Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1988 to 2003: the spread of fluoroquinolone resistance.

BACKGROUND: Over the past 60 years, Neisseria gonorrhoeae has acquired clinically significant resistance to sulfonamides, tetracyclines, penicillins, and ciprofloxacin. OBJECTIVE: To determine U.S. trends in the prevalence of antimicrobial resistance of N. gonorrhoeae from 1988 to 2003. DESIGN: 16-year, multisite, sentinel surveillance for gonococcal isolate susceptibility through the Gonococcal Isolate Surveillance Project (GISP). SETTING: Sexually transmitted disease clinics in 37 cities. PATIENTS: Male patients with a total of 82,064 episodes of urethral gonorrhea. MEASUREMENTS: Primary outcome measures included percentage of gonococcal isolates resistant to antimicrobials used to treat gonorrhea, percentage of patients treated with specific antimicrobials for gonorrhea, and trends of these measures over time. RESULTS: The median age of patients was 26 years, and 74.1% of patients were African American. The proportion of men treated with penicillins for gonorrhea declined from 39.5% in 1988 to 0% in 1994, while the proportion of those receiving fluoroquinolone treatment increased from 0% in 1988 to 42.0% in 2003. Penicillin resistance peaked at 19.6% in 1991, then declined to 6.5% in 2003. Tetracycline resistance peaked at 25.8% in 1997 and declined to 14.4% in 2003. The first fluoroquinolone-resistant isolate was found in 1991. Nationally, 0.4% of isolates were fluoroquinolone-resistant in 1999 and were identified in 39% of GISP cities. By 2003, 4.1% of isolates were fluoroquinolone-resistant and were identified in 70% of GISP cities. Isolates with decreased susceptibility to ceftriaxone, cefixime, azithromycin, and spectinomycin remained rare. In 2001, 3 multidrug-resistant isolates with decreased susceptibility to cefixime were identified. LIMITATION: Sentinel surveillance may not fully reflect trends for all patients with gonorrhea in the United States. CONCLUSIONS: Prevalence of penicillin resistance has declined in the years since gonorrhea treatment with penicillin was discontinued. Fluoroquinolone-resistant N. gonorrhoeae infections continue to increase at a time when fluoroquinolone use has increased. Ongoing nationwide and local antimicrobial susceptibility monitoring is crucial to ensure appropriate treatment of gonorrhea.

Fluoroquinolone-resistant Neisseria gonorrhoeae in Bali, Indonesia: 2004.

OBJECTIVES: In the mid-1990s, fluoroquinolones were introduced in Indonesia for the management of gonorrhea and are now part of the national recommended treatment guidelines. We recently documented introduction of ciprofloxacin-resistant Neisseria gonorrhoeae strains in female sex workers (FSWs) in Timika, Indonesia, 5 years after treating gonococcal cervicitis with ciprofloxacin and periodically monitoring antimicrobial susceptibility of isolates. To assess the importance of this observation, we determined antimicrobial susceptibilities and strain types of N. gonorrhoeae isolates from FSWs seen in a sexually transmitted infection (STI) clinic in Denpasar, Bali, Indonesia. GOAL: The goal of this study was to determine antimicrobial susceptibilities and strain types among N. gonorrhoeae isolated from FSWs in Denpasar, Bali. STUDY DESIGN: FSWs in Denpasar were screened for N. gonorrhoeae by standard culture. Endocervical isolates were frozen in Microbank tubes and sent to the University of California at San Francisco on dry ice. Antimicrobial susceptibility testing using a Clinical Laboratory Standards Institute-recommended agar dilution method was performed at the Centers for Disease Control and Prevention. Isolates were characterized by beta-lactamase production, antimicrobial resistance phenotypes, and auxotype/serovar class. RESULTS: One hundred forty-seven N. gonorrhoeae isolates were characterized. All isolates were highly resistant to tetracycline (minimum inhibitory concentration, >or=16.0 microg/mL): 117 (79.1%) were beta-lactamase-positive (PP-TR), 3 (2.0%) exhibited chromosomally mediated resistance to penicillin (PenR-TRNG), and 27 (18.2%) were susceptible to penicillin (TRNG). All isolates were susceptible to ceftriaxone, cefixime, and spectinomycin; lack of interpretive criteria do not allow interpretation of susceptibilities of cefoxitin, cefpodoxime, or azithromycin. Fifty-nine (40.1%) isolates were ciprofloxacin-resistant; 35 (59.3%) of the ciprofloxacin-resistant isolates exhibited high-level resistance to ciprofloxacin (Cip-HLR; minimum inhibitory concentration, >or=4.0 microg/mL of ciprofloxacin). Three (2.0%) isolates were intermediate to ciprofloxacin. Twenty-two strain types were identified among these isolates; small clusters were identified with 3 strain types. CONCLUSIONS: N. gonorrhoeae isolates from FSWs in Denpasar were resistant to penicillin and tetracycline; 40.1% of the isolates were fluoroquinolone-resistant. With gonorrhea prevalence of 35% at this clinic (by nucleic acid amplified tests), ongoing surveillance for antimicrobial resistance will be needed to appropriately choose treatment for infections caused by these resistant organisms.

Prevalence of and associated risk factors for fluoroquinolone-resistant Neisseria gonorrhoeae in California, 2000-2003.

BACKGROUND: Rates of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) are increasing worldwide and in California. METHODS: As a supplement to established surveillance, the investigation of QRNG in California included expanded surveillance in southern California, with in-depth interviews of patients (who had QRNG during the period of January 2001-June 2002) and a cross-sectional study of patients at 4 sexually transmitted diseases clinics with gonococcal isolates that underwent susceptibility testing (for the period of July 2001-June 2002). RESULTS: The rate of QRNG increased from <1% in 1999 to 20.2% in the second half of 2003. The 2001-2002 expanded surveillance demonstrated that 66 (4.9%) of 1355 isolates were resistant to fluoroquinolones; the majority of these infections occurred after August 2001. Cross-sectional analysis of 952 patients with gonorrhea revealed that the prevalence of QRNG varied geographically during 2001-2002, with the highest rate being in southern California (8.9%) and the lowest being in San Francisco (3.6%). The QRNG prevalence was 8.6% among men who have sex with men (MSM), 5.1% among heterosexual men, and 4.3% among women. Although risk factors for QRNG varied by clinic, multivariate analysis demonstrated independent associations with race/ethnicity, recent antibiotic use, and MSM. CONCLUSIONS: The emergence and spread of QRNG in California appeared to evolve from sporadic importation to endemic transmission among both MSM and heterosexuals. Monitoring of both the prevalence of and risk factors for QRNG infections is critical for making treatment recommendations and for developing interventions to interrupt transmission.

Fluoroquinolone resistance among Neisseria gonorrhoeae isolates in Hawaii, 1990-2000: role of foreign importation and increasing endemic spread.

OBJECTIVES: In 1999, an increase in ciprofloxacin-resistant Neisseria gonorrhoeae isolates was identified in Hawaii, prompting initiation of investigative studies. GOALS: The goal of this study was epidemiologic evaluation of this increase. STUDY: The authors conducted a review of laboratory data; case-series and case-control studies based on medical record review; and a prospective case-control study based on patient interviews. RESULTS: A total of 10.4% (21 of 201) of gonococcal isolates from Hawaii in 2000 were ciprofloxacin-resistant compared with <1.5% per year from 1990 to 1997. From medical record review for patients diagnosed with ciprofloxacin-resistant N. gonorrhoeae infection from 1990 to 1999, 59% were Asian/Pacific Islanders and 91% were heterosexual. From review of 1998 and 1999 sexually transmitted disease (STD) clinic medical records, patients with ciprofloxacin-resistant N. gonorrhoeae were more likely to report recent foreign travel or a sex partner with recent foreign travel than patients with ciprofloxacin-susceptible N. gonorrhoeae (6 of 12 vs. 10 of 117, P <0.001), but 50% (6 of 12) acquired a ciprofloxacin-resistant strain locally from a partner with no recent travel. In 2000, 70% (7 of 10) of STD clinic patients with ciprofloxacin-resistant N. gonorrhoeae acquired their infection locally from partners with no reported recent travel. CONCLUSIONS: Infections with ciprofloxacin-resistant N. gonorrhoeae are increasing and evolving in Hawaii.

The emergence of Neisseria gonorrhoeae with decreased susceptibility to Azithromycin in Kansas City, Missouri, 1999 to 2000.

BACKGROUND AND OBJECTIVES: We describe the first cluster of persons with Neisseria gonorrhoeae with decreased susceptibility to azithromycin (AziDS; minimum inhibitory concentration >/=1.0 microg/mL) in the United States. GOAL The goal of this study was to identify risk factors for AziDS N. gonorrhoeae and to describe isolate microbiology. STUDY DESIGN: Persons with AziDS N. gonorrhoeae (cases) were identified in Kansas City, Missouri, through the Gonococcal Isolate Surveillance Project (GISP) in 1999 and expanded surveillance, January 2000 to June 2001. A case-control study using 1999 GISP participants was conducted; control subjects had azithromycin-susceptible N. gonorrhoeae. RESULTS: Thirty-three persons with AziDS N. gonorrhoeae were identified. Case patients were older than control patients (median age, 33 years vs. 23 years; P <0.001). Fifty percent of cases and 13% of control subjects had a history of sex with a female commercial sex worker (odds ratio, 7.0; 95% confidence interval, 1.3-36.0); 50% of cases and 4% of control subjects met sex partners on street A (P <0.01). AziDS N. gonorrhoeae isolates were phenotypically and genotypically similar and contained an mtrR gene mutation. CONCLUSIONS: With few treatment options remaining, surveillance for antimicrobial-resistant N. gonorrhoeae is increasingly important, especially among persons at high risk.

Multidrug-resistant Neisseria gonorrhoeae with decreased susceptibility to cefixime-Hawaii, 2001.

We report 4 urogenital Neisseria gonorrhoeae isolates recovered from 3 patients that demonstrated resistance to penicillin, tetracycline, and ciprofloxacin and reduced susceptibility to cefixime. This report of the first 3 patients in the United States identified with this multidrug-resistant strain may portend an emerging problem for clinicians and public health officials.

Mutations causing in vitro resistance to azithromycin in Neisseria gonorrhoeae.

In 1999, a cluster of gonococcal isolates exhibiting high Minimal Inhibitory Concentrations (MICs), to azithromycin (2.0-4.0 mg/l) were identified in Kansas City, MO. Isolates were characterized by auxotype/serovar class, lipoprotein (Lip) subtyping and sequencing of the mtrR gene, which has been implicated in decreased azithromycin susceptibility in the gonococcus. Isolates were Pro/IB-3 and contained the 17c Lip subtype. Molecular characterization of the mtrR gene revealed a 153 base pair insertion sequence located between the mtrR/mtrC promoter and the mtrC gene. Some isolates also contained a frame shift within the mtrR gene. Transformation of these mutations into an azithromycin-sensitive recipient strain resulted in transformants with MICs as high as 2.0 mg/l and inactivation of the mtrD gene reduced azithromycin MICs 270-fold. These results demonstrated that the mtr mutations were responsible for the increased MICs in these isolates.

Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections--2002.

Since publication of CDC's 1993 guidelines (CDC, Recommendations for the prevention and management of Chlamydia trachomatis infections, 1993. MMWR 1993;42[No. RR-12]:1-39), nucleic acid amplification tests (NAATs) have been introduced as critical new tools to diagnose and treat C. trachomatis and Neisseria gonorrhoeae infections. NAATs for C. trachomatis are substantially more sensitive than previous tests. When using a NAAT, any sacrifice in performance when urine is substituted for a traditional swab specimen is limited, thus reducing dependence on invasive procedures and expanding the venues where specimens can be obtained. NAATs can also detect both C. trachomatis and N. gonorrhoeae organisms in the same specimen. However, NAATs are usually more expensive than previous tests, making test performance from an economic perspective a key consideration. This report updates the 1993 guidelines for selecting laboratory tests for C. trachomatis with an emphasis on screening men and women in the United States. (In this report, screening refers to testing persons in the absence of symptoms or signs indicating C. trachomatis or N. gonorrhoeae infection.) In addition, these guidelines consider tests from an economic perspective and expand the previous guidelines to address detection of N. gonorrhoeae as well as C. trachomatis infections. Because of the increased cost of NAATs, certain laboratories are modifying manufacturers' procedures to improve test sensitivity without incurring the full cost associated with screening with a NAAT. Such approaches addressed in these guidelines are pooling of specimens before testing with a NAAT and additional testing of specimens whose non-NAAT test result is within a gray zone. This report also addresses the need for additional testing after a positive screening test to improve the specificity of a final diagnosis. To prepare these guidelines, CDC staff identified pertinent concerns, compiled the related literature published during 1990 or later, prepared tables of evidence, and drafted recommendations. Consultants, selected for their expertise or disciplinary and organizational affiliations, reviewed the draft recommendations. These final guidelines are the recommendations of CDC staff who considered contributions from scientific consultants. These guidelines are intended for laboratorians, clinicians, and managers who must choose among the multiple available tests, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients.

Multiclonal increase in ciprofloxacin-resistant Neisseria gonorrhoeae, Thailand, 1998-1999.

BACKGROUND: isolates exhibiting clinically significant resistance to fluoroquinolones have been isolated most frequently in Asian and western Pacific countries, including Thailand. In Bangkok, Thailand, ciprofloxacin has been used to treat gonorrhea since 1987. GOAL: Our goal was to determine the prevalence of isolates of that exhibit resistance to ciprofloxacin in Bangkok and to characterize these strains with regard to ciprofloxacin MICs, auxotype/serovar (A/S) classification, A and C mutations responsible for ciprofloxacin resistance, and outer membrane lipoprotein (Lip) subtype analysis. STUDY DESIGN: MICs of gonococcal isolates from consecutive patients attending the Bangrak Hospital STD Clinic in Bangkok were determined by agar dilution. A/S class was determined by established procedures. Mutations within A and C were determined by DNA sequencing. Lip subtypes were determined by PCR and DNA sequencing. RESULTS: In 1998 and 1999, 115 of 168 isolated strains of exhibited decreased susceptibility or resistance to ciprofloxacin, and three cases of possible ciprofloxacin treatment failure were identified. Ciprofloxacin-resistant (CipR) strains increased from 13.8% (8/58) in 1998 to 25.4% (28/110) in 1999 ( = 0.08). Ciprofloxacin MICs of CipR isolates ranged from 1.0 microg/ml to 32.0 microg/ml. CipR strains belonged to a number of A/S classes and Lip subtypes. Different CipR strains contained alterations at both amino acid 91 and amino acid 95 of A and also contained an amino acid alteration in C. These alterations are known to be involved in gonococcal resistance to ciprofloxacin. CONCLUSIONS: The prevalence of CipR strains of isolated in Bangkok increased substantially in the 1990s. Characterization of the CipR isolates revealed a number of different strain subtypes, indicating that CipR isolates in Bangkok are not from a single clonal source and therefore result from multiple cases of importation or local emergence. Because of the high level of CipR isolates at Bangrak Hospital, in 2000 the Thai Ministry of Public Health issued recommendations against the use of fluoroquinolones for the treatment of gonococcal infection in Thailand.