeae that can be used in a new study has been demonstrated.

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