The Centers for Disease Control and Prevention has sounded the alarm about the potential for the gonococcus bacteria to become resistant to all of our currently available antibiotic regimens. Only one treatment is supported by sensitivity testing gleaned through national surveillance networks: ceftriaxone (250 mg IM) plus azithromycin (1 g orally). This dual therapy is a new addition to the CDC recommendations for isolated gonococcal infections, although it was previously the recommendation for treating gonococcus and coexistent Chlamydia infections.
Dual synergistic therapy cures more than 99 percent of uncomplicated gonococcal infections, and so far resistance has only been manifested by a laboratory-discovered rise in the minimal inhibitory concentration required to cure gonorrhea. Dual therapy is effective, but it will not ensure that resistance does not develop to either medication. A variety of treatment issues were outlined in last month's column, and this discussion will tackle the always difficult public health question of what to do with the infected patient's sex partner, a likely source for reinfection.
Toward Better Control of Sexually Transmitted Diseases
Erbelding EJ, Zenilman JM
New Eng J Med
The authors state the obvious: proper clinical treatment of patients with gonorrhea or chlamydial infections must include notifying and treating the sexual partner to treat asymptomatic individuals and prevent reinfection. This conundrum has been extant and problematic, if not inscrutable, for decades. Many current obstacles are age-old issues, now peppered with antibiotic-resistance concerns. Sex partners are frequently asymptomatic, and cohabitation is voluminous and anonymous. Erstwhile or even current partners cannot or will not be contacted by the infected individual, and some partners simply refuse to be tested or treated.
Reporting positive laboratory tests to a local health department is still mandatory in all states, and these agencies have traditionally attempted to notify sexual partners to expedite treatment. But it has been common knowledge for more than a decade that the resources to accomplish this laudable goal were simply inadequate. Overwhelmed and understaffed, many health departments stopped notifying patients unless HIV or syphilis was the culprit. The recent surge in gonococcus cases and antibiotic resistance has caused increased health department attempts at revitalizing gonococcus treatment verification programs in some cities.
The CDC encourages infected patients themselves to notify their sexual partners for medical evaluation and treatment, but this has limited impact and poor compliance for a cornucopia of social and human nature reasons. As one might suspect, this well-meaning public health department approach has largely been a failure. Essentially, minimal progress has been reported in the quest to eradicate gonococcus and chlamydia by well intentioned but poorly funded and otherwise logistically implausible public health efforts. Gonococcus and Chlamydia are winning, and likely will be even more victorious once antibiotic resistance is full blown.
A few years ago, a new model of patient-assisted partner care, termed “expedited treatment of sex partners,” was initiated and reviewed in an editorial of the same issue of the journal. (New Engl J Med 2005;352:676). About 2000 heterosexual men and women with gonococcus or chlamydial infections, diagnosed at various health venues, were randomly assigned to have CDC-approved antibiotics made available to sex partners without a clinical examination. The control group was simply urged to notify their partners about the need for follow-up. Both cohorts were the object of significant succor by the investigators, who made phone calls and facilitated medication dispensing. The study was conducted in Seattle in partnership with the CDC. The outcome was to assess persistent or recurrent gonococcus or chlamydial infections in patients three to 19 weeks after treatment, and to determine if individuals contacted their partners and if the partner complied with the recommended therapy.
The antibiotic regimen for partners of patients with the STD was a single 400 mg dose of cefixime and a 1 g packet of azithromycin. The package also contained condoms, information about STDs, offers for consultation, and various logistical instructions. The investigators made it easy to comply. Medications were supplied at the time of the first visit or the partner could go to a pharmacy or STD clinic or obtain the antibiotic packet by mail. Additional patient-friendly efforts were provided to help patients and their partners obtain follow-up and treatment. About a quarter of the patients were lost to follow-up in the treatment and control groups. Some 1,375 patients of the 26,656 cases reported were randomized to each group, but only about 930 patients in each group were available for analysis. Repeat laboratory testing was performed to assess cure rates or reinfection. Apparently the gold standard for whether the partner received and complied with therapy was a verbal report of the infected individual.
Compared with standard referral patterns, the health department intervention of providing medications to sexual partners of STD patients without requiring the partner's prior medical evaluation statistically reduced persistent or recurrent infections among the originally identified infected participants. It was unknown if the named partner was also infected, and the investigators relied on the index patient to facilitate the intervention. Recurrent gonococcus infections were decreased more than recurrent chlamydial infections.
The investigators were aware of the potential deleterious effects of treating patients without clinically evaluating them and the potential for allergic or other drug-related adverse effects, but they believed their drug cocktail consisted of rather low-risk medications. Penicillin allergy, for example, was not considered an issue for cefixime use. No drug-related adverse effects were reported by the participants. Potential legal issues and the problematic availability of cefixime were thought to be potential issues for widespread use of this particular regimen.
The authors conclude that their intervention reduced the rates of persistent or recurrent gonococcus/chlamydial infections with statistical significance, but the results were quite modest. This overall goal for gonococcus and chlamydia was obtained in 13 percent assigned to standard partner referral and in 10 percent assigned to the expedited treatment. This is a three percent absolute difference, with the number needed to treat of about 33. Better results were obtained with gonococcus, reporting an 11 percent versus three percent persistent or recurring infections in the standard versus expedited treatment group, respectively. Those in the expedited group also were more likely to report that all their partners were treated, and this group was significantly less likely to report subsequently having sex with an untreated partner. One wonders why anyone would have sex with a partner who outright said he had an STD. Go figure that one.
It is noted that this was exclusively a heterosexual population. Those with HIV and gay or bisexual men are at a much higher risk group for noncompliance or antibiotic-resistant infections. Problems included state laws prohibiting physicians from prescribing medications without medical records or an established physician-patient relationship and the liability of pharmacies that dispense antibiotics based on standard orders by a public health authority. These antibiotics were free, but most prescription plans do not cover such activities.
Comment: This was a nifty study that did everything possible to get the best results. I can't imagine such resources would be available or could be initiated in most EDs, certainly not in financially strapped hospitals with dismal reimbursement from the indigent ED patients most at risk. Curiously, however, ED patients were most likely to comply with the follow-up. The primary measurable outcome was a persistent or recurrent infection in the index patient, with the assumption that being culture negative at follow-up signaled success of partner treatment. The authors relied on verbal reporting and phone follow-up to obtain much of the information, so this is a limitation of the data concerning exactly which partners were actually treated. A verbal report said 64 percent in the expedited group and 52 percent in the standard referral group were “very likely” to have been treated or tested negative for an STD, again not a very impressive result considering the magnitude of the efforts.
If an index patient did not want to contact a partner, the investigator did it for him using multiple avenues to deliver medication to the partner. About a third of the patients refused to participate. The most likely candidate was a young woman with only a gonococcus infection who was diagnosed in an ED. About 70 percent of those participating agreed to give medication to at least one partner. About a third of those randomized were lost to follow-up. God bless these investigators, but the roadblocks to accomplish their goals were gargantuan.
These intensive and patient/partner-friendly interventions did reduce the rate of recurrent or persistent infection but not by much. Only 29 more patients of the 930 patients in each group lacked persistent or recurrent gonococcus or Chlamydia. The cost per patient must have been astronomical. The numbers were most statistically significant for gonorrhea and less impressive for Chlamydia, but the results were rather lukewarm, with primarily a statistical difference. The study may have had a better result if the medications were dispensed at the time of treatment in the seemingly more-motivated ED patients, but most of the subjects were found in other areas. I have not seen this innovative approach continued nor is it practiced in any institution with which I have been involved. The time and effort required for this protocol is likely prohibitive in the real world.
That is a sad commentary in today's medico-legal environment, but it's a gutsy move to embark on this tactic. Perhaps a better way would be to provide easy access for the sex partner to receive treatment discreetly in a more formal environment where records can be kept and a general medical evaluation can be performed. Given the new treatment recommendations and the poor availability of cefixime, this initiative may not be possible today. While the legality of patient-delivered partner therapy remains poorly defined in most states, good luck convincing appropriately wary or medical-legal savvy clinicians to adopt this intervention. I can envision a Philadelphia malpractice lawyer suing an emergency physician because an unseen-yet-treated patient experienced a Mallory-Weis tear from vomiting after taking azithromycin, and he had not been warned that vomiting was a side effect. I also cannot see the RiteAids in Philadelphia even considering participation in this program.
Treating sexual partners remains a perplexing and frustrating problem, and one that does not have a readily available solution. It seems like a good idea and some minor progress was made with this study, but it does not yet appear to be standard of care to dole out free antibiotics for treating STDs by supplying partner therapy, sight unseen, with no medical record or encounter. There is still no good answer at this juncture. Gonococcus has always won in the past, and it looks like it's going to continue to be a winner despite our best efforts. Accepting the status quo is a painful reality, but I am skeptical that an effective alternative is possible. Let's get that vaccine fast-tracked with a hefty governmental grant.
Patient-delivered partner treatment programs in other studies have been a bit more successful than standard reporting methods, but the impact has been modest at best. (Clin Infect Dis 2005;41:623; Sex Transm Dis 2003;30:509.)
The CDC recommends empirically treating those who were partners of patients within 60 days of symptom onset for gonorrhea and Chlamydia. Laudable goal but easier said than done and likely a CDC fantasy. I will treat any asymptomatic partner in the ED with the index case, but despite my urging, the STD-bearer does not always give me permission to expose his infection to a clueless companion. I can't remember a single time where I was able to find out exactly which STD was confirmed at another hospital (not that it matters) for those seeking treatment after learning of a partner's exposure.
Many patients have multiple sex partners, and are not willing to inform them of their infections. Trying to find and convince a sex partner, often from a casual affair, to seek evaluation and treatment is not easy. Bodily fluids may be readily exchanged, but correct names and phone numbers are often not exchanged the next morning. Good luck trying to ferret out the particulars; it's usually a waste of time. I simply treat for gonorrhea and Chlamydia empirically if I see a patient who says her partner was treated for an STD. I do not culture these individuals or withhold treatment if they are asymptomatic.
Arguments can be made for providing antibiotics for your ED patient to give to a sexual partner, but that tactic has mixed reviews. I personally don't do it. It's better than partner referral but clearly not the Holy Grail. This quandary is probably one reason it is so difficult to contain this epidemic.
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Dr. Roberts: I enjoyed reading your article on uncomplicated cystitis. (“Uncomplicated Acute Cystitis: Times Have Changed,” EMN 2012;34:10; http://bit.ly/InFocusCystitis.) It seems that our OB colleagues are still using amoxil to treat cystitis in pregnant patients. Do you know what the resistance rate is for E. coli with amoxicillin? Is amoxil no longer recommended as treatment modality for pregnant patients with cystitis? Thank you. — Marcus Ma, MD, Temperance, MI
Dr. Roberts responds: You ask a seemingly simple question, but it is complicated for sure. There are many experts and guidelines when it comes to empiric antibiotics, and they are annoyingly inconsistent across the board. The article I reviewed was for uncomplicated cystitis, so pregnancy is excluded. Generally a drug should not be used if there is greater than 20 percent resistance, and E. coli, per hospital sensitivity testing of all isolates, including those with sepsis and immunocompromise, is universally more than 20 percent resistant to amoxicillin. Unfortunately, the lab cannot duplicate the antibiotic concentrations reached in the urine. We don't culture cystitis anymore, so who knows what is causing simple cystitis or the sensitivity, but presumably E. coli is a common culprit. Pregnancy aside, per the ID mavens of those guidelines, “Amoxicillin or ampicillin shouldnotbe used for empirical treatment of acute uncomplicated cystitis given the relatively poor efficacy, and the very high prevalence of antimicrobial resistance to these agents worldwide.”
UpToDate says these empiric treatment regimens are suggested for acute cystitis of pregnancy (pending urine culture and sensitivity testing): nitrofurantoin (Macrobid), amoxicillin-clavulanate (Augmentin), and fosfomycin. Listed as an “other acceptable regimen” is amoxicillin. Fluoroquinolones should be avoided in pregnancy.
The bottom line is that amoxicillin is probably still acceptable in pregnancy, and the antibiotic has its advocates. Amoxicillin is safe, seems to work, and concentrates in the urine, but other antibiotics are academically preferred. I empirically use nitrofurantoin for five days in pregnant women with acute cystitis, but I always get a culture. I am starting to like single-dose fosfomycin, pregnant or not. TMP-SMX can be used in the second trimester, but not the first trimester or near-term, so you can probably forget about that one.
Dr. Roberts: I am a longstanding and regular reader and great admirer of yours. Your recent article, “Treatment of Uncomplicated Pyelonephritis in Women,” recommended considering an intravenous loading dose of ceftriaxone, aminoglycoside, or a fluoroquinolone as intuitively reasonable prior to discharge on oral agents. (EMN 2012;3414:; http://bit.ly/QN5asx.) My concern with this approach has always been that switching from one drug (IV) to a different one (oral) has the potential to develop antibiotic resistance to the intravenous drug, agents that we commonly reserve for the most serious infections.
When I clarify for patients why they should take all of the antibiotics I prescribe, I note that shorter courses eliminate the weaker and most susceptible bacteria, but the longer course is required to “get them all.” While I can cite no references, the idea that a single dose of an intravenous antibiotic can foster resistance to that antibiotic has always seemed intuitively reasonable to me. I also occasionally use an intravenous loading dose, then oral medication for those going home with pyelonephritis. When doing so, I use antibiotics with the same or similar spectra of activity by both routes: ceftriaxone followed by cephalexin and IV ciprofoxacin or TMP/SMX when I'm prescribing the same drug orally. For similar reasons, I rarely use levofloxacin (oral or IV) because its valuable gram-positive spectrum of activity is less commonly required in the urinary tract. — Kenneth Frumkin, MD, Chesapeake, VA
Dr. Roberts responds: Points well taken, Dr. Frumkin, but I posit the issues are mostly theoretical. I did reference an article that studied IV and then oral agents (not sure of the specific antibiotics). The practice seems commonplace and was advised by the stilted guidelines I reviewed, with no caveats about specific meds or resistance. One would intuit that clinicians smarter than I would advise against mixing antibiotics if it were problematic. It seems reasonable to use the same drug by both routes, and levofloxacin fits that bill nicely. Although you are not a fan, many still are. For me, it's IV ceftriaxone and TMP/SMX pills.Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.