This article is more than 5 years old. Information may no longer be current.
Limited options left to treat N. gonorrhoeae
Click Here to Manage Email Alerts
The CDC estimates that more than 700,000 people in the United States develop new gonorrhea infections each year, with 27% of cases occurring among 15- to 19-year-olds, and the incidence of reported gonorrhea among blacks is 17 times the rate among whites. 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.
“The threat of cephalosporin-resistant gonorrhea is alarming, given this sexually transmitted pathogen can rarely disseminate and cause septic arthritis, endocarditis and meningitis,” said
Last summer, 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 could once 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,”
Infectious Diseases in Children 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
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 gonorrhea,” Ghanem said in an interview with Infectious Diseases in Children. “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.”
Khalil Ghanem
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 was not 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.
Resistance to antimicrobials is determined by monitoring changes in the minimum inhibitory concentrations. According to
“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 STD clinics and their respective state/local public health authorities, GISP regional laboratories, and the CDC and Prevention. 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
Drug-resistant N. gonorrhoeae is most prevalent on the West Coast and also among men who have sex with men.
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.
“Intramuscular ceftriaxone remains an effective therapy, and the combination of ceftriaxone with azithromycin provides two different mechanisms of bacterial inhibition, which may aid in prevention of resistance to either agent alone,” Darville, an Infectious Diseases in Children Editorial Board member, said.
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 (Suprax, Lupin Pharmaceuticals) combined with azithromycin, according to Kirkcaldy. 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.
Toni Darville
“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 because continued use of the oral therapy may contribute to more resistance developing, Kirkcaldy said.
“The lack of an effective oral regimen makes administration of patient therapy less convenient, and EPT problematic, despite the greater need to treat partners to prevent spread of potentially drug-resistant isolates,” Darville said.
Prevention and control
Besides surveillance programs, providers also must be knowledgeable of 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.
Primary screening of 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, also is a critical component to gonorrhea prevention and control.
“Many patients 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.”
Darville said considering the significant proportion of resistant gonorrhea in adolescents, providers also should offer counseling to this patient population.
“Given that more than one-quarter of gonorrhea cases occur in adolescents, and another one-third of cases occur in young adults 19 to 25 years of age, a sexually transmitted infection history, counseling and testing should be performed whenever adolescents and young adults present for care,” she said.
After ceftriaxone
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.”
At this time, it is unclear what other treatment options physicians have for resistant gonorrhea. According to Ghanem, there are some treatments available, but they are not simple. “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.” – by Emily Shafer
For more information:
CDC. MMWR. 2012;61:590-594.CDC. MMWR. 2013;62:103-106.
Owusu-Edusei K. Sex Transm Dis. 2013;40:197-201.
Satterwhite CL. Sex Transm Dis. 2013;40:187-193.
Workowski K. Ann Intern Med. 2008;148:606-613.
For more information:
Toni Darville, MD, can be reached at toni.darville@chp.edu.
Khalil Ghanem, MD, PhD, can be reached at: MFL Center Tower, 5200 Eastern Ave., #378, Baltimore, MD 21224; email: kghanem@jhmi.edu.
Robert Kirkcaldy, MD, MPH, can be reached at cdcinfo@cdc.gov.
Susan Philip, MD, can be reached at STD Prevention and Control Services, San Francisco Department of Public Health, 1360 Mission St., Suite 401, San Francisco CA, 94103; email: susan.philip@sfdph.org.
Kimberly Workowski, MD, can be reached at Division of Infectious Diseases, Emory University, 550 Peachtree St., Suite 7000, Atlanta, GA, 30308; email: kworkow@emory.edu.
Disclosure: Darville, Ghanem, Kirkcaldy, Philip and Workowski report no relevant financial disclosures.
Adolescents should have access to confidential testing and treatment.
While all adolescent medicine providers would agree that having a trusted and responsible adult involved in the care of an adolescent is important, requiring parental involvement in care, particularly reproductive health care, can be a significant barrier to an adolescent seeking timely care and treatment.
Meera S. Beharry
The position paper of the Society for Adolescent Health and Medicine (SAHM) on Confidential Health Care for Adolescents cites studies in which adolescents indicate they would delay or discontinue use of STI services if their parents were notified (SAHM. J Adolesc Health. 2004;35:160-167). The public health effects of such a delay or lack of care are considerable given the high STI rates among adolescents. Additionally, the support staff and tracking needed to inform parents can present a significant burden to most practices and public health clinics. Furthermore, debates about requiring parental notification for adolescent reproductive health issues must take into consideration adolescents who are not in the care of their parents due to foster care placement, incarceration or homelessness. For these adolescents, parental notification may not only cause a delay in care, but may put the young person in further harm.
The AAP, the American College of Obstetrics and Gynecology, the AMA, and the SAHM all agree that confidential care for adolescents is essential to their health and well-being and parental notification should not be a barrier to care.
Indeed, all 50 states and the District of Columbia permit minors to consent to STI services on their own. These laws expedite care and also permit adolescents to take responsibility for their own health, which is an important step in healthy development. In an era of resistant gonorrhea, the focus should be on helping adolescents get the appropriate treatment as quickly as possible. Having the least amount of barriers to care is the best way to do this.
Meera S. Beharry, MD, FAAP, is regional vice president of the International Association for Adolescent Health and is assistant professor of pediatrics at Texas A&M Health Science Center. She also is adolescent medicine section chief in the department of pediatrics at McLane Children’s Hospital at Scott & White in Temple, Texas. Disclosure: Beharry reports no relevant financial disclosures.
Requiring parental consent for treatment can represent a significant barrier to such care.
From a legal perspective, all 50 states allow adolescents of a certain age access to testing and treatment for some/all STIs without parental consent. An up-to-date summary of individual state laws can be found at www.guttmacher.org/statecenter/spibs/spib_MASS.pdf.
Kym Ahrens
As a clinician, I strongly believe that teens should be allowed access to confidential testing and treatment, for the simple reason that STIs can be life- or fertility-threatening without appropriate care, and requiring parental consent for treatment can represent a significant barrier to such care. The risk of getting an STI is immediate with the first sexual experience, and many parents are not aware when their teen first begins having sex. Hongmei Yang and colleagues performed a study (Yang H. J Adolesc Health Health. 2006;39:353–361) published in 2005 that showed that for more than half of teens who reported being sexually active, their parents were unaware of their sexual activity. Jocelyn Lehrer and colleagues published another study (Lehrer JA. J Adolesc Health Health. 2007;40:218–226) in 2007 that showed youth who reported forgoing health care because of a confidentiality concern were more likely to report many health risk behaviors, including having had sexual intercourse, not using birth control during their last sexual encounter, and having had a prior STI. This research suggests that the very youth who are concerned about confidentiality may be the youth who most need access to medical services, including testing and treatment for STIs.
This does not mean, however, that physicians should be prevented from encouraging teens to talk to their parents or another trusted adult if they are diagnosed with an STI. To the contrary, situations such as STI diagnoses can represent opportunities for savvy clinicians to discuss with teens the importance of having a parent or mentor to go to for advice on difficult issues and to maintain open lines of communication so that they (clinicians) themselves can fill that role, especially for teens who do not have access to other trusted adults. The Society for Adolescent Health and Medicine (SAHM) has two relevant position papers on this subject, both of which advocate for confidential access to reproductive health care for adolescents: SAHM. J Adolesc Health. 2004;35:160-167 and SAHM. J Adolesc Health. 2004;35:420-42.
Kym Ahrens, MD, MPH, is assistant professor and associate adolescent medicine fellowship director in the division of adolescent medicine, department of pediatrics, Seattle Children’s Hospital and Research Institute, University of Washington, Seattle. She can be reached at Kym.ahrens@seattlechildrens.org. Disclosure: Ahrens reports no relevant financial disclosures.
Parents should be informed because they need to provide support and direct future healthy behaviors.
For 4 decades, law and medicine have debated an adolescent’s rights and capacity to direct personal health decisions. When a diagnosis has the potential to impact long-term well-being, the debate takes on additional gravity. Three principles of adolescent development should be considered: adolescent brain development, compliance with medical care, and the role of the teen’s support system.
Policies that exclude parents from adolescent care were developed decades before research demonstrated the delay in brain maturation in adolescents. The adult-like body of the teen masks the incomplete frontal lobe and the age-appropriate struggles of decision-making and impulse control. We now recognize that parents should serve the role of "external frontal lobes" when adolescents are pressured by peers, media or exploitative partners. Eliminating parental involvement can diminish short-term health outcomes, as well as future healthy behaviors.
Medical care can be a challenge for many adolescents. When a serious diagnosis like resistant gonococcal infection is confirmed, the patient needs a caregiver who recognizes the illness, the importance of treatment and follow-up, and the signs of complications or recurrence. Adolescents may also need medications, procedures and access that are dependent on parental insurance or resources. If the parent is not "notified" and educated, the best source of support may be lost and optimal therapy and follow-up may not be completed.
Perhaps the most compelling reason to involve parents in STD treatment is to protect teens. Sexual exploitation and violence are frequently co-occurring with STDs, especially among adolescents aged younger than 16 years. If parents are not informed, if it is assumed that parents do not care, then how can parents help? Health providers do not go home with these vulnerable youth, so they do not know their social environments. Research demonstrates that adolescents do better when they are connected to their parents, so it should be the role of the provider to help these patients and parents build communication and trust that leads to lasting health, not simply "effective antibiotic treatment."
Jane E. Anderson, MD, is a retired clinical professor of pediatrics at the University of California, San Francisco. Alma L. Golden, MD, is vice chair for community pediatrics at Texas A&M Health Science Center in Temple, Texas. Disclosure: Anderson and Golden report no relevant financial disclosures.