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Changes to first-line therapy for gonorrhea in Canada

13 Mar 2012 -

Gonorrhea is a common sexually transmitted infection (STI) caused by bacteria called N. gonorrhoeae . These germs are easily spread by inadequately protected intercourse (for example, starting without a condom) and, of course, unprotected anal, oral and vaginal sex. If medical help and treatment is not sought, gonorrhea can cause serious complications in both men and women and in babies born to women who have gonorrhea. These complications can arise because gonorrhea-causing germs can quickly move from the genitals further into the body-to the testicles in men and to the fallopian tubes and ovaries in women. These bacteria can also reach the blood and spread to other parts of the body, such as the skin, joints, heart and brain. In addition to causing pain and distress, gonorrhea can also cause inflammation inside delicate tissues such as the anus, urethra, throat and cervix. Such inflammation makes it easier to acquire or transmit HIV.

Growing resistance

For part of the past decade in Canada and in some other high-income countries, commonly used treatments for gonorrhea have been antibiotics belonging to a group called cephalosporins, as follows:

  • cefixime (Suprax) taken orally as a single dose
  • ceftriaxone given via an injection into muscle

Cefixime, because it can be taken orally and in one dose, has been the mainstay of the treatment of uncomplicated gonorrhea. However, because gonorrhea is so common and antibiotic use so widespread, gonorrhea-causing germs have been under what scientists call "selective pressure" to evolve and better tolerate antibiotic therapy.

Therefore, not surprisingly, there have been increasing numbers of cases of gonorrhea treatment failure with at least one these of these antibiotics-first in East Asia and Australia and more recently in Western Europe, in at least Austria, France, Norway, Sweden and the UK.

The rise of gonorrhea that is resistant to cefixime or ceftriaxone is concerning because such strains of gonorrhea are usually resistant to other commonly used antibiotics, including a class called quinolones (a widely used quinolone is ciprofloxacin [Cipro]), penicillins, tetracyclines and azithromycin (Zithromax). Gonorrhea-causing bacteria tend to accumulate resistance to antibiotics even after such antibiotics are no longer in common use and these germs rapidly exchange information about antibiotic resistance with other kind of bacteria, helping the spread of antibiotic resistance. Moreover, pharmaceutical companies are generally not pursuing the development of antibiotics as they once were. Furthermore, despite years of hard work by scientists, the interaction between gonorrhea-causing germs and the immune system is not fully understood, so there will not be an effective vaccine for at least the next decade. A further issue to consider is this: People who have had gonorrhea in the past are not protected from further episodes of gonorrhea in the future should they be exposed to these germs. Collectively, all of these points raise the disturbing possibility that, in the near future, in certain circumstances, gonorrhea may become untreatable.

The situation in Canada

Since 1997, rates of gonorrhea in Canada have been increasing. STI researchers now estimate that there are about 11,000 cases of gonorrhea each year.

The Public Health Agency of Canada (PHAC), together with Public Health agencies in British Columbia, Alberta, Ontario and Quebec and Canada's National Microbiology Laboratory, has collaborated on a number of research projects on STIs. In its latest study, a Canadian team has been collecting and analysing samples of gonorrhea.

Its research has revealed that in the past decade strains of gonorrhea in Canada have evolved and are losing their susceptibility to cefixime and ceftriaxone. In other words, the concentration of these antibiotics needed to kill gonorrhea-causing bacteria has significantly increased, according to lab experiments; but, up until now, this phenomenon has not been commonly seen in Canada.

Lab vs. person

Laboratory experiments with bacteria and antibiotics can merely serve as guides for future research. Such experiments cannot reproduce the complexity of the challenges that drugs face when taken by a person. For instance, a person first has to swallow a drug, and then it has to be absorbed in the intestine, processed by the liver, go into the bloodstream and spread to tissues and cells. Once inside cells, it has to achieve a high concentration and kill its target bacteria-in this case, those that cause gonococcal disease. Thus, although a person may take a particular drug, 100% of the drug swallowed does not end up in the tissues and cells where it is needed.

The challenge of emerging technologies

These days, more and more people are tested for the presence of gonorrhea-causing germs with a technique called nucleic acid amplification techniques (NAAT), because the NAAT sample travels better to the lab than the swab. NAAT is very useful for detecting gonorrhea-causing germs but it is not generally useful, outside of a research laboratory, for assessing the antibiotic resistance pattern of gonorrhea. In cases where a NAAT detects gonorrhea-causing bacteria, STI experts recommend that a culture be obtained from the patient so that antibiotic susceptibility can be assessed.

The changing profile of gonorrhea

Gonorrhea was much more common among men in the 1980s and 1990s, affecting about four men for every one woman. However, recently in Canada its distribution has become less skewed and more women are being affected. Perhaps part of the reason for this is a change in sexual behaviour among heterosexual men and women-namely, an increase in anal and oral sex. The throat and anus have become important reservoirs for gonorrhea-causing bacteria and samples from these sites are not often tested.

The looming future

To try to predict how gonorrhea-causing bacteria in circulation around the world are likely to react to standard doses of cefixime and ceftriaxone, scientists have turned to complex computer programs. Such programs can run scenarios or simulations of how gonorrhea might respond when exposed to antibiotics in people. The results of such simulations suggest that at the doses used up to the end of 2011, treatment failure can be expected with cefixime (in a single dose of 400 mg orally) or ceftriaxone (in a single intramuscular dose of 125 mg). PHAC no longer recommends those doses.

People who have sex outside of a monogamous relationship are part of a sexual network. Past research has found that once STIs develop resistance to an antibiotic, such resistance can spread relatively quickly within a sexual network, greatly complicating treatment options. To minimize the development and spread of cephalosporin resistance in Canada, PHAC has acted quickly by changing the dose of drugs used for gonorrhea treatment in Canada.

Changes to first-line gonorrhea therapy in Canada

PHAC has issued interim guidance for doctors and nurses treating people with gonorrhea. Selected highlights from this guidance are as follows:

  • Lab tests. Whenever possible, samples should be taken from patients and sent for culture. Nucleic acid amplification (NAAT) should be used to screen patients who are symptom free but suspected of having gonorrhea-causing bacteria. If positive, a culture should be done, especially in men who have sex with men (MSM), because of reports of treatment failure in this population.
  • Higher doses of antibiotics are now recommended. This means that the dose of cefixime has been increased to a single oral dose of 800 mg and the dose of ceftriaxone has doubled to 250 mg via intramuscular injection. Note that intramuscular injections with ceftriaxone can be painful. Injecting a small amount of the anesthetic lidocaine into the targeted area before injecting ceftriaxone should help to minimize this problem.
  • MSM. Due to reports of treatment failure when cefixime was used, PHAC now recommends that cases of gonorrhea in MSM be treated with ceftriaxone 250 mg given by intramuscular injection.
  • PID. In cases of complicated gonorrhea where a high concentration of the drug is needed, such as in cases of pelvic inflammatory disease (PID) and gonorrhea affecting the throat, ceftriaxone 250 mg is PHAC's preferred regimen. Cefixime should not be used for treating PID.
  • Avoid quinolones. PHAC reminds healthcare providers that gonorrhea resistance to a group of antibiotics called quinolones (ciprofloxacin, ofloxacin) has become relatively common and quinolones are no longer the preferred first-line therapy for gonorrhea.
  • Chlamydia needs to be treated, too. People who have gonorrhea are also very likely co-infected with another STI called Chlamydia and require treatment for both gonorrhea and Chlamydia. PHAC's preferred treatment for Chlamydia is a single oral dose of the antibiotic azithromycin 1 gram. Alternatively, doxycycline 100 mg twice daily for seven consecutive days can be given if adherence is not a concern.

Safety of higher doses of cefixime and ceftriaxone

Cefixime was originally licensed in Canada for multiple doses of 400 mg and only later was recommended for gonorrhea treatment. Now that PHAC has recommended doubling this dose to 800 mg, some readers may be concerned about cefixime's safety. However, clinical trials done in the late 1980s and early 1990s found that a single dose of 800 mg cefixime was well tolerated. If side effects occurred, they were generally mild and limited in duration. In one clinical trial, the proportion of 91 participants exposed to cefixime who developed side effects was relatively low, as follows:

  • diarrhea or flatulence - 13%
  • nausea or intestinal discomfort - 4%
  • any one of the following: fever, headache, feeling sleepy during the daytime - 2%

Other studies have reported that if these side effects did occur, they did not persist.

In a randomized Canadian study, among 99 men who received cefixime 800 mg, side effects were also considered mild and temporary, as follows:

  • nausea - 7%
  • dizziness or headache - 7%
  • diarrhea, flatulence or cramps - 17%

Studies on the use of ceftriaxone for gonorrhea were also done decades ago. However, results from one randomized trial of a single dose of 250 mg (given via intramuscular injection) among 104 recipients revealed that side effects were uncommon:

  • diarrhea or flatulence - 4%
  • any one of the following: fever, headache, feeling sleepy during the daytime - 5%
  • painful injection site - 7%

PHAC considers the higher doses of cefixime and ceftriaxone safe for use in pregnant women with gonorrhea. Both drugs have been used at high doses for long periods in the management of pregnant women with serious abdominal bacterial infections and have been found to be safe.

Resources

Public Health Agency of Canada - Canadian Guidelines on STIs

L'Institut national d'excellence en santé et en services sociaux (INESSS) - Guidelines for the treatment of sexually transmitted and blood-borne infections

Our next CATIE News bulletin focuses on possible future options that some researchers are considering for treating gonorrhea.

Acknowledgement

We thank Marc Steben, MD, Institut national de santé publique du Québec, and La Clinique A in Montreal, for his research assistance, helpful discussion and expert review.

-Sean R. Hosein

REFERENCES:

  1. PHAC. Important notice. Public health information update on the treatment for gonococcal infection. 21 December 2011. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/alert/2011/alert-gono-eng.php
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  19. Handsfield HH, McCormack WM, Hook EW 3 rd . A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The gonorrhea treatment study group. New England Journal of Medicine . 1991 Nov 7;325(19):1337-41.
  20. Plourde PJ, Tyndall M, Agoki E, et al. Single-dose cefixime versus single-dose ceftriaxone in the treatment of antimicrobial-resistant Neisseria gonorrhoeae infection. Journal of Infectious Diseases. 1992 Oct;166(4):919-22.
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  22. Ramus RM, Sheffield JS, Mayfield JA, et al. A randomized trial that compared oral cefixime and intramuscular ceftriaxone for the treatment of gonorrhea in pregnancy. American Journal of Obstetrics and Gynecology. 2001 Sep;185(3):629-32.
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CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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