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Fluoroquinolone Resistance in Neisseria gonorrhoeae -- Colorado and Washington, 1995

The fluoroquinolones ciprofloxacin and ofloxacin are among the antimicrobial agents recommended by CDC for treating gonorrhea (1). In the United States, decreased susceptibility or resistance of strains of Neisseria gonorrhoeae to the fluoroquinolones has been reported only sporadically, and treatment failure associated with in vitro resistance has not been described (2). However, the recent occurrence of resistant cases in Denver and Seattle suggests that clinically important resistance to the fluoroquinolones may be emerging. This report describes the findings of the investigations of these cases.

Denver

On May 24, 1995, a 35-year-old man presented to the Denver Public Health Sexually Transmitted Diseases Clinic with a history of dysuria and urethral discharge of approximately 1 month's duration. On March 11, he had returned from a "dating tour" of the Philippines during which he had had sexual contact with seven or eight female sex workers (i.e., prostitutes); he denied sexual contact since returning to the United States. He was treated with 400 mg ofloxacin orally in a single dose and was given 100 mg doxycycline to take orally twice a day for 7 days. A B-lactamase-positive strain of N. gonorrhoeae was isolated from a urethral specimen. On June 7, when the patient returned to the clinic with continuing symptoms, gram-negative intracellular diplococci were detected in a smear of urethral discharge. He denied sexual contact since the previous visit but reported he had not completed the prescribed doxycycline regimen. He was again treated with 400 mg ofloxacin and given 500 mg erythromycin to take orally four times a day for 7 days. A B-lactamase-negative strain of N. gonorrhoeae was isolated from a urethral specimen.

Because of suspected quinolone-resistant N. gonorrhoeae infection, the patient was recalled to the clinic on June 16 and treated with 250 mg ceftriaxone intramuscularly, even though his symptoms had resolved. He reported taking erythromycin for 3-4 days. Both a gram-stained smear and culture were negative for N. gonorrhoeae.

The susceptibilities of N. gonorrhoeae isolates from the patient's first and second visits were determined by agar dilution and disk diffusion tests (3). The minimum inhibitory concentrations (MICs) of the B-lactamase-positive isolate from the first visit were 1.0 ug/mL and 2.0 ug/mL of ciprofloxacin and ofloxacin, respectively (Table_1); the corresponding disk diffusion susceptibilities (inhibition zone diameters) were 21 mm to ciprofloxacin (5-ug disk) and 20 mm to ofloxacin (5-ug disk). This isolate possessed a 3.2-megadalton B-lactamase plasmid. The MICs of the B-lactamase-negative isolate from the second visit were 4.0 ug/mL and 8.0 ug/mL of ciprofloxacin and ofloxacin, respectively; corresponding inhibition zone diameters were 11 mm to ciprofloxacin and 12 mm to ofloxacin. Both isolates were susceptible to ceftriaxone (MICs, 0.004 ug/mL and 0.015 ug/mL); the second isolate was resistant to tetracycline- hydrochloride (HCl) (2.0 ug/mL). The isolates were further characterized by auxotype/serovar (A/S) class; both belonged to the same A/S class, Pro/IB-8 (Table_1) (4).

Seattle

From late May through early August 1995, fluoroquinolone-resistant strains of N. gonorrhoeae were isolated from eight residents of Seattle-King County, Washington. These strains represented eight (4%) of 225 gonorrhea cases from which isolates were available for testing during this period. Of the eight cases, five occurred among women. Five (63%) of the eight patients infected with this strain were commercial sex workers or sex partners of sex workers compared with 14 (11%) of 126 of a random sample of patients infected with other N. gonorrhoeae strains (p less than 0.01). None of the patients infected with a fluoroquinolone-resistant strain had been treated with a quinolone or had a history of international travel; all had been treated with a broad-spectrum cephalosporin (cefixime or ceftriaxone). Despite expanded laboratory surveillance in King and adjacent counties, no additional cases have been identified since August 10.

These strains had ciprofloxacin and ofloxacin MICs of 8.0 ug/mL; inhibition zone diameters to ciprofloxacin and ofloxacin were 12 mm-14 mm and 10 mm-12 mm, respectively. All isolates had a 3.05 megadalton B-lactamase plasmid and were resistant to tetracycline-HCl (2.0 ug/mL) but were susceptible to ceftriaxone, cefixime, and spectinomycin (Table_1). All isolates belonged to the same A/S class, Proto/IB-1, and had indistinguishable antimicrobial susceptibility profiles (Table_1), suggesting the spread of a single strain of N. gonorrhoeae.

Reported by: J Ehret, MS, JM Douglas, MD, FN Judson, MD, Denver Dept of Health and Hospitals, Colorado. J Hale, MS, Dept of Medicine, Univ of Washington; B Krekeler, MSPA, HH Handsfield, MD, Seattle-King County Dept of Public Health, Washington. Epidemiology and Surveillance Br, Div for Sexually Transmitted Diseases Prevention, National Center for Prevention Svcs; Gonorrhea, Chlamydia, and Chancroid Br, Div of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The confirmation of the resistant strains in Colorado and Washington has at least four important epidemiologic and clinical implications. First, the infection in the patient from Denver failed to respond to therapy with the CDC-recommended dose of ofloxacin, and the susceptibilities of the infecting strains were consistent with fluoroquinolone resistance (5). Despite reports of sporadic therapy failures in Australia, Hong Kong, and the United Kingdom (6-8), this case report is the first documentation in the United States of a gonococcal infection caused by a strain with in vitro resistance failing to respond to fluoroquinolone therapy. Second, the report from Seattle is the first documentation of sustained transmission of this resistant phenotype in the United States. Third, both the case in Denver and the outbreak in Seattle were associated with commercial sex workers. The isolation of resistant strains from persons who may have large numbers of anonymous sexual contacts suggests the possibility of rapid spread of these strains. Finally, the fluoroquinolone MICs of these strains (Table_1) are substantially higher than those of other fluoroquinolone-resistant strains (ciprofloxacin MIC, 2.0 ug/mL) previously isolated in the United States (2).

The MICs of the strains isolated in both Denver and Seattle suggest that infections caused by such strains often would fail to respond to treatment with the CDC-recommended doses of these fluoroquinolones. Although doxycycline is used to treat patients with gonorrhea for possible coexisting chlamydial infection, one of the strains isolated from the patient in Denver and all the isolates from Seattle were resistant to tetracycline (Table_1) (3). Thus, infections caused by such strains that fail to respond to treatment with a fluoroquinolone also may fail to respond to doxycycline.

The patient in Denver probably acquired his fluoroquinolone-resistant gonococcal infection in the Philippines -- an exposure that is consistent with a recent report of high-level fluoroquinolone-resistant N. gonorrhoeae among commercial sex workers in the Philippines (9). No international link has been identified for the cluster of cases in Seattle.

The findings in this report of high-level fluoroquinolone resistance are consistent with recent results from the Gonococcal Isolate Surveillance Project (GISP), a national surveillance system (10). During 1994, two (0.04%) of 4996 isolates from 24 sexually transmitted diseases clinics had ciprofloxacin MICs greater than or equal to 1.0 ug/mL, the provisional criterion for resistance to ciprofloxacin (5). However, 65 (1.3%) of 4996 isolates exhibited decreased susceptibilities to ciprofloxacin (MICs, 0.125-0.5 ug/mL), an increase from 17 (0.3%) of 5238 isolates tested in 1991 (p less than or equal to 0.001). Only one additional ciprofloxacinresistant N. gonorrhoeae case has been detected among approximately 2500 isolates tested by GISP during 1995 (CDC, unpublished data, 1995).

Although fluoroquinolone resistance does not appear to be widespread in the United States, the cases described in this report emphasize the need for heightened awareness about the potential for the emergence of clinically important resistance. Isolates obtained from patients whose infections fail to respond to fluoroquinolone therapy or from patients who have acquired their infections in certain parts of Asia should be tested for susceptibility to fluoroquinolones using the disk diffusion method recommended by the National Committee for Clinical Laboratory Standards (3). Based on theoretical predictions and a limited number of documented failures of gonococcal infections to respond to fluoroquinolones, CDC has proposed criteria for defining a resistance category of susceptibilities to ciprofloxacin and ofloxacin (5). Strains with MICs of greater than or equal to 1.0 ug/mL ciprofloxacin or greater than or equal to 2.0 ug/mL ofloxacin are interpreted as resistant to these agents. The corresponding inhibition zone diameters obtained by disk diffusion susceptibility testing are less than or equal to 29 mm to ciprofloxacin and less than or equal to 24 mm to ofloxacin (5).

Because fluoroquinolone-resistant N. gonorrhoeae strains appear to be occurring infrequently in the United States, CDC continues to recommend treating gonorrhea either with a single dose of 500 mg ciprofloxacin, 400 mg ofloxacin, 400 mg cefixime orally, or 125 mg ceftriaxone intramuscularly. Each agent should be followed by treatment with a regimen effective against possible infection with Chlamydia trachomatis. Lower doses of either the fluoroquinolones or cephalosporins should not be used. For patients who may have acquired infection in certain parts of Asia, clinicians should consider treatment with cefixime, ceftriaxone, or spectinomycin when treatment with a cephalosporin is contraindicated. The appropriateness of these recommendations will be reassessed based on surveillance of the prevalence of fluoroquinolone-resistant gonococci.

References

  1. CDC. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(no. RR-14):4-5.

  2. CDC. Decreased susceptibility of Neisseria gonorrhoeae to fluoroquinolones -- Ohio and Hawaii, 1992-1993. MMWR 1994;43:325-7.

  3. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests: approved standard. 5th ed. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1993: NCCLS document no. M2-A5. (Vol 13, no. 24).

  4. Sarafian SK, Knapp JS. Molecular epidemiology of gonorrhea. Clin Micro Rev 1989;2(suppl):S49-S55.

  5. Knapp JS, Hale JA, Neal SW, Wintersheid K, Whittington WL. Proposed criteria for the interpretation of susceptibilities of strains of Neisseria gonorrhoeae to ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, and norfloxacin. Antimicrob Agents Chemother 1995;39 (in press).

  6. Tapsall JW, Lovett R, Munro R. Failure of 500 mg ciprofloxacin therapy in male urethral gonorrhea. Med J Aust 1992;156:143.

  7. Birley H, MacDonald P, Carey P, Fletcher J. High-level ciprofloxacin resistance in Neisseria gonorrhoeae. Genitourin Med 1994;70:292-3.

  8. Kam KM, Lo KK, Ng KYH, Cheung MM. Rapid decline in penicillinase- producing Neisseria gonorrhoeae in Hong Kong associated with emerging 4-fluoroquinolone resistance. Genitourin Med 1995;71:141-4.

  9. Manalastas R, Abellanosa IP, Melosa VP, et al. Fluoroquinolone resistance in Neisseria gonorrhoeae in the Republic of the Philippines {Abstract}. In: Proceedings of the IUVDT World STD/AIDS Congress 1995. Singapore: International Union Against the Venereal Diseases and the Treponematoses,1995:136.

  10. Schwarcz SK, Zenilman JM, Schnell D, et al. National surveillance of antimicrobial resistance in Neisseria gonorrhoeae. JAMA 1990;264: 1413-7.


Table_1
Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.


TABLE 1. Laboratory findings for isolates of fluoroquinolone-resistant Neisseria
gonorrhoeae, by patient visit -- Denver and Seattle, 1995
==================================================================================
                                    Denver
                              ----------------------
Laboratory Findings           Visit  1     Visit 2       Seattle *
--------------------------------------------------------------------
B-Lactamase production        positive    negative      positive

B-lactamase plasmid
 (megadalton)                     3.2         ---          3.05

MICs + (ug/mL)
 Ciprofloxacin                    1.0         4.0          8.0
 Ofloxacin                        2.0         8.0          8.0
 Tetracycline-hydrochloride
  (HCl)                           0.5         2.0          2.0
 Ceftriaxone                     0.004       0.015        0.01
 Cefixime                        0.015       0.03         0.03
 Erythromycin                     0.06        0.5          2.0
 Spectinomycin                  <128.0      <128.0       <128.0

Inhibition zone
 diameter (mm)
  Ciprofloxacin (5-ug)            21          11          12-14
  Ofloxacin (5-ug)                20          12          10-12

Auxotype/serovar class        Pro &/IB-8    Pro/IB-8    Proto @/IB-1
--------------------------------------------------------------------
* Eight visits by eight different patients.
+ Minimum inhibitory concentration.
& Proline-requiring.
@ Prototrophic.
==================================================================================


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