In August, the CDC issued new treatment guidelines for Neisseria gonorrhoeae, based on evidence that resistance to cefixime, an oral cephalosporin, was emerging. Patients who test positive for gonorrhea are now to be treated with a combination of drugs: ceftriaxone, an injectable cephalosporin, and either azithromycin or doxycycline.
After ceftriaxone, however, there are no highly effective and well-studied options for this infection, which was once able to be treated with just an oral drug. Because resistance to ceftriaxone is almost inevitable, based on the history of
N. gonorrhoeae, there is a call by public health officials worldwide to scale-up research for new treatment options for this common STD.
“There have been increasing reports of resistance to oral cephalosporins, which were the mainstay of treatment for several years,” Robert Kirkcaldy, MD, MPH, medical epidemiologist in CDC’s Division of STD Prevention, told Infectious Disease News. “We have seen this bug do this before so it’s not entirely unexpected, but it’s still alarming because we have so few drugs available. Our prevention and control efforts really rely on effective treatments for gonorrhea.”
Kimberly Workowski, MD, said the percentage of isolates with elevated MICs for oral cephalosporins is increasing in the US.
Photo courtesy of Workowski K
The CDC estimates that more than 700,000 people in the United States develop new gonorrhea infections each year. In 2010, data from the Gonococcal Isolate Surveillance Program (GISP) showed that 27.2% of the isolates collected were resistant to penicillin, tetracycline and ciprofloxacin.
Infectious Disease News discussed the emergence of drug-resistant N. gonorrhoeae with several experts to find out how this emerging resistance is going to affect patients and what must be done to make sure that gonorrhea remains a treatable disease.
History of resistance
Gonorrhea treatment resistance has a long history, dating back to when antibiotics were first used to treat gonorrhea. According to Khalil Ghanem, MD, PhD, associate professor of medicine at Johns Hopkins University School of Medicine and director of HIV, STD and TB Clinical Services for Baltimore City Health Department, the first antimicrobial used to treat gonorrhea was a sulfa drug, to which gonorrhea developed resistance very quickly.
When penicillin came along, it was introduced on a large scale for gonorrhea treatment in the late 1940s. Within a few years, a penicillin-resistant strain of gonorrhea was evident. However, penicillin was the treatment of choice for several decades, Ghanem said. To overcome the resistance, which was slowly developing, penicillin was prescribed in higher doses. However, by the early 1980s, penicillin could no longer be used to treat gonorrhea.
“At that point, we had fluoroquinolones available, so we could still give a pill and treat the gonorrhea,” Ghanem said in an interview. “Within a few years, the first strain of fluoroquinolone-resistant gonorrhea had manifested, and by 2007, the CDC changed the treatment recommendations for gonorrhea from oral fluoroquinolones to oral cephalosporins.”
According to Ghanem, the first case of cephalosporin-resistant gonorrhea was detected as early as 1982, but because fluoroquinolones were the mainstay of treatment, it wasn’t a problem at the time. Now, after being the CDC-recommended treatment for 5 years, resistance to cephalosporins has emerged throughout the world. Injectable cephalosporins are the last remaining drugs, which are reliably effective at treating gonorrhea, but resistance has been documented.
Patterns of resistance
Resistance to antimicrobials is determined by monitoring changes in the minimum inhibitory concentrations of an antimicrobial. According to Kimberly Workowski, MD, professor of medicine at Emory University, the percentage of isolates with elevated MICs for oral cephalosporins has been increasing slowly in the United States, from 0.7% in 2009 to 13% in 2011.
“The increases in MICs for cephalosporins may seem small, but on a bigger scale, it is likely to increase in the future,” Workowski said in an interview. “Because this increase was first in Southeast Asia, CDC recommended combination therapy with ceftriaxone and either azithromycin or doxycycline.”
Patterns of resistance are detected through GISP, a CDC national sentinel surveillance system, which was established in 1986. GISP is a collaborative project between sentinel sites STD clinics selected throughout the country, five regional laboratories. Each month, N. gonorrhea isolates are collected from the first 25 men who present with gonorrhea to STD clinics throughout the country. The laboratories perform antimicrobial susceptibility testing on the isolates and determine the MICs.
In the United States, there has been no resistance observed to ceftriaxone. But there have been reports of clinical failure to the drug in Japan, according to Susan Philip, MD, MPH, director of STD prevention and control services at the San Francisco Department of Public Health.
“We know from historical trends that resistance to different classes of antibiotics is typically identified initially in Japan and then in other Pacific countries,” Philip said in an interview. “In the United States, drug resistance is usually first identified in Hawaii and then on the West coast, so here in San Francisco, we’re especially concerned. It’s worrisome because there are no other classes of drugs left to treat N. gonorrhoeae after cephalosporins and we already have seen resistance to the oral cephalosporins.”
Drug-resistant N. gonorrhoeae is most prevalent on the West Coast and also among men who have sex with men. Ghanem said that the MICs tend to be higher in both of these populations and that the same phenomenon happened when fluoroquinolone-resistance emerged.
The current treatment recommendation is 250 mg ceftriaxone given intramuscularly, combined with either a 1-g single oral dose of azithromycin or a 100-mg dose of doxycycline given twice-daily for 7 days. According to the CDC, azithromycin is the preferred second agent because of the convenience and compliance advantage with single-dose therapy and because of the higher prevalence of resistance to tetracyclines. Those with an allergy to cephalosporins should receive a 2-g single dose of azithromycin and return within 7 days for a test of cure.
“The test of cure should be considered for patients who receive any treatment other than the combination treatment of ceftriaxone plus azithromycin or doxycycline,” Ghanem said. “Having to bring a patient back for this test is a huge strain on public health clinics, so everyone tries to use the recommended first-line treatment to prevent this.”
The recommendation for an injectable drug as first-line therapy poses problems for expedited partner therapy (EPT), a practice in which physicians treating patients with gonorrhea or chlamydia can also provide the patient with prescriptions for treatment for their sexual partners, without them coming in for exams.
Not all states allow EPT. But for those that do, the preferred regimen is cefixime in combination with azithromycin, Kirkcaldy said. However, because these patients are not receiving the optimal therapy, they are urged to present to a physician’s office for a test of cure after completing treatment.
“Under the current treatment guidelines, every effort should be made to ensure that a patient’s sex partners from the past 60 days are evaluated and treated with the recommended regimen,” Kirkcaldy said. “However, that may not always be possible, so providers can still consider the oral regimen for EPT for heterosexual partners who cannot be linked to evaluation and treatment in a timely manner.”
From a public health standpoint, EPT is recommended, Philip said. But with the treatment guidelines, there is concern about whether this practice should continue, since continued use of the oral therapy may contribute to the development of additional resistance, she said.
Use of culture
Of the approximately 320,000 new gonorrhea infections that occur in the United States yearly, only about 5% of them are evaluated as part of the GISP network. Patients that are part of this network have specimens that are cultured and tested for antimicrobial susceptibility.
In regular practice, however, patients do not provide cultures for this testing.
“One of the quandaries we have is that over the years, we’ve moved away from culture as the diagnostic method and onto nucleic acid amplification tests,” Philip said. “They are excellent tests that are much more sensitive than culture. But we do not yet have the ability to do antimicrobial susceptibility testing on those specimens. Culture use is waning, except for those patients in GIST.”
Patients with a positive gonorrhea test by nucleic acid amplification test are treated with ceftriaxone and need no further evaluation. If patients are treated with any other regimen, they should return in 7 days for a test-of-cure. But if a patient’s symptoms do not resolve, and there is concern about treatment failure, the physician should notify the local health department and obtain a culture, Philip said.
However, it is not that simple, Workowski said, since most physicians and regional laboratories no longer have the capability to perform culture in their offices. Even for those that use off-site laboratories, these specimens cannot be transported easily.
“If someone fails the recommended treatment, you should perform culture at the relevant site and perform susceptibility testing,” Workowski said. “But when providers don’t have the capacity to perform culture, they need to identify labs that have retained the ability to do culture.”
There is research under way to establish molecular methods to detect resistance that do not require culture, Workowski said. There are limited data on the specific mutations that are associated with resistance, however, there may be different mutations that can be associated with resistance.
Prevention and control
Besides to surveillance programs, providers also must be about prevention and screening recommendations.
According to Workowski, effective antimicrobial treatment is the foundation of a gonorrhea prevention program. Surveillance programs for antimicrobial resistance are crucial to make sure that treatment remains effective.
In study results published in the Annals of Internal Medicine, Workowski said there must be international collaboration to monitor resistance, and geographic information systems must be expanded to monitor infections. In addition, risk factors for antimicrobial resistance must be evaluated.
Primary screening the populations at highest risk for infection is another component of gonorrhea control. The US Preventive Services Task Force recommends that all sexually active women at increased risk be screened. In addition, CDC recommends MSM to be screened for gonorrhea and other STDs. Secondary screening, by retesting patients 3 to 4 months after treatment and evaluating and treating partners is also a critical component to gonorrhea prevention and control.
“Many patients that are asymptomatic and need to be aware of their risk,” Workowski said. “Providers should be aware of the screening criteria, and make sure that partners of patients with gonorrhea are evaluated and treated.”
For now, ceftriaxone with azithromycin is an effective combination treatment for gonorrhea. Yet, with the development of resistance to oral cephalosporins, and a history of resistance developing to every other available antimicrobial class, the hunt for new treatment options is a top priority.
“From a business model perspective, this is a challenging thing to do because the economics of antimicrobial development are not always favorable to developing new ones,” Kirkcaldy said. “That said, there are several drug companies that are still committed to it and investing in it. We need to continue to highlight this emerging threat of antimicrobial resistance and continue to encourage drug companies to invest in this critical area.”
Within the Prescription Drug User Fee Act, which was renewed by Congress in 2012, the Generating Antibiotic Incentives Now (GAIN) Act incentivizes pharmaceutical companies to research and develop new antimicrobial drugs for the treatment of infectious diseases.
At this time, it is not clear what other treatment options physicians can turn to. According to Ghanem, there are some treatments available, but they are not simple. For example, gentamicin has shown some efficacy against gonorrhea, he said, but it is an injectable agent that is associated with kidney toxicity and ototoxicity. Another option is carbapenams, but with a single dose ranging from $40 to $60, compared with the less than $5 for a dose ceftriaxone, this option would pose a huge burden on public health clinics, Ghanem said.
“When we lose cephalosporins, there are other options available, but none of those options are ideal,” Ghanem said. “When we lose cephalosporins, which will only be in a matter of time, we will be in a difficult situation.”
According to Kirkcaldy, there is a study being funded by the National Institutes of Allergy and Infectious Diseases that recently completed enrollment, in which combinations of antibiotics currently available in the United States are being evaluated. In addition, there is a phase 2 study of a new drug ongoing, but, if the results are favorable, larger, phase 3 studies will still need to be conducted.
“We are calling on our researchers and pharmaceutical companies to jumpstart research to identify new drugs or evaluate currently existing drugs,” Kirkcaldy said. “Before the crisis emerges, now is the time to prevent untreatable gonorrhea from becoming a reality.” — by Emily Shafer
CDC. MMWR. 2012;61:590-594.
Workowski K. Ann Intern Med. 2008;148:606-613
For more information:
Khalil Ghanem, MD, PhD, can be reached at: 5200 Eastern Ave. MFL Center Tower #378, Baltimore, MD 21224. Email: firstname.lastname@example.org.
Robert Kirkcaldy, MD, MPH, can be reached at email@example.com.
Susan Philip, MD, can be reached at: STD Prevention and Control Services, San Francisco Department of Public Health, 1360 Mission Street, Suite 401, San Francisco CA, 94103. Email: firstname.lastname@example.org
Kimberly Workowski, MD, can be reached at: Division of Infectious Diseases, Emory
University, 550 Peachtree St., Suite 7000, Atlanta, GA, 30308. Email: email@example.com
Disclosure: Ghanem, Kirkcaldy, Philip and Workowski report no relevant financial disclosures.