Emergence of Gonococcal and Chlamydial Resistance and Implications for Therapy

James M. Toomey, M.D., Infectious and Communicable Diseases Division, Dept. of Medicine, University of Florida, Jacksonville, FL
 
Despite advances in education, surveillance, and treatments, sexually transmitted diseases remain all too frequently encountered in clinical practice. The average age of onset of sexual activity in the United States continues to decrease, and the catalog of diseases transmitted by sexual contact slowly but steadily expands. Fortunately, with few exceptions such as HIV and herpes infections, sexually transmitted diseases have been easily cured with antibiotics. For example, syphilis remains fully susceptible to penicillin at a time when many bacteria have evolved or been pressured into mechanisms that resist the effects of that â-lactam.

Neisseria gonorrhoeae and Chlamydia trachomatis are common causes of sexually transmitted disease. Clinical manifestations of these organisms include urethritis and other mucosal infections of the genitourinary tract, as well as conjunctivitis, pharyngitis, epididymitis, proctitis, salpingitis and infertility. Co-infection with these two organisms is not uncommon, occurring in between one third and one half of cases. Because of this, treatment for gonococcal urethritis should include an antibiotic that covers Chlamydia. (See tables, below.)

Antimicrobial resistance has been documented for N. gonorrhoeae since the mid-1970s. Penicillinase-producing N. gonorrhoeae (PPNG) became widespread throughout the world, especially in Asia, Africa, and parts of Europe by the mid-1980s, and also emerged in the United States, though not nearly as commonly as in the rest of the world. In the U.S. currently, only about 5% of strains are PPNG, down from a peak of 11%. However, chromosomal mutations can also result in resistance to penicillin, and approximately 4% of N. gonorrhoeae strains in the U.S. are chromosomally resistant to penicillin. 1

Resistance to tetracyclines may result from either plasmids or chromosomal mutation. High-level plasmid-mediated resistance of N. gonorrhoeae to tetracycline has been spreading recently in the United States, Europe and Africa. 2

Fluoroquinolone antibiotics such as ciprofloxacin and ofloxacin (and its L-isomer, levofloxacin) have been used to treat gonorrhea since the 1980's. Their use was spurred in part because of the emergence of resistance to older antibiotics, and also due to their ability to cure gonorrhea with a single dose. As would be expected, it didn't take long before reports of decreased susceptibility and frank resistance of gonorrheal strains to fluoroquinolones began to appear in the literature, in the latter 1980's and early 1990's. Most of the first reports came out of Asian countries. By the mid-1990's, as high as 10% of gonococcal strains in Hong Kong and the Philippines were resistant to fluoroquinolones. More recently, as many as 70% of strains in the Philippines demonstrate resistance to ciprofloxacin. 3 In Japan, a case of gonorrhea developed resistance to sparfloxacin only a few days into the treatment course. 4 China recently reported a gonococcal fluoroquinolone resistance rate between 60% and 80%. 5 Australia is also beginning to see increases in resistance, some of which is related to commercial sex workers arriving from other countries. 6

Quinolone antibiotics kill bacteria by targeting and inhibiting the enzymes DNA gyrase and topoisomerase IV, thereby interfering with DNA synthesis. Bacterial wisdom responds to the pressure of these antibiotics with chromosomal mutations in the genes coding for these enzymes, thereby changing the targets and making the antibiotics less effective or ineffective. Gonococcal resistance to fluoroquinolones results from mutations in the gyrA subunit of DNA gyrase and in the parC subunit of topoisomerase IV. Active efflux of antibiotic from the bacterial cell may also contribute to resistance. The chromosomal mutations may be transferable from one gonococcus to another, and may in fact be associated with cross-resistance to the broad-spectrum cephalosporins, such as ceftriaxone, which have been so reliable thus far. 7

In the United States, the Centers for Disease Control and Prevention has established a sentinel surveillance program called the Gonococcal Isolate Surveillance Project (GISP) to monitor for the emergence of gonococcal resistance. Although still very rare in comparison to the rest of the world, isolates of N.gonorrhoeae resistant to fluoroquinolones have been found in Hawaii, Washington, and Colorado. Recent increase in the percentage of strains resistant to ciprofloxacin in Hawaii has prompted the CDC to recommend that practitioners in Hawaii should no longer treat gonorrhea with fluoroquinolones. Additionally, if a patient anywhere in the U.S. has likely acquired a case of gonorrhea in Hawaii, Asia or the Pacific Islands, or from a contact from these areas, fluoroquinolones should not be used. Furthermore, if a patient appears to have failed standard therapy for gonorrhea, a culture should be obtained and sent to the local health department laboratory for susceptibility testing. 8

Chlamydial infections have historically been treated with confidence, with either tetracycline, doxycycline, and more recently, azithromycin. Other macrolides and fluoroquinolones have also been effective. The issue of resistance has not been an issue until very recently. Resistance in vitro has been demonstrated for several years, but these laboratory phenomena had not been associated with clinical treatment failures. For example, quinolone resistance has been produced in the laboratory in an L2 strain of C. trachomatis, resulting from a mutation of the gyrA gene. 9

Clinical treatment failures for Chlamydia are beginning to be reported in the literature. In one report, three chlamydial isolates were shown to be resistant to doxycycline, azithromycin, and ofloxacin. The mechanism by which Chlamydia becomes resistant is not understood, but it seems to result in what has been termed heterotypic resistance. In a given population of chlamydial organisms, only some exhibit resistance. Unlike typical mechanisms by which bacteria become resistant to antimicrobials, chlamydial resistance may be due to changes in the life cycle or growth patterns in the organisms. 10

As with other bacteria, we must stay vigilant for the emergence of resistance in N. gonorrhoeae and C. trachomatis. Although Duval County is not an official site of the Gonococcal Isolate Surveillance Program, informal surveillance of gonococcal susceptibility in this area has identified no new trends in gonococcal resistance. Nevertheless, our awareness has been heightened to the possibility, and no doubt we will eventually begin seeing instances of clinical resistance with these organisms. Fluoroquinolones remain included in the list of recommended treatment for gonorrhea, although in my practice, I have preferred using ceftriaxone, partly in an effort to delay emergence of resistance. The most recent recommendations for treatment of gonorrheal and chlamydial infections were published in the MMWR in 1998, and are summarized below. For details, please see the MMWR 1998 Guidelines referenced at the end of this article.

References

  1. Sparling PF, Handsfield HH. Neisseria gonorrhoeae. Principles and Practice of Infectious Diseases, 5th edition. 2000; 2242-58.
  2. Lind I. Antimicrobial Resistance in Neisseria gonorrhoeae. Clinical Infectious Diseases. 1997;24(Suppl 1):S93-7.
  3. Knapp JS. Neisseria gonorrhoeae Resistant to Ciprofloxacin and Ofloxacin. Sexually Transmitted Diseases. 1998;25:425-6.
  4. Tanaka M, Nakayama H, Haraoka M, et al. Analysis of Quinolone Resistance Mechanisms in a Sparfloxacin-Resistant Clinical Isolate of Neisseria gonorrhoeae. Sexually Transmitted Diseases. 1998;25:489-93.
  5. Guoming L, Qun C, Shengchun W. Resistance of Neisseria gonorrhoeae Epidemic Strains to Antibiotics. Sexually Transmitted Diseases. 2000;27:115-8.
  6. Tapsall JW, Limnios EA, Shultz TR. Continuing Evolution of the Pattern of Quinolone Resistance in Neisseria gonorrhoeae Isolated in Sydney, Australia. Sexually Transmitted Diseases. 1998;25:415-7.
  7. Ehret JM, Judson FN. Quinolone-Resistant Neisseria gonorrhoeae: The Beginning of the End? Sexually Transmitted Diseases. 1998;25:522-6.
  8. Fluoroquinolone-Resistance in Neisseria gonorrhoeae, Hawaii, 1999, and Decreased Susceptibility to Azithromycin in N. gonorrhoeae, Missouri, 1999. Morbidity and Mortality Weekly Report. 2000;49:833-7.
  9. Robinson AJ, Ridgway GL. Concurrent Gonococcal and Chlamydial Infection. Drugs 2000. 2000;59:801-13.
  10. Somani J, Bhullar VB, Workowski KA, et al. Multiple Drug-Resistant Chlamydia trachomatis Associated with Clinical Treatment Failure. Journal of Infectious Diseases. 2000;181:1421-7.
  11. 1998 Guidelines for Treatment of Sexually Transmitted Diseases. Morbidity and Mortality Weekly Report. 1998;47(RR-1).
Jacksonville Medicine / February, 2001
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