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The Emergence of Neisseria gonorrhoeae With Decreased Susceptibility to Azithromycin in Kansas City, Missouri, 1999 to 2000

McLean, Catherine A. MD*; Wang, Susan A. MD, MPH*; Hoff, Gerald L. PhD; Dennis, Lesha Y. BA; Trees, David L. PhD; Knapp, Joan S. PhD; Markowitz, Lauri E. MD*; LEVINE, William C. MD, MSc*

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Sexually Transmitted Diseases: February 2004 - Volume 31 - Issue 2 - p 73-78
doi: 10.1097/01.OLQ.0000109514.91508.FC
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SEXUALLY TRANSMITTED INFECTION (STI) resulting from Neisseria gonorrhoeae is the second most commonly reported infection in the United States with 361,705 cases reported in 2001. 1 Gonorrhea is a leading cause of pelvic inflammatory disease, ectopic pregnancy, and infertility, 2 and gonorrhea infection increases HIV transmission 3- to 5-fold. 3

Antimicrobial resistance in N. gonorrhoeae was first identified in the 1940s, soon after the introduction of antibiotics. 4 Widespread, high-level resistance to sulfonamide, penicillin, and tetracycline has limited use of these therapies, 5–8 and they are no longer recommended by the Centers for Disease Control and Prevention (CDC) for the treatment of gonorrhea in the United States. 9 Currently, fluoroquinolones, cefixime, or ceftriaxone are recommended by the CDC for the primary treatment of uncomplicated gonococcal infections.

In 1986, the CDC established the Gonococcal Isolate Surveillance Project (GISP) to monitor trends in antimicrobial resistance in N. gonorrhoeae. 10 Each month, sexually transmitted disease (STD) clinics from across the United States send the first 25 positive urethral N. gonorrhoeae cultures from men to 5 regional laboratories for antimicrobial susceptibility testing by agar dilution. In 2001, STD clinics in 26 cities contributed 5472 gonococcal isolates to GISP. 11

Azithromycin, an azilide antibiotic closely related to the macrolides, is not recommended by the CDC for the routine treatment of gonorrhea; the 1.0-g dose of azithromycin, currently recommended by the CDC for the treatment of chlamydia, 9 has low efficacy for gonorrhea, 12,13 and the 2.0-g dose can cause gastrointestinal intolerance (in approximately 30% of patients) 14 and is more expensive than other recommended regimens. However, azithromycin (2.0-g dose) is approved by the U.S. Food and Drug Administration for use for the treatment of uncomplicated gonococcal infections. 15

N. gonorrhoeae susceptibility to azithromycin has been monitored by GISP since 1992. The correlation between azithromycin minimum inhibitory concentration (MIC) for N. gonorrhoeae and treatment failure is not well-studied, and therefore, the National Committee for Clinical Laboratory Standards (NCCLS) has not established MIC criteria for azithromycin resistance 16,17; treatment failure has been reported for gonococcal isolates with azithromycin MICs of 0.125 to 0.25 μg/mL after treatment with 1.0 g of azithromycin. 18,19 For this investigation, we defined decreased susceptibility to azithromycin (AziDS) in N. gonorrhoeae as isolates with MIC ≥1.0 μg/mL.

AziDS gonococcal isolates were first identified in the United States in 1993. From 1993 through 1998, AziDS gonococcal isolates reported through GISP were geographically scattered, ranging from 1 to 26 isolates per year; in 1999, 25 (0.4%) of the 5180 gonococcal isolates submitted to GISP had AziDS. From 1993 through 1998, only 11% (6 of 56) of AziDS isolates identified through GISP were from patients from Kansas City, Missouri, but in 1999, 48% (12 of 25) of AziDS GISP isolates were obtained from patients from that city (Figure 1). 11 This large increase in number and percentage of total AziDS gonococcal isolates from a single city represents the first identified cluster of persons with gonorrhea caused by AziDS isolates in the United States. 20

Fig. 1
Fig. 1:
Neisseria gonorrhoeae with decreased susceptibility to azithromycin, Gonococcal Isolate Surveillance Project (GISP), Kansas City, Missouri, and all other GISP sites, 1992 to 1999.

This article summarizes the results of an investigation of persons with AziDS gonorrhea in Kansas City, Missouri. The objectives of the investigation were 1) to describe the demographic and behavioral characteristics of persons with AziDS gonorrhea, 2) to identify risk factors for acquiring AziDS gonorrhea, and 3) to describe the microbiology of AziDS N. gonorrhoeae isolates.


We performed a detailed description of consecutively identified cases (ie, a case series), a case-control study, and microbiologic analyses.

Case Series, 1999 to 2001

Case patients were persons diagnosed with culture-confirmed AziDS gonorrhea identified through 1) review of all Kansas City, Missouri, Health Department (KCHD) STD Clinic GISP laboratory records from January through December 1999, and 2) enhanced surveillance that was established at the time of the Kansas City investigation in January 2000 and continued through June 2001. For the enhanced surveillance, all positive gonococcal cultures from the KCHD STD Clinic and positive cultures from 3 local clinics and 1 emergency department in the Kansas City, Missouri metropolitan area were tested for decreased susceptibility to azithromycin at the CDC Neisseria Reference Laboratory.


Fig. 2
Fig. 2:
Reported gonorrhea cases and AziDSNeisseria gonorrhoeae isolates, Kansas City, Missouri, 1999 to 2000.

Case-Control Study

All participants in the case-control study had culture-confirmed gonorrhea diagnosed at the KCHD STD Clinic and were enrolled in GISP in 1999.

Case Patient Definitions

Case patients, a subset of the case-series patients, were defined as 1999 GISP patients infected with gonococcal isolates with MICs ≥1.0 μg/mL of azithromycin.

Control Patient Selection

Control patients were selected in January 2000 from 1999 GISP records and were eligible if infected with gonococcal isolates with MICs ≤0.25 μg/mL of azithromycin. For interviews, 2 control patients were selected for each case patient, and for medical record abstraction, 4 control patients were selected for each case patient. Control patients were evaluated for inclusion in the study in the following order: first, patients enrolled in GISP immediately before and after the case patient, then patients enrolled 2 before and 2 after the case patient. For each control patient whose record was not located or who we were unable to interview, the next eligible control patient was selected.

Data Collection

For the case-series and case-control study, data were collected through medical record abstraction and standardized interviews. Information abstracted from the medical record included patient’s age, race, sexual orientation, HIV test results, history of injection drug use, commercial sex work, history of STDs, and antibiotic use, and partner injection drug use, commercial sex work, and antibiotic use. Interviews were conducted by trained public health disease investigators and included questions regarding patient and sex partner travel, antibiotic use, and sexual behaviors in the month before the diagnosis of gonorrhea.

Microbiologic Studies

Gonococcal strains were isolated on modified Thayer-Martin medium, purified on chocolate agar, and identified presumptively by Gram stain and oxidase reaction. Isolates were frozen in trypticase soy broth containing 20% glycerol and stored at −20°C until shipped to the CDC on dry ice. At the CDC Neisseria Reference Laboratory, isolates were inoculated onto modified Thayer-Martin medium, subcultured on chocolate agar, and pure cultures were frozen at -70°C in trypticase soy broth containing 20% glycerol.

Antimicrobial susceptibilities were determined using methods recommended by NCCLS 16; susceptibilities were determined using GC II agar base (Becton-Dickinson, Cockeysville, MD) supplemented with 1% IsoVitaleX (Becton-Dickinson) and inoculated with 104 CFU. To detect AziDS isolates, MICs of azithromycin were determined for the first 557 isolates, and thereafter, isolates were tested for their ability to grow on medium containing 0.5 μg/mL of azithromycin (ie, MICs >0.5 μg/mL of azithromycin). Isolates that either had an MIC ≥1.0 μg/mL of azithromycin or demonstrated the ability to grow on medium containing 0.5 μg/mL of azithromycin and confirmed with an MIC ≥1.0 μg/mL of azithromycin were characterized by 1) susceptibilities to azithromycin, cefixime, ceftriaxone, ciprofloxacin, penicillin, spectinomycin, and tetracycline; 2) auxotype 21 and serovar 22; and 3) Lip subtyping 23 as described previously.

Statistical Methods

Data were analyzed using EpiInfo (version 6.02; CDC). Categorical variables were analyzed using the chi-squared test (2-tailed). Fisher’s exact test was used when an expected value was less than 5. Medians of continuous variables were compared using the Kruskal-Wallis test.


Case Series, 1999 to 2001

A total of 1248 N. gonorrhoeae isolates were tested at the CDC Neisseria Reference Laboratory; of these, 33 AziDS isolates were identified. Overall, 12 of 33 isolates were identified as AziDS at the GISP Regional Laboratory in 1999, and the remaining 21 AziDS isolates were detected among 1236 isolates collected through enhanced surveillance from January 2000 through June 2001. Three of the enhanced surveillance isolates were also identified through GISP. No AziDS gonococcal isolates were identified in 2001. Two AziDS gonococcal isolates were cultured from 1 patient, separated by 5 months. AziDS gonococcal isolates were obtained from 31 patients evaluated at the KCHD STD clinic, 1 patient at a general medical clinic and 1 at the emergency department.

Data were abstracted from medical records for the 32 case patients. Of the 32 case patients, 20 (62%) were men and 12 (38%) were women. The median age of male case patients was 31 years (range, 16–46 years) and of female case patients, was 21 years (range, 16–53 years). Case patients resided in 11 different zip codes. Two (6%) of 32 case patients were female commercial sex workers, and 9 (29%) of 31 case patients had had a sex partner who was a female commercial sex worker.

Of 32 case patients, 31 (97%) were interviewed. In the 30 days before their gonorrhea diagnosis, 3 (10%) of 29 used antibiotics, 9 (31%) of 29 used nonprescription drugs, 6 (21%) of 29 gave drugs or money for sex, and 10 (32%) of 31 reported meeting sex partners on the street. Overall, 19 (63%) of 30 case patients reported a history of N. gonorrhoeae infection, and 7 (64%) of 11 women and 6 (35%) of 17 men reported a history of Chlamydia trachomatis infection.

Case-Control Study, 1999 to 2000

Medical Record Abstraction.

Medical records were located for the 12 case patients. Of the 48 eligible control patients selected, medical records could not be located for 2, and 2 additional control patients were selected. Case patients were older than control patients (median age, 33 years vs. 23 years; P <0.001) and were more likely to have reported sexual contact with a female commercial sex worker (50% vs. 13%; P <0.05). There were no differences in race, ethnicity, HIV status, or proportion of patients who were men who have sex with men, had used antibiotics in the prior month, or had been previously diagnosed with gonorrhea at the KCHD STD Clinic.


We were able to interview all 12 (100%) case patients. Of the 24 eligible control patients selected for interviews, 7 either did not respond or refused to participate, and the next eligible control patients were selected. We contacted 31 eligible control patients to obtain 24 interviews; all interviews were conducted within 2 months of selecting the control patients. All control patients interviewed were also control patients for the medical record abstraction.

The case patients were more likely than the control patients to have had a new sex partner in the month before the diagnosis of gonorrhea (92% vs. 46%; P <0.05) and were more likely to have had a sex partner who received drugs or money for sex (67% vs. 6%; P <0.01)(Table 1). Fifty percent (6 of 12) of the case patients compared with 4% (1 of 24) of the control patients reported meeting a sex partner on street A (P <0.01); 3 of these case patients reported sex with a partner who received drugs or money for sex. We found no association between infection with AziDS N. gonorrhoeae and travel.

Characteristics and Behaviors Associated With Gonorrhea With Decreased Susceptibility to Azithromycin Among Men, Case-Control Study, Kansas City, Missouri, 1999–2000

Microbiologic Studies

Of the 33 AziDS gonococcal isolates, the median azithromycin MIC was 2.0 μg/mL (range, 1.0–4.0 μg/mL). All 33 isolates were susceptible to cefixime (median MIC, 0.03 μg/mL; range, 0.015–0.06 μg/mL), ceftriaxone (median MIC, 0.008 μg/mL; range, 0.002–0.015 μg/mL), ciprofloxacin (median MIC, 0.002 μg/mL; range, approximately 0.002–0.008 μg/mL), and spectinomycin (all ≤256 μg/mL). Isolates exhibited MICs of 0.25 to 1.0 μg/mL (median MIC, 0.5 μg/mL) of penicillin (resistance = MIC ≥2.0 μg/mL) and MICs of 0.5 to 2.0 μg/mL (median MIC, 1.0 μg/mL) of tetracycline (resistance = MIC ≥2.0 μg/mL), respectively. All 33 isolates belonged to the serovar IB-3 and Lip subtype 17c. Two auxotypes were represented: 22 (67%) isolates were proline-requiring and 11 (33%) isolates were prototrophic (nonrequiring). Further laboratory evaluation of 12 of the 33 AziDS N. gonorrhoeae isolates identified a mutation of the mtrR gene resulting from a 153 base pair DNA insert, which was responsible for the decrease in susceptibility to azithromycin. 24


This cluster of persons with AziDS gonorrhea is the first reported in the United States. Infection with AziDS gonorrhea in Kansas City, Missouri was associated with older age, sex with a new sex partner, sexual contact with female commercial sex workers, and meeting sex partners on street A. Although evidence suggests that penicillin, tetracycline, and fluoroquinolone resistance in N. gonorrhoeae emerged in Asia and were subsequently imported to the United States, 7,8,20,25 we found no association between AziDS gonorrhea and travel.

The microbiologic studies indicate that the 33 AziDS gonococcal isolates are phenotypically and genotypically similar, suggesting that persons with AziDS gonorrhea in this cluster in Kansas City could be epidemiologically linked. Although we were able to identify few sexual associations, case patients could have been exposed to a common source of AziDS gonorrhea, possibly through common sex partners involved in exchanging money or drugs for sex on street A.

Our findings are consistent with previous studies that have identified older age and sex with a commercial sex worker as risk factors for acquiring antibiotic resistant gonorrhea. 26 We also found that having one or more new sex partners and meeting sex partners on street A were associated with AziDS gonorrhea. Because we did not compare risk factors for different types of antibiotic resistant gonorrhea in Kansas City, we cannot determine which of the identified risk factors could be specific for AziDS gonorrhea.

The association of AziDS gonorrhea and sexual contact with women exchanging money or drugs for sex suggests that the prevalence of this strain may be high among sex workers. Although we do not know what the behavioral risk factors for AziDS gonorrhea are among these women, hypotheses include frequent antibiotic use (possibly taken before or after sex) or widespread use of azithromycin among sex workers in this community for community-acquired infections.

There are several limitations to these data. First, our participants are a limited sample. GISP, our primary source of cultures, might not be representative of all persons with AziDS gonorrhea in Kansas City, because GISP only collects specimens and information from men attending public STD clinics, and we could have failed to identify some risk factors that are more prevalent among women and among persons seeking care from private providers. Enhanced surveillance was limited to persons evaluated in public settings because most private laboratories in Kansas City were using nonculture methods (particularly nucleic acid probe tests) for gonorrhea diagnosis. Second, recall bias could have led to an overestimate of risk among the case patients. However, corroboration of the interview data with the medical record data supports the validity of the association of AziDS gonorrhea with sexual contact with commercial sex workers. Third, interviewer bias was possible. Study personnel were not masked to the disease status of participants and could have elicited risk factor information more thoroughly from case patients than from control patients. The lack of blinding in this study could have led to an overestimate of case patient risk; however, the study personnel were trained to collect information from both case and control patients in a consistent manner.

Azithromycin is an antibiotic commonly used by clinicians because of the long half-life and convenient single-dose therapy for many infections. 27 However, this same asset could be a liability because it creates conditions likely to foster the development of antimicrobial resistance. After ingestion of azithromycin, other bacteria in the body are exposed to azithromycin, potentially at low levels, and prolonged exposure to low levels of an antibiotic may facilitate the development of resistance. Azithromycin is currently widely used in STD control programs; CDC recommends azithromycin (1.0 g) for the treatment of C. trachomatis infections and as cotreatment for presumed C. trachomatis infection in persons being treated for gonorrhea with another drug. Therefore, STD clinic patients, who are at high risk for being infected with N. gonorrhoeae, are likely to be exposed to azithromycin, possibly increasing the selective pressure for azithromycin resistance. If azithromycin is used to treat gonorrhea, the 2.0-g dose should be used because the 1.0-g dose has limited efficacy against N. gonorrhoeae.

In the face of increasing azithromycin use for treatment of C. trachomatis and other community-acquired infections, 27 azithromycin resistance in N. gonorrhoeae could further limit the diminishing number of available antibiotics for the treatment of gonorrhea.

With the emergence of increasing antimicrobial resistance in N. gonorrhoeae, the decrease in local capacity to culture gonorrhea and to conduct gonococcal antimicrobial susceptibility testing is concerning. 11 Even where gonococcal antimicrobial susceptibility testing is conducted, azithromycin is rarely one of the antibiotics tested. 11

Numerous antibiotics are no longer appropriate for use in treating gonorrhea, including penicillin, tetracycline, and, in some communities, fluoroquinolones. 9 The emergence of AziDS gonorrhea globally, 28–30 along with the rapid increase in fluoroquinolone resistance 20,31,32 and the identification of gonococcal isolates with decreased susceptibility to cefixime, 33 is worrisome and a reminder of the urgent need to protect the effectiveness of azithromycin and other antibiotics that are active against N. gonorrhoeae. With few treatment options remaining for N. gonorrhoeae infections, surveillance for antimicrobial-resistant N. gonorrhoeae is becoming increasingly important, especially among persons at high risk, including those participating in commercial sex work.


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