14 March 2012
Research on possible future treatment options for gonorrhea
When penicillin was first introduced in the 1940s it was a highly effective treatment for gonorrhea. Back then, as little as 72 mg of penicillin could cure that infection. Over the subsequent decades, gonorrhea began to lose its initial susceptibility to penicillin. By the late 1960s, a 40-fold increase in the amount of penicillin was needed to cure gonorrhea.
In the mid-1970s, strains of gonorrhea were developing resistance to even large doses of penicillin, and so another antibiotic, spectinomycin, became favoured by doctors. However, spectinomycin had to be given via injection and was much more expensive.
In the 1980s, another antibiotic called ciprofloxacin (Cipro)—first at a single oral dose of 250 mg and later at a dose of 500 mg—became the mainstay of gonorrhea therapy. But in the mid-1990s, reports of treatment failure with ciprofloxacin began to emerge. At first these reports were isolated. However, by the end of the decade it became clear that gonorrhea resistant to ciprofloxacin could be found in many countries.
Over the past decade, as ciprofloxacin-resistant strains of gonorrhea became common, doctors switched to cephalosporins, a class of antibiotics derived from penicillin. Cephalosporins have activity against a broad range of bacteria. Two cephalosporins—cefixime (Suprax) and ceftriaxone—became the preferred treatment for gonorrhea in many high-income countries. However, isolated reports of treatment failures with cefixime and ceftriaxone have been appearing. As was the case with ciprofloxacin-resistant gonorrhea, the reports of treatment failure with cefixime and ceftriaxone first appeared in the Asia-Pacific region and then in other regions of the world, including Western Europe.
In Canada, research by public health scientists has found that gonorrhea is on the cusp of becoming resistant to cefixime and ceftriaxone. To forestall the development and spread of cephalosporin-resistant gonorrhea, the Public Health Agency of Canada has recently alerted health care professionals to interim guidance on this issue. See our previous CATIE News bulletin “Changes to first-line therapy for gonorrhea in Canada” for further details about this interim guidance. In summary, PHAC has doubled the recommended doses of cefixime and ceftriaxone for the treatment of gonorrhea:
- cefixime – a single oral dose of 800 mg and now only for uncomplicated forms of gonococcal disease in the cervix, urethra and rectum and no longer for throat infections, PID and other complications. This is a major change because previously cefixime was was used for even complicated forms of infections with gonorrhea-causing germs.
- ceftriaxone – an intramuscular injection of 250 mg
However, this should be viewed as a provisional step because gonorrhea will eventually develop resistance to even these higher doses. In the meantime, leading researchers on sexually transmitted infections (STIs) around the world are discussing what future steps might be taken to more firmly prevent the spread of cephalosporin-resistant gonorrhea. In the rest of this report, we explore some of these ideas. We remind our readers that such ideas will require well-designed clinical trials to be certain about their effectiveness.
Don’t forget Chlamydia
The current recommended practice in many high-income countries is to treat a person diagnosed with gonorrhea with an antibiotic for the gonorrhea (usually cefixime or ceftriaxone) as well as with another antibiotic (usually azithromycin), because someone who has gonorrhea often will also have the common STI Chlamydia. Azithromycin has some activity against gonorrhea, so some researchers suspect that the use of a cephalosporin and azithromycin has delayed the rise of gonorrhea with high-level resistance to cephalosporins, at least in countries where dual treatment is used. However, this dual treatment, while safe, carries the risk that resistance may emerge against two important drugs used for the treatment of gonorrhea. In addition to cases of gonorrhea resistant to cephalosporins, there are also cases of gonorrhea resistant to azithromycin.
Strategies against cephalosporin resistance—raising the dose
The simplest and quickest step to take in delaying the appearance of cephalosporin-resistant gonorrhea is to raise the dose. This has been done in Canada. In the UK, the recommended dose of ceftriaxone is now 500 mg for treating gonorrhea, together with 1 gram of azithromycin for treating Chlamydia. As such a large dose of ceftriaxone is likely somewhat painful, it will be interesting to read future reports from STI clinics in the UK about how patients react to this therapy.
Note that computer simulations of gonorrhea’s response to antibiotics suggest that treatment failure is still possible at even these higher doses of cephalosporins, but hopefully such failure will be uncommon in the short term.
Due to reports of treatment failure with cefixime, PHAC prefers that doctors give men who have sex with men (MSM) who have gonorrhea an intramuscular injection of ceftriaxone. Unfortunately, injections are more cumbersome than simply taking a pill and are sometimes painful, though injecting a small amount of the anesthetic lidocaine into the target muscle greatly helps to reduce the pain.
Some researchers worry that the switch to injectable antibiotics and their associated pain may discourage some patients with gonorrhea from seeking treatment.
Ceftriaxone is highly effective but can cause abnormal heart rhythms, mostly when given repeatedly and, even then, only in rare cases.
Using two cephalosporins
Another potential avenue to explore might be increasing the dose of ceftriaxone to 1 gram and combining this with two consecutive days of cefixime at either 400 mg or 800 mg per day. But this strategy is risky because currently there are strains of gonorrhea with reduced susceptibility to both cephalosporins.
As mentioned earlier, co-treatment with azithromycin 1 gram is currently recommended to treat Chlamydia in cases with gonorrhea. There is not much room for further use of azithromycin against gonorrhea because the 1-gram dose used for Chlamydia has only limited activity against gonorrhea. If this dose of azithromycin by itself were to be widely used to treat gonorrhea, resistance would likely occur quickly.
The newer 2-gram extended-release formulation of azithromycin (Zmax) might be an option. This formulation is meant to be used for bacterial pneumonia. However, strains of gonorrhea resistant to azithromycin have appeared in China, the UK, the U.S. and elsewhere, so even the extended-release formulation of azithromycin may not be effective for long. Plus, the 2-gram formulation of azithromycin is expensive—another factor that might affect its widespread use.
Gentamicin and its chemical cousin amikacin belong to an older class of antibiotics called aminoglycosides. These drugs are poorly absorbed and must be injected into muscle or given intravenously. Although these drugs have potential for renal or auditory toxicity, such problems are very rarely seen in single-dose therapy. Aminoglycosides are not commonly used in high-income countries for first-line therapy except for treatment of severe infections such as drug-resistant tuberculosis. However, given the dwindling treatment options for cephalosporin-resistant gonorrhea, some STI researchers are reviewing the possibility of using gentamicin.
Small clinical trials conducted in the 1970s and 1980s have studied a single intramuscular injection of gentamicin 240 mg as a treatment for gonorrhea. At this dose it was found to be effective. This is close to the maximum amount that can be given in a single injection; higher amounts would require multiple doses.
Since 1993, in the Southern African country of Malawi, public health authorities have been using a single intramuscular injection of gentamicin (240 mg) as first-line therapy for gonorrhea. Limited surveys have found that apparently gonorrhea has not mutated and developed resistance to gentamicin in that country over the past two decades.
As previously mentioned, most clinical trials of gentamicin were done in the 1970s and early 1980s. Such trials would probably not meet the standards and scrutiny required of clinical trials today. Therefore, new and well-designed clinical trials of gentamicin are necessary. To meet this need, the American National Institutes of Allergy and Infectious Diseases (NIAID) is conducting a randomized clinical trial of the following interventions in cases of gonorrhea:
- gentamicin 240 mg (intramuscular injection) + azithromycin 2 g (orally)
- gemifloxacin (Factive) 320 mg + azithromycin 2 g, both drugs taken orally
Sufficient data from which to draw robust conclusions about the effectiveness of either regimen is not expected to become available for several years.
Will solithromycin be a solution?
The antibiotic solithromycin is chemically related to older antibiotics such as erythromycin, azithromycin and clarithromycin. Solithromycin is being developed by Cempra Pharmaceuticals in the U.S. for treating people with community-acquired bacterial infections. It has undergone Phase I and II trials with promising results.
In laboratory experiments, researchers tested solithromycin against strains of gonorrhea that had been isolated from patients. The strains in question were resistant to at least one of the following antibiotics:
In all cases, solithromycin showed powerful antibacterial activity.
Also, researcher teams tested solithromycin against strains of gonorrhea with that were simultaneously resistant to several antibiotics (multidrug-resistant and extremely drug-resistant gonorrhea). Again, solithromycin was effective against all strains in these laboratory experiments.
Additional experiments revealed that solithromycin was effective against the common STIs Chlamydia and M. genitalium. These findings raise the possibility that solithromycin may be suitable as a simple treatment for common STIs such as gonorrhea and Chlamydia.
Results from Phase I and II studies suggest that solithromycin is well absorbed when taken orally and it accumulates inside cells. This drug has anti-inflammatory activity, which makes it useful for treating infections. At doses between 200 and 600 mg, it is well tolerated and safe.
Cempra Pharmaceuticals is primarily developing solithromycin for the treatment of bacterial pneumonia. Solithromycin has passed Phase I and II clinical trials, but it still needs to succeed in Phase III clinical trials against bacterial pneumonia. Such trials are large, expensive and take a long time to complete, so it will be several years before solithromycin becomes available for sale. After that, clinical trials testing solithromycin are needed to confirm its antibacterial effects in people with gonorrhea and other STIs.
Plants may prove a source of future drugs
Many species have been a fruitful source of drugs for people. For instance, penicillin came from a fungus, as did the transplant drug cyclosporine. Some bacteria have given us antibiotics, such as streptomycin and tetracycline. So it should come as no surprise that in searching for new compounds on which to base the development of new antibiotics, some researchers have been investigating plants.
A team of Canadian scientists has been studying plants traditionally used by Aboriginal healers to treat several conditions. They have extracted chemicals from these plants and found that they can somewhat impair the growth of gonorrhea-causing bacteria. The plants used in their experiments were as follows:
- black cherry
Although extracts of these herbs are available in some health food stores and pharmacies, independent analysis of some of these extracts available for sale has found varying levels of their active ingredients. Moreover, relying on herbal extracts that have not been tested in well-designed clinical trials in people is not a wise course of action (for the treatment of drug-resistant gonorrhea or anything else). No one knows if they will be effective in people or how they might interact with commonly used drugs.
Instead, the compounds isolated by the Canadian scientists can serve as a template to be used to create other more potent compounds that could one day be used to treat drug-resistant gonorrhea and possibly other bacterial infections.
The last word
One of Canada’s leading STI researchers, Marc Steben, MD, says: “The easiest gonorrhea to treat is the kind that is prevented by condoms.”
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
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