Resistant organisms are a way of life in modern medicine, and primarily are the result of our own technology and clinical zeal that have produced and overused extremely powerful antimicrobials. But Mother Nature always wins out in the end. Bacteria are clever enough to develop resistance to even the most powerful antibiotics produced by the highly competitive and gargantuanly profitable pharmaceutical industry.
Perhaps unknown to other clinicians, Neisseria gonorrhoeae, AKA the wily gonococcus, has slowly developed antibiotic resistance that has morphed this once easy-to-treat organism into a potential superbug. This is not yet water cooler fodder in the ED, but this phenomenon has not escaped the watchful eye of the Centers for Disease Control and Prevention or publications in erudite but rarely read infectious disease journals. It's time for an update for emergency physicians who treat gonococcus regularly so they understand the rather scary scenario that may make gonococcal infections untreatable.
The Emerging Threat of Untreatable Gonococcal Infection
Bolan GA, Sparling PF, Wasserheit JN
N Engl J Med
This New England Journal of Medicine perspective from the CDC's Division of STD Prevention proclaims that it is time to sound the alarm and rat out gonococcus as a true superbug. The authors kindly dub the nefarious and reviled gonococcus as wily, and conclude that this bacterium is becoming less susceptible to our last line of antimicrobial defense. Such resistance may threaten our ability to treat gonorrhea altogether or to prevent sequelae. Currently, only two antibiotic subclasses are recommended to treat gonococcus: late-generation cephalosporins, particularly ceftriaxone and the largely unknown cefixime, and high-dose azithromycin. If any other bacteria had only two consistent antimicrobial foes, the medical community would be up in arms immediately. This is not so with resistant gonorrhea, except for the diligent CDC.
More than half a million cases of gonorrhea are reported to the CDC every year, but this is probably only the tip of the iceberg. Minorities and those marginalized from regular medical care are particularly vulnerable. Gonococcus has developed resistance to penicillin, tetracycline, and most recently, fluoroquinolones over the years. Quinolone-resistant N. gonorrhoeae strains are now widely disseminated throughout the United States and the developing world. This bacterium has become so adept at evolving, surviving, and flourishing that treatment options have become sparse. Unfortunately, even once iron-clad susceptibility to cephalosporins has been faltering, mostly in Asia. Cephalosporin resistance in the United States so far is only a laboratory perturbation, manifested by a rise in the minimal inhibitory concentration (MIC) of ceftriaxone required for a cure. Azithromycin resistance is rare but already here.
Increased resistance has followed a familiar path: first in Asia, then Hawaii, and now the western United States. Resistance in Asia is particularly problematic, prompting the CDC to recommend: “To ensure appropriate antibiotic therapy, clinicians should ask patients testing positive for gonorrhea about recent travel to, and sexual activity in, these [Asian] countries.” Gonococcus resistance is especially prevalent among men having sex with men. The journals mention a gonococcus isolate totally resistant to ceftriaxone in a sex worker in Japan, but fortunately it has not yet disseminated. But air travel and the human penchant for unprotected sex will likely have N. gonorrhoeae duplicate the disastrous HIV scenario, now well known but also initially ignored.
Gonococcus mutates the gene that encodes for penicillin-binding proteins, which affect drug entry through bacterial cell walls. The recently reported elevated MIC for ceftriaxone increased by an amazing factor of 10 since 2006, mirrored the emergence of fluoroquinolone resistance. It's probably only a matter of time until gonococcus highly resistant or totally impervious to ceftriaxone will be routinely encountered in the ED. Tetracycline resistance is also increasing enough to make its use tenuous and not recommended even in the United States. Because resistance is first manifested in the lab, with higher doses needed to produce the required higher MICs, increasing the dose of cephalosporins can currently mitigate the threat. The effective dose of ceftriaxone, however, is clearly higher than it was even a few years ago.
Currently, a 250 mg IM dose of ceftriaxone will likely cure gonococcus infections at genital and extragenital sites. A few years ago, 125 mg was powerful enough but no longer. One gram of azithromycin is also now recommended routinely to cover co-pathogens and to provide additional antimicrobial synergistic activity against gonococcus (and to treat Chlamydia). Using this combination may provide a better cure rate for an isolated gonococcus infection. The synergy does not, however, guarantee that resistance to either antibiotic will not eventually emerge.
This information does not seem earth-shattering now, but it is an ominous warning that we are running out of options to treat gonorrhea. The true magnitude of resistance is probably unknown because we no longer routinely culture or test for gonococcus antibiotic susceptibility. Perhaps a vaccine will emerge, but that appears to be a far distant goal. The alarm has been appropriately sounded, but we have no easy way to turn it off.
Comment: Gonococcus is rampant and often clinically silent in the ED. The Philadelphia Department of Public Health received positive reports of 2964 gonorrhea cases in the first 20 weeks of 2012, a 25 percent increase compared with last year and a 35 percent increase over 2010. That's quite an impressive epidemic! Treatment verification for gonorrhea by the health department increased in June 2012. My Philadelphia hospital recently participated in a health department-sponsored program where patients with totally unrelated complaints were offered free testing for gonococcus with a noninvasive DNA-based urine test. Amazingly, about eight percent of patients with sprained ankles, back pain, gastroenteritis, and no gonococcus-like symptoms tested positive. It overwhelmed the health department team trying to track down those infected. They were able to contact less than half of those testing positive.
Hardly a shift goes by when a clinician is not called on to evaluate or empirically treat someone for gonorrhea. The vast majority of cases in the ED are cervicitis or urethritis, but PID and gonococcemia are not rare. The vast majority of mild cases seen in the ED will be cured with the current recommended combination of ceftriaxone and azithromycin, but this appears to be our last line of defense. Pharyngeal gonococcus is relatively common in some populations. Gonococcus pharyngitis can produce adenopathy and a mild exudate, but it's often minimally symptomatic or totally asymptomatic and can be easily overlooked. I wonder how many cases of gonococcus pharyngitis I have labeled viral or even strep, probably quite a few in a population with an eight percent silent genital infection. The pharynx is one reservoir that can account for reinfection, and it's not cured by penicillin therapy for a strep throat. The only regimen that can reliably cure pharyngeal gonococcus is the same ceftriaxone 250 mg IM plus azithromycin 1 g orally.
I can remember the day when a relatively modest dose of IM procaine (aka Novocain) penicillin G (1.2 million units) was the recommended gonococcus treatment. The dose required to obtain the correct MIC escalated, and one then needed to add probenecid to prolong the action of even high-dose penicillin. Penicillin doses became so high (higher than 4.8 million units) that this intervention fell by the wayside. Penicillin was adequately replaced by single-dose oral quinolone therapy for a while, but the CDC in April 2007 no longer recommended any quinolone to treat gonorrhea in the United States. Quinolone-resistant gonorrhea accounts for more than 50 percent of N. gonorrhoeae isolates from Hong Kong, China, Korea, Cambodia, Taiwan, and the Philippines, 15 percent of strains in Sydney, Australia, and in 2002 10 percent of isolates in England and Wales, good statistics to remember when treating a world traveler. About 30 percent of gonococcal isolates in Hong Kong from 2005 to 2010 were azithromycin-resistant. Don't get gonococcus in another country!
Only one class of antibiotics, late-generation cephalosporins, is currently recommended for treating gonococcus in this country: the universal workhorse IM ceftriaxone. Ceftriaxone has maintained a rather amazing potency, and it has been the go-to treatment that rarely failed for more than 20 years. Now the required dose of ceftriaxone has increased, and should be routinely supplemented with azithromycin or doxycycline. I am not sure the current recommended treatment is much different from what we always do empirically: also treat for Chlamydia. But dual therapy for gonococcus alone is now recommended if for some reason you are treating only for gonococcus, perhaps for a positive test or suspected pharyngeal infection.
The ED is the safety net for the community for the treatment of gonococcus, as it is with many communicable diseases. Patients suspected of having gonococcus infection should be treated real-time and in the ED with ceftriaxone (250 mg IM) and azithromycin (1 g orally). This one-time treatment should suffice for uncomplicated gonococcus and Chlamydia. I see no reason to prescribe tetracycline; it's just unrealistic to expect that someone is going to get the prescription filled and take it for the recommended seven days. Treatment is empiric, and one needs only a cervical discharge or burning with urination in a man to prompt therapy. Few places perform routine cultures anymore, one reason antibiotics sensitivities are somewhat obscure.
Empiric treatment should be the norm. Resist the urge to send them to an awful STD clinic because they are not an emergency and you fantasize better care there. Don't wait for the test to return, and dole out the antibiotic cocktail in the ED with gusto. The chance of finding an untreated discharged patient a second time and having him return to the ED to wait a few hours to receive therapy is unrealistic. Many patients with gonococcus have a strange tendency to give false contact information and go to another ED that has none of their records (go figure), so spending hours trying to track down positive tests in those who are not initially treated is counterproductive. A few other caveats should be mentioned.
HIV Infections: Patients with gonococcal infections who are infected with HIV should receive the same treatment as those who are HIV-negative. A gonococcus infection is a risk factor for HIV infection, and it is recommended that all patients treated for gonococcus receive routine HIV testing. That's a formidable task for the ED, but such testing should at least be routinely recommended. I doubt if many patients follow that advice. It certainly would be nice to offer rapid oral testing for HIV at the time of gonococcus treatment, but that has not become a standard ED mandate. Note that the rapid oral test requires additional confirmation (Western blot test).
Perhaps reporting positive cultures to the local health department, a law in all 50 states, facilitates a modicum of such follow-up. Positive gonococcus tests are still required to be sent to a governmental agency for surveillance and follow-up, but resources for adequate follow-up are scarce and impossible for many frustrated government employees. Such traditional notification programs have been an outright failure in many cities for years.
Alternative Regimens: The CDC recommends oral cefixime as an alternative when ceftriaxone can not be used, in a single oral dose in conjunction with azithromycin, but this antibiotic is rarely stocked in most hospitals. Cefixime is always mentioned but probably never used. It is in limited supply, and I have never prescribed it. It was sold under the trade name Suprax in the United States until 2003 when it was taken off the market by drug manufacturer Wyeth after its patent expired. The oral suspension form of Suprax was relaunched by Lupin in the United States, but there seems to be no reason to use it over ceftriaxone. The oral dose of cefixime does not provide as high or as sustained bactericidal levels as provided by ceftriaxone, and it does not appear to have good efficacy in treating gonococcus infections of the pharynx. None of the other injectable cephalosporins offers any advantage over ceftriaxone.
The often-recommended spectinomycin has not been available in the United States for years. Given our plight, it seems like some enterprising entrepreneur should start importing spectinomycin; it is available in Europe.
Penicillin Allergy: One could use 2 grams of azithromycin in patients with proven severe allergy to cephalosporins rather than the supplemental 1 gram recommended for uncomplicated gonococcus infections. Using this routinely to avoid an IM injection of ceftriaxone is not recommended; it only courts further resistant to the macrolide. Most people who think they are allergic to penicillin have no clue whether they are truly allergic. The vast majority are not. Often times their mother (usually based on spurious physician advice) told them that those little red bumps they developed when they were prescribed amoxicillin for an imagined ear infection (actually a viral infection with exanthem) was a life-long allergy to penicillin. Avoiding cephalosporins in poorly documented penicillin allergy is bad practice.
Contrary to the oft-quoted 10% cross reactivity, an extremely low cross-reaction rate is seen between penicillin and cephalosporins. A recent literature review is an erudite discussion that debunks the commonly promulgated axiom of cross-reactivity of penicillin and cephalosporins. (J Emerg Med 2012;42:612.) In fact, penicillins have a negligible cross allergy with third- and fourth-generation cephalosporins because of a different side chain responsible for an IgE-mediated reaction. This evidence-based review states: “In patients with a documented IgE-mediated response to penicillin, third- and fourth-generation cephalosporins can be used generously.”
The overall penicillin cross-reactivity is only about one percent even with first-generation cephalosporins that have a similar penicillin side chain. The third- and fourth-generation cephalosporins lack this side chain. The general caution has been that a patient with a severe allergy to penicillin who wears a bracelet to support a true anaphylactic experience, should not receive cephalosporins. This caution is scientifically unwarranted for ceftriaxone, but many still would not be so bold to believe the evidence over myth.
Rashes with penicillin do not contraindicate ceftriaxone. I would administer ceftriaxone patients who say they are allergic to penicillin but don't know why or have no true history. If they give a good story of severe anaphylaxis, I would still give ceftriaxone and keep them around for an hour just in case. Skin testing identifies penicillin sensitivity but not cephalosporin sensitivity. The CDC, apparently not yet a full convert, said the use of cephalosporins is contraindicated only in those with histories of severe reaction to penicillin, such as anaphylaxis, Stevens-Johnson syndrome, or toxic epidermal necrolysis.
Pregnancy: Pregnant women exposed or infected with N. gonorrhoeae should be treated with the recommended therapy for non-pregnant patients except that doxycycline is not used. I have seen no data on this, but one scenario would be a pregnant woman coming to the ED requesting empiric treatment in the absence of symptoms after receiving the bad news from her paramour. I would treat and congratulate her simply for showing up with a history of exposure. Obviously, one would not treat pregnant women with tetracycline but the onetime ceftriaxone/azithromycin regimen.
Treatment Failures: Treatment failures are most likely a reinfection, and asymptomatic pharyngeal infection is one mentioned culprit. If someone returns with a treatment failure, this is the time for a formal culture and sensitivity. It also would be the time to ask if his partner was ever treated. My experience is that we usually simply retreat for a presumed reinfection, rather than institute sensitivity testing or more stringent follow-up. Some recommend that retreatment consist of a repeat 250 mg IM ceftriaxone injection but increase the supplemental azithromycin to 2 g.
Follow-Up: Patients treated empirically or those with uncomplicated positive cultures who receive the recommended therapy do not need retesting. Ideally, those with persistent symptoms should be tested for antimicrobial susceptibility. Note that urethritis or cervicitis can be caused by Chlamydia, and retreatment should also include tetracycline.
Some of the questions raised in this column, other than the resistance issue, have plagued me for 40 years, and the answers are always the same: there are numerous approaches, physician bias, and problematic patients. It is important to be aware of the current recommendation, provide treatment in real time, at least discuss the HIV and partner issue, and treat empirically those exposed and asymptomatic, even if they have no clue to what they were exposed. Future columns will discuss the vagaries of laboratory testing and the thorny issue of treating a sex partner.
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Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum1
Ceftriaxone 250 mg IM in a single dose
or if not an option
Cefixime2 400 mg orally in a single dose
Single-dose injectable cephalosporin3 regimens
Azithromycin 1g orally in a single dose4
Doxycycline 100 mg a day for 7 days
1. Sexually Transmitted Diseases Treatment Guidelines: Gonococcal Infections. Centers for Disease Control and Prevention, 2010; http://1.usa.gov/RqkSsk. See text for the treatment of pharyngeal infections.
2. Cefixime (Suprax) not preferred. The only oral gonococcus treatment is recommended, but the drug has limited availability, and is slightly less effective than ceftriaxone. It also has limited efficacy for pharyngeal infections. Quinolones no longer recommended.
3. Other cephalosporins are no better than ceftriaxone. Consider ceftizoxime (500 mg IM), cefoxitin (2g IM with probenecid 1 g orally), or cefotaxime (500 mg IM). These alternates may not adequately treat pharyngeal gonococcus.
4. If a cephalosporin cannot be used, give azithromycin 2 g orally in single dose. GI side effects are problematic.
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Read this month's Special Report, “The Black-Box Bug,” about a hypervirulent strain of Klebsiella pneumoniae that researchers say is a real threat. See p.18.© 2012 by Lippincott Williams & Wilkins