Bauer, Heidi M. MD, MPH*; Wohlfeiler, Dan MJ, MPH*; Klausner, Jeffrey D. MD†‡; Guerry, Sarah MD§; Gunn, Robert A. MD, MPH∥; Bolan, Gail MD*; the California STD Controllers Association
Background and Rationale
Public Health Importance of Chlamydia and Gonorrhea
SEXUALLY TRANSMITTED CHLAMYDIAL AND GONOCOCCAL infections are significant public health problems. More than 136,000 cases of chlamydia and more than 33,000 cases of gonorrhea were reported in California in 2005, making them the top 2 most common reportable communicable infections.1 These genital infections can lead to pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, and preventable infertility in women.2 Patients with these infections are also at increased risk of acquiring sexually transmitted HIV.3 Repeat infections, which increase the risk of complications, occur in nearly 15% of women and men within 6 months after treatment.4–6 To prevent repeat infections, reduce complications in individuals, and reduce further transmission of infections in the community, sex partners of infected patients must be provided timely and appropriate antibiotic treatment.
Barriers to Effective Partner Management
Public health efforts to notify and treat sex partners have proven successful and are considered a cornerstone of syphilis control.7–9 However, because of the high burden of infection and limited public health resources for partner notification activities, it is difficult for local health departments to ensure partner notification for all cases of chlamydia and gonorrhea.10 Although providers have the option to collect the partners’ contact information and notify them, few clinics have the resources for this activity. Further, there are few mechanisms through which providers can be reimbursed for these activities. Thus, the standard of care for partner management for chlamydia and gonorrhea cases has become patient referral, whereby providers counsel patients about the need for partner treatment and the need for taking responsibility for notifying partners. The effectiveness of patient referral is dependent on the patient’s motivation and ability to notify the partner(s), as well as the partner’s motivation and ability to obtain treatment. Lack of health insurance and limited access to medical care limit the effectiveness of partner referral. Further, infected partners who are asymptomatic may be less likely to seek needed medical treatment.
California Legislation Allowing Expedited Partner Therapy for Chlamydia and Gonorrhea
In 2001, SB 648 amended California law to allow expedited partner therapy (EPT) for chlamydia, and in January 2007, AB 2280 further amended the law to allow EPT for gonorrhea.11 The California Department of Public Health was given the authority to determine whether other STDs will be appropriate for EPT in the future. The law allows physicians to prescribe, and nurse practitioners, physician assistants, and certified nurse-midwives to dispense, antibiotic therapy for the male and female sex partners of individuals infected with Chlamydia trachomatis or Neisseria gonorrhoeae, even if they have not been able to perform an exam of the patient’s partner(s).12
This legislation provides an exception to the Medical Practice Act, which states that the prescribing, dispensing, or furnishing of dangerous drugs without a good-faith prior examination and medical indication, constitutes unprofessional conduct. The legislated exception provides that a licensee acting in accordance with provisions of the law with regard to a prescription for antibiotic therapy has not committed unprofessional conduct. Allowing EPT provides an important means to combat a serious public health problem and prevent adverse reproductive health outcomes.
Although not intended as a first-line strategy for ensuring treatment of partners of patients diagnosed with chlamydia and gonorrhea, EPT can serve as a useful alternative when the partner is unable or unlikely to seek care. Providers should use their best judgment to determine whether partners will or will not come in for treatment, and to decide whether to dispense or prescribe additional medication to their patient. These guidelines are intended to assist providers in making these decisions.
Health Care Provider Responsibilities for Ensuring Partner Treatment
Patients diagnosed with chlamydia or gonorrhea cannot be considered adequately treated until all their partners have been treated. All sexual contacts within the previous 60 days from the onset of symptoms or diagnostic test results need to be treated. In California, physicians are required by law to: endeavor to discover the source of infection, as well as any sexual or other intimate contacts that the patient made while in the communicable stage of the disease13; make an effort, through the cooperation of the patient, to bring these persons in for examination and, if necessary, treatment13; and report cases to the local health officer.14
Evidence for the Effectiveness of EPT for Chlamydia and Gonorrhea
EPT is the general term for the practice of treating sex partners of patients diagnosed with an STD without an intervening medical evaluation. Patient-delivered partner therapy is the most common type of EPT, in which the patient delivers the medication or a prescription to his or her sex partner(s). Other types of EPT involve alternative delivery mechanisms, such as direct provision through a pharmacy under clinical protocol.15
Several research studies, including randomized clinical trials, have demonstrated that EPT is effective in facilitating partner notification and reducing recurrent infection among initial cases. A recent meta-analysis that included 5 clinical trials showed an overall reduced risk (summary risk ratio, 0.73; 95% confidence interval (CI): 0.57–0.93) of recurrent infection in patients with chlamydia or gonorrhea who received EPT, compared with those who received standard partner treatment methods.16
One randomized trial demonstrated that partner management strategies that included EPT as an option, compared with conventional strategies, significantly reduced recurrent chlamydia and gonorrhea among heterosexual men and women.15 In that study, EPT was more effective than standard referral in reducing recurrent infection among patients with gonorrhea (3% vs. 11%, P = 0.01), compared with those with chlamydial infection (11% vs. 13%, P = 0.17). In a separate study of men with urethritis, EPT, compared with patient referral, reduced recurrent infection rates by half, from 43% to 23%.17 In another study, of women with chlamydia, EPT reduced recurrent infection rates from 15% to 12% (P = 0.10).18 A report published by the Centers for Disease Control and Prevention (CDC) in 2006 provided a thorough review of the research literature, a discussion of programmatic issues related to EPT, and guidance for public health programs and clinicians.19
Implementation and Use of EPT
In a national physician survey conducted in 2000, researchers at CDC found that the practice of EPT for chlamydia and gonorrhea was already common.20,21 According to a 2002 California survey, nearly half of California physicians and nurse practitioners reported that they routinely use EPT to treat partners of patients with chlamydia.22 A local evaluation in the public STD clinic in San Francisco, CA, demonstrated that EPT implementation resulted in 23% of patients with chlamydia and gonorrhea receiving EPT.23 As of January 2007, the STD Control Branch had not received any reports of adverse events related to EPT for chlamydia, despite the availability of a toll-free reporting line since 2001. For some insurance plans in California, reimbursement for EPT has not kept up with policy and practice changes. Because this practice provides preventive care for the patient by reducing recurrent infection and subsequent reproductive health complication, public and private insurers should make certain their reimbursement and coverage policies support EPT.
The current legislation allowing EPT for sexually transmitted infections does not protect health care providers from lawsuits resulting from adverse outcomes related to the practice. This liability is no different from the liability of any other action taken by a health care provider, including prescribing or dispensing medicine for any medical condition. However, guidelines establish a standard of care, and standard of care is the primary medicolegal standard for appropriate practice. When the prescribing physician is a public official or employee, he or she is immune from tort liability in California when acting within the scope of their authority.24
Potential Concerns in Using EPT
There are several concerns about EPT. First, the medication could cause a serious adverse reaction, including hypersensitivity reaction. Second, EPT may compromise the quality of care provided to partners, particularly if it is used as a first-line approach for partners who would otherwise seek clinical services. Optimal care for contacts to STD includes testing for other STDs and HIV, physical examination for signs of complications, and risk-reduction counseling. Ideally, partners who receive EPT will still access these clinical services. Despite these concerns, the benefits of EPT outweigh the risks, since doing nothing for exposed partners is more harmful. Further, risks may be mitigated through patient education and written materials for partners that provide warnings and encourage visiting a health care provider. Additional concerns about EPT include misuse of the medication and waste if the medication is not delivered or not taken. Currently, there are no data that indicate that EPT is misused.
Guidelines for Using EPT for Chlamydia and Gonorrhea
Selecting Appropriate Patients for EPT
Providers should consider those patients with a clinical diagnosis of sexually transmitted chlamydia or gonorrhea as appropriate for EPT (Table 1). Laboratory confirmation of the diagnosis may include a Gram stain of urethral exudate showing Gram-negative intracellular diplococci indicative of gonorrhea or a positive culture, nucleic acid hybridization test, or nucleic acid amplification test (NAAT) for chlamydia or gonorrhea. Because of their high sensitivity, NAATs are the tests of choice for detecting chlamydial infection. In fact, only a negative NAAT negates the need for cotreatment for chlamydia in a patient with gonorrhea.25 Providing EPT without laboratory confirmation should be considered when the provider has a high clinical suspicion for chlamydia or gonorrhea (e.g., male patients with urethritis or female patients with overt mucopurulent cervicitis) and is concerned about loss of follow-up.
Patients most appropriate for EPT are those with partners who are unable or unlikely to seek prompt clinical services. Factors to consider include the patient’s report that the partner is uninsured, lacks a primary care provider, faces significant barriers to accessing clinical services, or will be unwilling to seek care. Whenever possible, clinicians should attempt to provide clinical services to partners to ensure treatment; confirm the diagnosis; complete a physical examination; test for other STDs, HIV, and pregnancy; provide needed vaccinations; and offer risk-reduction counseling and community referrals. Even if EPT is provided, the partner should be encouraged to seek follow-up care as soon as possible. Clinicians also should assess the acceptability of EPT to both the patient and the partners receiving it.
Providers should ask patients about the partner’s symptom status, particularly symptoms indicative of a complicated infection; pregnancy status; and history of severe medication allergies. If the partner is pregnant, every effort should be made to contact her for referral to pregnancy services and/or prenatal care. Many local health departments are able to provide assistance for these situations. For partners with known severe allergies to antibiotics, EPT should not be used.
The legislation permits EPT regardless of the patient’s gender or sexual orientation. However, the use of EPT to treat certain partners [e.g., females, and gay men and other men who have sex with men (MSM)] may increase the risk of inadequately treating a complicated infection or missing a concurrent STD/HIV infection in the partner. Further, EPT is not appropriate for patients known to be coinfected with STDs not covered by EPT medication; cases of suspected child abuse, sexual assault, or abuse; or a situation in which the patient’s safety is in doubt.
Recommended Treatment Regimens
The legislation does not mandate a specific antibiotic. The recommended antibiotic therapies for EPT include azithromycin 1 g to treat chlamydia and cefpodoxime 400 mg to treat gonorrhea (Table 1). Azithromycin is among the first-line treatment recommendations for chlamydial infections and cefpodoxime is considered an alternative treatment regimen for gonococcal infection.25
Fluoroquinolones (e.g., ciprofloxacin, ofloxacin, and levofloxacin) should not be used to treat gonorrhea.26 The frequency of gonococcal isolates resistant to fluoroquinolones increased from less than 1% in 2000 to 2.8% in 2001 in California, which prompted new gonorrhea treatment recommendations.27 In 2004, the CDC announced high rates of fluoroquinolone-resistant gonorrhea among MSM28; and in April 2007, the CDC announced that rates nationally had reached 13%.29 The rate of QRNG in California in 2005 exceeded 25%.30
Few oral cephalosporins have been studied and found to be effective against gonorrhea. Although cefixime remains a recommended regimen to treat uncomplicated infections of the cervix, urethra, or rectum, the tablet form is not available in the United States. If cefixime tablets become available, a single dose of 400 mg would be an appropriate medication for EPT for gonorrhea.25 Because available data support the effectiveness of cefpodoxime 400 mg for urogenital gonorrhea, it is the drug of choice for EPT for gonorrhea. Importantly, oral cephalosporins are less effective in eradicating gonococcal infections of the pharynx.
Patients infected with gonorrhea have high rates (35%–50%) of coinfection with chlamydia.31 Because of the high sensitivity of NAATs for chlamydial infection, a patient’s negative chlamydial NAAT result precludes the need for the patient or partner(s) to be treated for chlamydia. However, if chlamydial test results are not available or if a non-NAAT was negative for chlamydia, the patient and partner(s) should be treated for both gonorrhea and chlamydia.25 To avoid confusion, the partner should be treated for the same infections as the patient. However, some providers may opt to provide EPT for chlamydial infection, even if the patient’s chlamydia NAAT is negative. This approach was suggested in national guidelines, since the partner may be infected with chlamydia.19
A 2-g oral dose of azithromycin is discouraged for EPT for gonorrhea. Although small studies have shown that this regimen is effective against uncomplicated gonococcal infections, it causes significant gastrointestinal distress. Because the average azithromycin susceptibility levels of gonococcal isolates appears to be decreasing,32 it is possible that widespread use may hasten the emergence of antimicrobial resistance.
All sex partners in the 60 days before diagnosis should be considered at risk for infection and should be treated. If the last sexual encounter was more than 60 days before diagnosis, the most recent sexual partner should be treated. The law does not specify how many partners may be treated using this strategy. Thus, patients should be provided with the number of doses necessary to treat each at-risk partner who can be contacted. A combination of partner strategies also may be used; for example, a patient with several partners may refer one partner to the clinic but take EPT for other partners.
The medication for EPT may be dispensed or prescribed. The preferable method is dispensing in a prepackaged partner pack that includes medication, informational materials, and clinic referrals. If dispensing is not possible, prescriptions can be provided; however, these prescriptions should be accompanied by informational materials for the partner. The prescriptions can be written separately for the patient and for each of the patient’s partners, or as a single prescription with the name of the patient and partner(s).
Risk of Adverse Reactions to Medications
Adverse reactions to single-dose cefpodoxime and azithromycin, beyond mild to moderate side effects, are rare. This risk of allergy and adverse drug reactions may be mitigated through educational materials that accompany the medication, which include explicit warnings and instructions for partners who may be allergic to penicillin, cephalosporins, or macrolides, to seek medical advice before taking the medication. Examples of partner therapy instructions and information are available online in English and Spanish, and California providers are encouraged to report any adverse reactions or outcomes.33
Azithromycin is generally well tolerated.34 The most common side effects in patients receiving a single-dose regimen of 1 g of azithromycin are related to the gastrointestinal system: diarrhea or loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), and dyspepsia (1%). Vaginitis occurs in about 1% of women taking azithromycin. No other side effects have been documented with a frequency greater than 1%. Anaphylaxis or severe allergy to macrolides generally, and to azithromycin specifically, is very rare.
Cefpodoxime is generally well tolerated. The most common side effects in patients receiving a single dose of cefpodoxime were related to the gastrointestinal system: nausea (1.4%) and diarrhea or loose stools (1.2%).35 No other side effects occurred with a frequency greater than 1%.
Approximately 1% to 3% of patients have a primary hypersensitivity to cephalosporins; however, rates and cross-reactivity vary, depending on the molecular structure.36 The risk of anaphylaxis with cephalosporin in the general population is 0.0001 to 0.1%.37–39 However, patients with IgE-mediated allergy to penicillin are at increased risk for severe allergic reactions to cephalosporins. Evidence of IgE-mediated allergy includes anaphylaxis, hypotension, laryngeal edema, wheezing, angioedema, and/or uticaria. Approximately 10% of patients report penicillin allergy; however, more than 90% of them are found not to be allergic and are able to tolerate the drug.40 Cephalosporins are less allergenic than penicillin. The risk of cephalosporin reaction among patients with penicillin allergy is 5% to 17% for first-generation cephalosporins, 4% for second-generation, and only 1% to 3% for third- and fourth-generation cephalosporins.41 Cefpodoxime, cefixime, and other cephalosporins recommended for the treatment of gonorrhea are third-generation cephalosporins.
In a retrospective cohort study of patients receiving penicillin and a subsequent cephalosporin, the risk of an allergic event was about 10-fold higher among those who had had a prior allergic reaction to penicillin; however, the absolute risk of anaphylaxis was very small: 1 in 100,000.42 Further, because the risk was similarly elevated among those subsequently given a sulfonamide antibiotic, cross-reactivity may not be an adequate explanation for the increased risk. The American Academy of Pediatrics guidelines, which establish a medicolegal standard of care, state that third-generation cephalosporins can be used to treat penicillin-allergic patients as long as the penicillin reaction is not severe (i.e., not IgE-mediated).37,38 Skin testing for penicillin allergy is recommended for patients if the allergic reaction was consistent with IgE-mediated mechanism or if the history is unclear.43 Such partners are not appropriate for EPT.
Risk of Inadequate Treatment of Complicated Infections and Missing Concurrent STD/HIV
One risk in providing EPT to male patients with female partners is the risk of inadequate treatment of undiagnosed PID. Currently, there are no data available to evaluate the frequency with which female partners of male patients with gonorrhea and/or chlamydia have developed symptoms of PID. Another risk of EPT is missing concurrent STD and HIV infections. There is particular concern related to using EPT in MSM, because of the risk of undiagnosed HIV infection. In a multisite study of STD/HIV coinfection among STD patients who presented as contacts to an infected individual, 6.3% of MSM had newly diagnosed HIV infection.44 The risk of missing new HIV infections may be higher in areas with less access to HIV screening. No data are available on the effectiveness of EPT in reducing repeat infection among MSM. Because of the absence of efficacy data in subpopulations, such as men who have sex with men, current national recommendations only support EPT in heterosexuals.19
Because oral cephalosporins are less effective in eradicating pharyngeal gonococcal infection, inadequate treatment of partners with pharyngeal infection is a potential limitation of EPT. Providers who are concerned that the partner is at risk for pharyngeal infection, specifically if the partner has been exposed to a male urethral infection at this site, should discuss with the patient that oral treatment may not cure pharyngeal gonorrhea in all patients and that the partner should seek care.
Each of these risks can be mitigated through educational materials that clearly instruct all EPT recipients that they should seek care for STD and HIV testing, regardless of whether they take the medication. In particular, those with specific symptoms such as pelvic pain or testicular pain should seek medical care; pregnant women should seek regular prenatal care and receive a test of cure; and MSM should seek HIV testing. Examples of partner therapy instructions and information are available online.33 Assistance from the local health department may be available for challenging partner situations.
EPT and Pregnancy
Although EPT is not contraindicated when a patient reports that his female partner may be pregnant, providers should assess whether the pregnant partner is receiving pregnancy services or prenatal care. Every effort should be made to contact the pregnant partner and ensure appropriate care; EPT should be considered a last resort. The local health department may be of assistance for these situations. The need for a test of cure 3 weeks after completing treatment for chlamydia and gonorrhea in pregnancy should be emphasized. Both recommended EPT regimens are safe in pregnancy.25 Doxycycline, a potential substitute for azithromycin, should not be used in pregnancy.
Key Education and Counseling Messages
It is essential that educational material be given to the patient to deliver to the partner along with the EPT medication or prescription. Providers should discuss the following key counseling messages with their patient when providing EPT: (a) Partners should seek a complete STD evaluation as soon as possible, regardless of whether they take the medication; (b) Partners should read the informational material very carefully before taking the medication; (c) Partners who have allergies to antibiotics or who have serious health problems should not take the medications and should see a health care provider; (d) Partners who have symptoms of a more serious infection (e.g., lower abdominal pain in women, testicular pain in men, fever in women or men) should seek care as soon as possible; (e) Partners who are or could be pregnant should seek care as soon as possible; (f) Patients and partners should abstain from sex for at least 7 days after treatment and until 7 days after all partners have been treated, in order to decrease the risk of repeat infection; (g) Patients and partners should be advised to seek clinical services for retesting 3 months after treatment. Examples of partner therapy instructions and information are available online.33
Patient Follow-Up and Retesting at Three Months
To ensure the effectiveness of EPT, providers should schedule both male and female patients to return for retesting for chlamydia and gonorrhea 3 months after treatment. Partners also may benefit from retesting 3 months after treatment.
Effective partner treatment for chlamydia and gonorrhea is critical for preventing repeat infection and interrupting transmission in the community. In light of current challenges in traditional approaches to partner management and the demonstrated effectiveness of EPT alternatives, EPT for chlamydia and gonorrhea is a valuable evidence-based tool for clinical providers. If used appropriately, EPT can benefit patients, partners, and the community while minimizing any potential risk. Further evaluation should be conducted to assess the impact of this approach on reducing the high rates of chlamydia and gonorrhea in California.
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11. Ortiz, Chapter 835, Statutes of 2000; Leno, Chapter 771, Statutes of 2006. Accessible online: www.leginfo.ca.gov
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