The new CDC sexually transmitted treatment guidelines have finally arrived and are available on line at www.cdc.gov/std .  These guidelines are evidence based, and although they emphasize treatment, prevention strategies and diagnostic recommendations are also discussed.  The guidelines present new information in several areas for both men and women, such as:

1. Expanded diagnostic evaluation for cervicitis and trichomoniasis;
2. New treatment recommendations for bacterial vaginosis and genital warts;
3. Clinical efficacy of azithromycin for chlamydial infection in pregnancy;
4. Role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications;
5. Lymphogranuloma venereum proctocolitis among men who have sex with men (MSM);
6. The criteria for spinal fluid examination to evaluate for neurosyphilis;
7. The emergence of azithromycin-resistant Treponema pallidum;
8. The increasing prevalence of antimicrobial-resistant Neisseria gonorrhoeae;
9. The sexual transmission of hepatitis C;
10. Diagnostic evaluation after sexual assault; and,
11. STD prevention approaches. 

This web update will focus on what’s new regarding the diagnosis and treatment of non-gonococcal urethritis in men.  However, several webcasts reviewing the Guidelines are available through the CDC’s STD website as well as the National Network of Prevention Training Centers’ website (nnptc.org).  In our next web update we will discuss treatment approaches for Neisseria gonorrhoeae infections.

WHERE TO BEGIN: THE FIVE P’s:

The four principal outcomes of STD therapy for each individual disease are treatment of infection based on microbiologic eradication, alleviation of signs and symptoms, prevention of sequelae, and prevention of transmission.  Often in the clinical setting, the patient presents for alleviation of signs and symptoms and the clinician’s job is to determine what the infection may be, what tests to order, what treatment to give, and what prevention and risk-reduction messages to impart to the specific client.  This process begins with a sexual history which should be taken in a nonjudgmental and empathetic manner which is appropriate to the patient’s culture, language, sex, sexual orientation, age and developmental level.  Box 1, which is taken from the 2010 STD Treatment Guidelines, nicely outlines the five P’s of a good sexual history:  Partners, Prevention of pregnancy, Protection from STDs, Practices, and Past history of STDs.  Although we usually consider pregnancy prevention questions mainly for women, men should be queried regarding prevention of pregnancy also.  Although this may not be pertinent for men who have sex exclusively with other men, assumptions should not be made without asking about partners: “Do you have sex with men, women, or both?”  Getting the “Five P’s” information will also inform what interactive counseling approach the clinician will choose that can be directed at the patient’s personal risk, the situations in which risk occurs, and the use of personalized goal-setting strategies that may be effective for his STD/HIV prevention (2,3).

Urethritis:  What’s new?

Urethritis among males is characterized by urethral inflammation which may be accompanied by discharge of mucopurulent or purulent material, dysuria, or urethral pruritis.  Asymptomatic infections, however, are common.  According to the CDC 2010 treatment guidelines, clinicians should attempt to obtain objective evidence of urethral inflammation (1).  Diagnostic, on-site, clinic-based tools include Gram-stain microscopy.  Ideally, urethritis can be documented on the basis of mucopurulent or purulent discharge on examination and a Gram stain of urethral secretions demonstrating > 5 white blood cells (WBCs) per oil immersion field.  A positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstration > 10 WBC per high-power filed can also be used.  The Gram stain is currently the preferred rapid diagnostic test for evaluating urethritis since it is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection in symptomatic males.  Gonococcal infection can be determined is Gram-negative intracellular diplococcic are seen on the Gram’s stain of urethral discharge. 

If microscopy is not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia since Neisseria gonorrhoeae is associated with 5 to 20% of urethritis cases and Chlamydia trachomatis is associated with 15-40% of cases (4).  Urethritis that is not caused by gonorrhea, or nongonococcal urethritis (NGU), is a common chlamydia-associated syndrome in men; however, Trichomonas vaginalis and Mycoplasma genitalium are associated with its etiology and should be considered in approaches to therapy.  M. genitalium accounts for 15-25% of urethritis cases in the United States.  T. vaginalis has been associated with 5-20% of urethritis cases and is associated with age and geography(4-6).  With primary herpes simplex virus infections, 15-30% of males have symptomatic urethritis (7).  Other reported causes of urethritis include adenovirus, enteric bacteria often associated with insertive anal intercourse, Candida and anaerobes.   A specific diagnosis may help with partner referral and, therefore, gonorrhea and chlamydia testing is recommended.  All partners in the past 60 days should be referred for evaluation and appropriate treatment.  Partners of males with NGU should always be treated for chlamydia infection, regardless of whether a specific etiology is identified.

A recent study by Schwebke and colleagues re-evaluated the treatment of NGU, emphasizing emerging pathogens.  In general treatment for NGU is targeted toward Chlamydia trachomatis and recommended treatment regimens include doxycycline 100 mg twice daily for one week or azithromycin 1 gram given in one dose.  These treatments do not cover trichomonas infections and although failure to cure M. genitalium with both doxycycline and azithromycin has been documented (9), one randomized study showed azithromycin therapy was more efficacious than doxycycline therapy (10).  In this randomized, controlled, double-blinded phase IIB trial of men with urethritis, participants were randomized to receive doxycycline plus or minus tinidazole or azithromycin plus or minus tinidazole.  Participants were then observed for up to 24 days.  Figure 1 demonstrates the prevalence of pathogens at baseline.   The prevalences of C. trachomatis, M. genitalium, and T. vaginalis were 43%, 31% and 13%, respectively.  Of note, even with the use of non-commercially available PCR detection methods for M. genitalium and T. vaginalis along with nucleic acid amplification tests for both gonorrhea and chlamydia, no pathogens were identified in 29% of participants.  Clinical cure rates at the first follow-up visit were 74.5% for the doxycycline-containing regimens and 68.6% for azithromycin-containing regimens.  There were no differences in clinical response rates among the treatment arms.  However, the chlamydia clearance rate was 94.8% (55 of 58 patients) for the doxycycline arm and 77.4% (41 of 53 patients) for the azithromycin arm, and the M. genitalium clearance rate was 30.8% (12 of 39 patients) for the doxycycline arm and 66.7% (30 or 45 patients) for the azithromycin arm.   The results of this article confirm the 2010 STD treatment recommendations for NGU as shown in box 2. 

To minimize transmission, men treated for NGU should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen, provided their symptoms have resolved.  They should be instructed to return for evaluation if symptoms persist or recur after completion of therapy.  Upon return visit, they should be evaluated for signs of inflammation because symptoms alone are not sufficient bases for retreatment.   Repeat testing for gonorrhea and/or chlamydia 3 to 4 weeks after completing therapy – which is a test-of-cure – is not recommended for persons with either or both of these infections who have received and completed recommended therapy.  Men with persistent or recurrent urethritis can be retreated with the initial regimen if they did not comply with the treatment regimen or if they were re-exposed to an untreated sex partner.  If the patient was compliant with the initial regimen and re-exposure can be excluded, then clinicians should consider infection with doxycycline-resistant M. genitalium or Ureaplasma urealyticum as well as the possibility of T. vaginalis infection.  Men can be tested for T. vaginalis by sending a urethral swab, first void urine, or semen for culture or a NAAT on a urethral swab or urine if available.  Testing for M. genitalium and U. urealyticum is not currently commercially available.  So, if the patient was treated with azithromycin, metronidazole 2 grams or tinidazole 2 grams orally in a single dose can be given.  If azithromycin was given initially, retreatment with metronidazole or tinidazole as above plus azithromycin 1 gram in a single dose can be given while awaiting the results of the trichomonas test if done.

Some men have persistent symptoms even after repeat treatment.  A limited number of patients who experienced NUG treatment failures in two reported studies demonstrated that moxifloxacin 400 mg orally given daily for 7 days was highly effective against M. genitalium (11,12).  Chronic prostatitis/chronic pelvic pain syndrome, however, does occur and symptoms may include persistent perineal, penile, or pelvic pain, discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for greater than 3 months.  These patients may have urethral inflammation without any identifiable microbial pathogens.  Referral to a urologist is in order if pain lasts more than 3 months within a 6-month period. 

References

1. www.cvdc.gov/std/treatment/2010
2. Lin JS, Whitlock E, O'Connor E, et al. Behavioral counseling to prevent sexually transmitted infections: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2008; 149:497--9.
3. U.S. Preventive Services Task Force. Behavioral counseling to prevent sexually transmitted infections: recommendation statement. Ann Intern Med 2008;149:491--6.
4. Bradshaw CS, Tabrizi SN, Read TR, et al. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006;193:336--45.
5. Martin DH. Nongonococcal urethritis: new views through the prism of modern molecular microbiology. Curr Infect Dis Rep 2008;10:128--32.
6. Schwebke JR, Hook EW, III. High rates of Trichomonas vaginalis among men attending a sexually transmitted diseases clinic: implications for screening and urethritis management. J Infect Dis 2003;188:465--8.
7. Madeb R, Nativ O, Benilevi D, et al. Need for diagnostic screening of herpes simplex virus in patients with nongonococcal urethritis. Clin Infect Dis 2000;30:982--3.
8. Schwebke JR, Rompalo A, Taylor S, Sena AC, Martine DH, Lopen LM, Lensing S, Lee JY.  Re-evaluating the treatment of nongonoccal urethritis:  emphasizing emerging pathogens – a randomized clinical trial.  Clin Infect Dis 2011: In press.
9. Falk L, Fredlund H, Jensen JS. Tetracycline treatment does not eradicate Mycoplasma genitalium. Sex Transm Infect 2003;79:318--9.
10. Mena LA, Mroczkowski TF, Nsuami M, et al. A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men. Clin Infect Dis 2009;48:1649--54.
11. Jernberg E, Moghaddam A, Moi H. Azithromycin and moxifloxacin for microbiological cure of Mycoplasma genitalium infection: an open study. Int J STD AIDS 2008;19:676--9.
12. Bradshaw CS, Chen MY, Fairley CK. Persistence of Mycoplasma genitalium following azithromycin therapy. PLoS One 2008;3:e3618