Joan S. Knapp

Antimicrobial Resistance in Neisseria gonorrhoeae in the United States, 1988–1994: The Emergence of Decreased Susceptibility to the Fluoroquinolones

Antimicrobial susceptibilities of Neisseria gonorrhoeae have been prospectively determined in the Gonococcal Isolate Surveillance Project of the Centers for Disease Control and Prevention. From 1988 through 1994, susceptibilities were determined for 35,263 isolates from 27 clinics. Patients were demographically similar to those in nationally reported gonorrhea cases. In 1994, 30.5% of isolates had chromosomally or plasmid-mediated resistance to penicillin or tetracycline. Penicillin resistance increased from 1988 (8.4%) to 1991 (19.5%) and then decreased in 1994 (15.6%). Tetracycline resistance decreased from 1988 (23.4%) to 1989 (17.3%) and then increased in 1994 (21.7%). Most isolates (99.9%) were highly susceptible to broad-spectrum cephalosporins. Isolates with decreased susceptibility to ciprofloxacin increased from 1991 (0.4%) to 1994 (1.3%); 4 isolates were ciprofloxacin-resistant. Ciprofloxacin-resistant strains may not respond to therapy with recommended doses of fluoroquinolones, and the clinical importance of strains with decreased susceptibility is unknown. The emergence of fluoroquinolone resistance in N. gonorrhoeae in the United States threatens the future utility of this class of antimicrobials for gonorrhea therapy.

Presence of antibodies to the major anaerobically induced gonococcal outer membrane protein in sera from patients with gonococcal infections.

Anaerobically grown Neisseria gonorrhoeae induces and represses the synthesis of outer membrane proteins. One of the anaerobically induced proteins, Pan 1, reacted strongly on Western blots with sera from patients with uncomplicated gonococcal infection, pelvic inflammatory disease, and disseminated gonococcal infection, but not with normal human serum. The pattern of reactivity of the sera against Pan 1 from several gonococcal strains suggested that the protein was antigenically heterogeneous, containing both common and unique epitopes. Staphylococcus aureus V8 protease digestion of Pan 1 from four gonococcal strains revealed the presence of common peptides, with one strain also containing some unique peptides and lacking others. The class of the antibody reactive with gonococcal outer membrane antigens was examined; anti-Pan 1 antibody was found to be IgG or IgM, but not IgA. The IgM antibody present reacted predominantly with Pan 1. These data indicate that the Pan 1 protein is expressed in vivo and strongly suggest that N. gonorrhoeae can grow anaerobically in vivo.

Molecular epidemiology of Neisseria gonorrhoeae exhibiting decreased susceptibility and resistance to ciprofloxacin in Hawaii, 1991-1999

Background Clinically significant resistance to Centers for Disease Control and Prevention (CDC)-recommended doses of fluoroquinolones (ciprofloxacin and ofloxacin) has been reported for Neisseria gonorrhoeae. In Hawaii, fluoroquinolone-resistant gonococcal isolates were first identified in 1991. Goal To assess the diversity, based on phenotypic and genotypic characterization, of gonococcal isolates exhibiting decreased susceptibility (CipI; MICs = 0.125–0.5 &mgr;g/ml) or clinically significant resistance (CipR; MICs ≥ 1 &mgr;g/ml) to ciprofloxacin in Hawaii from 1991 through 1999. Study Design Antimicrobial susceptibilities, auxotype/serovar (A/S) class, GyrA/ParC alteration patterns, and plasmid profiles were determined for gonococci isolated in Honolulu from 1991 through 1999 that exhibited intermediate or clinically significant resistance to ciprofloxacin. Strain phenotypes were defined by A/S class, GyrA/ParC alteration pattern, and penicillin–tetracycline resistance phenotype supplemented with plasmid profiles for &bgr;-lactamase–producing isolates. Results Altogether, 68 isolates exhibiting intermediate or clinically significant resistance to ciprofloxacin belonged to 23 and 19 strain phenotypes, respectively. Among the CipI and CipR isolates, 4 and 13 GyrA/ParC alterations patterns were identified, respectively. The 91,95/Asp-86 alteration pattern occurred most frequently among CipR isolates. Forty-four strain phenotypes were represented by only one isolate. In addition, seven pairs and two clusters of isolates were identified. Conclusions From 1991 through 1997, few gonococcal strains exhibiting intermediate or clinically significant resistance to CDC-recommended doses of fluoroquinolones were identified from Hawaii. Isolates belonged to a large number of phenotypic and genotypic types, suggesting that most cases were imported, with only a few instances in which isolate pairs indicated that secondary transmission of infections had occurred in Hawaii. Beginning in 1998, the number of CipR isolates increased markedly, and more isolates belonged to fewer phenotypic and genotypic types, suggesting either more frequent importation of fewer strain types or the possibility that the endemic spread of a few strains is beginning to occur.

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 &mgr;g/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.

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.

Molecular epidemiology in 1994 of Neisseria gonorrhoeae in Manila and Cebu City Republic of the Philippines.

Background and Objectives: Failure of gonococcal infections to respond to 500 mg of ciprofloxacin or 400 mg of ofloxacin has been reported from Australia, the United Kingdom, and the United States. Recently, high rates of decreased susceptibility to the fluoroquinolones have been detected in penicillinase‐producing Neisseria gonorrhoeae in the Republic of the Philippines. Goals: To assess the diversity of antimicrobial‐resistant gonococcal strains isolated from female sex workers in Manila and Cebu City in the Republic of the Philippines in 1994. Study Design: Isolates of N. gonorrhoeae isolated from 92 female sex workers in Manila (n = 28) and Cebu City (n = 64), respectively, were characterized by plasmid profile, auxotype/serovar class, and antimicrobial susceptibility profile. Results: Plasmid‐mediated resistance to penicillin or tetracycline was identified in 79.3% (73/92) of the isolates: penicillinase‐producing N. gonorrhoeae (65/92; 70.7%), tetracycline‐resistant N. gonorrhoeae (6/92; 6.5%), and penicillinase‐producing/tetracycline‐resistant N. gonorrhoeae (1/92; 1.1%). A β‐lactamase plasmid of 3.9 megadaltons was discovered. Of 54.3% (50/92) of strains resistant to nalidixic acid, 84% (42/50) of strains had minimum inhibitory concentrations of ≥0.125 μg/ml ciprofloxacin; penicillinase‐producing N. gonorrhoeae (possessing the 3.05‐, 3.2‐, 3.9‐, and 4.4‐megadalton β‐lactamase plasmids, respectively) accounted for 68% (34/50) of these strains. Conclusions: In the Republic of the Philippines, gonococcal isolates resistant to penicillin or tetracycline accounted for 85.9% (79/92) of the isolates examined and included strains exhibiting resistance to fluoroquinolones. All gonococcal infections should be treated with antimicrobial therapies known to be active against all gonococcal strains to reduce the spread of strains exhibiting decreased susceptibilities to fluoroquinolones.

Antimicrobial resistance in Neisseria gonorrhoeae.

Despite a declining incidence of gonorrhea in much of the industrialized world, antimicrobial resistance continues to present a challenge to the treatment of gonococcal infections. Although no clinically significant resistance to the broad-spectrum cephalosporins has been identified, fluoroquinolone-resistant gonococcal strains are now prevalent in Australia and much of the Far East. Ongoing surveillance for antimicrobial resistance is crucial to obtain the information needed to choose effective empiric therapies for gonorrhea.