Medication Summary
In the emergency department, antibiotic therapy for urethritis is administered to cover both gonococcal urethritis (GU) and nongonococcal urethritis (NGU), since results of NAAT testing may not be immediately available, and compliance with outpatient treatment and follow-up may be uncertain. Consider presumptive treatment for T vaginalis, or base treatment on evidence of this organism on first catch urine microscopy (which may be insensitive) or NAAT.
Therapy for GU
The primary antibiotic choice recommended by the 2020 CDC updated guidelines [11, 47] in the treatment of GU is ceftriaxone 500 mg IM single dose, or 1 g IM for persons ≥ 150 kg. For the ceftriaxone 1 g IM dose, use 2 separate syringes, and to minimize pain, consider diluting with 2.1 mL of 1% lidocaine. If the patient already has an intravenous (IV) line, the ceftriaxone can be given IV instead of IM. Alternative choices include a single-dose of cefixime 800 mg by mouth (despite concerns for less-than-ideal bactericidal blood levels), or gentamicin 240 mg IM single dose with azithromycin 2 g PO in a single dose for patients with cephalosporin allergy. [11] The results of a single-arm open label clinical trial of aztreonam suggest that it may be an effective alternative treatment for men with beta-lactam allergies. [48]
Routine dual treatment with single dose azithromycin for GU is no longer recommended by the CDC. Although monotherapy with azithromycin 2 g by mouth has previously been demonstrated to be 99.2% effective against uncomplicated urogenital gonorrhea, it is no longer recommended by the Centers for Disease Control and Prevention (CDC) because of concerns about effects on the microbiome and the ease with which N. gonorrhoeae can develop resistance to macrolides, the high proportion of isolates with decreased susceptibility to azithromycin, and documented azithromycin treatment failures. [11]
Quinolone resistance has increase worldwide, at approximately 21%, [49] and is common in Asia, the Pacific, Europe, and the Middle East, as well as in some parts of the United States. [50] Quinolone-resistant GU is also more prevalent in men who have sex with men. Because of increasing resistance, quinolones (eg, ciprofloxacin 500 mg PO single dose, levofloxacin 250 mg PO single dose, or ofloxacin 400 mg PO single dose) are not currently recommended by the CDC for routine or alternative regimens. [11] The recommendation was based on analysis of new data from the CDC's Gonococcal Isolate Surveillance Project (GISP). The data from GISP showed the proportion of gonorrhea cases in heterosexual men that were fluoroquinolone-resistant (QRNG) reached 6.7%, an 11-fold increase from 0.6% in 2001. [51]
During 2007, emergence of fluoroquinolone-resistant N gonorrhoeae in the United States prompted the CDC to cease recommending fluoroquinolones for gonorrhea treatment, leaving cephalosporins as the only remaining class of antimicrobials available for gonorrhea treatment in the United States. [11] For more information see the CDC's Antibiotic-Resistant Gonorrhea Web site.
Therapy for NGU
Current CDC guidelines recommend doxycycline 100 mg orally twice daily for 7 days. [11] Due to concerns for treatment failures for chlamydia and possibility of antibiotic resistance in M genitalium, azithromycin is considered an inferior alternative, and can be given as a single dose of 500 mg orally, followed by 250 mg orally daily for 4 days, or as a one time single 1 g oral dose. [11] The advantage of the single dose is compliance (especially when dosing is observed) and convenience, whereas the multiday regimen may minimize antibiotic resistance in M genitalium.
Doxycycline may have a higher clearance rate for Chlamydia than azithromycin [1, 2] ; however, azithromycin may be more effective than doxycycline for M genitalium [52, 53, 1, 2] and U urealyticum infections. In a follow-up study of 293 young heterosexual patients with NGU detected by NAAT, C trachomatis was present in 23% after azithromycin and 5% after doxycycline, whereas M genitalium was present in 68% after doxycycline and 33% after azithromycin. [2]
Caution has been expressed about single-dose azithromycin 1 g inducing macrolide resistance in M genitalium, [54, 55, 56] despite ensuring compliance and successful treatment of cases of NGU in which test results are negative for Chlamydia, Mycoplasma, and Ureaplasma species. [57, 58] Because of this concern for induced macrolide resistance of M genitalium after single-dose azithromycin 1 g, some researchers have recommended initial treatment with 7 days of doxycycline 100 mg orally twice daily [24] or the extended azithromycin regimen (500 mg initially, then 250 mg daily for 4 days orally). [27, 56]
For patients in whom initial doxycycline therapy fails, treatment can be based on resistance testing (see section below: Therapy for recurrent or persistent urethritis), or empirically, with an extended azithromycin regimen (with less concern for macrolide resistance); then failures of the extended azithromycin regimen are treated with moxifloxacin 400 mg daily for 7 - 10 days.
Alternative initial regimens for NGU include 10 days of moxifloxacin 400 mg daily (which may be more effective than azithromycin for M genitalium, [59, 60, 61] although there is concern regarding emerging quinolone resistance. [5, 27, 24, 25] Other choices could include 7 days of erythromycin base 500 mg 4 times daily, erythromycin ethylsuccinate 800 mg 4 times daily, ofloxacin 300 mg twice daily, levofloxacin 500 mg once daily, [6] or sitafloxacin 100 mg twice daily. [26] Minocycline or tetracycline is a reasonable alternative to doxycycline. Ciprofloxacin is ineffective against chlamydial infection. Combinations of probenecid with penicillin, amoxicillin, or ampicillin are no longer used because of resistance.
The CDC no longer recommends levofloxacin for treatment of NGU because of its inferior efficacy, especially for M genitalium. [11]
Therapy for T vaginalis
Consider empiric treatment for T vaginalis or base treatment, with single treatment of metronidazole or tinidazole 2 g orally, if this organism is present on urinary microscopy or detected by NAAT. [11]
Antibiotic therapy with 2 g metronidazole or tinidazole is also recommended for sexual partners of individuals with documented Trichomonas, even if asymptomatic.
Therapy for recurrent or persistent urethritis
Recurrent symptoms may be related to reexposure (especially if the sexual partner also has not been treated), noncompliance, drug resistance, chronic nonbacterial prostatitis, or infection with T vaginalis, M genitalium, or U urealyticum. Noncompliance with medications may not be as important a factor in recurrent or persistent symptoms as previously thought [45] and should prompt consideration of atypical organisms.
A single dose of metronidazole 2 g orally or tinidazole 2 g orally should be used (especially if not given initially) for suspected Trichomonas. Recurrent trichomonal urethritis is often from reinfection, and retreatment is appropriate. Without re-exposure, metronidazole is dosed as 500 mg orally twice daily for 7 days. [11]
M genitalium can be a common cause of persistent urethritis. Failure rates after doxycycline therapy are high, [62] and azithromycin resistance and failure are increasing. [5, 52] The current CDC guidelines recommend drug resistance testing (specimens can be sent to the CDC). [11] For macrolide-sensitive infections, the following is recommended: doxycycline 100 mg orally 2 times a day for 7 days, followed by azithromycin 1 g orally as an initial dose and then 500 mg orally once daily for 3 additional days (2.5 g total). For macrolide-resistant infections or if testing is not available, the recommended treatment is doxycycline 100 mg orally 2 times a day for 7 days, followed by moxifloxacin 400 mg orally once daily for 7 days. [11]
Antibiotics
Class Summary
Antibiotics should aim to cover GU (high dose ceftriaxone IM) and NGU (doxycycline 100 mg orally twice daily for 7 days)'
Cefixime (Suprax)
Arrests bacterial cell wall synthesis and inhibits bacterial growth by binding to one or more penicillin-binding proteins.
Ceftriaxone (Rocephin)
Used because of increasing prevalence of penicillinase-producing N gonorrhoeae. Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms; arrests bacterial growth by binding to one or more penicillin-binding proteins.
Spectinomycin (Trobicin)
Structurally different from related aminoglycosides, inhibits protein synthesis in bacterial cells. Site of action is 30S ribosomal subunit. Used as alternative antimicrobial in treatment of urethral, endocervical, or rectal gonococcal infections in patients who cannot take cephalosporins or fluoroquinolones. Same regimen of this medication administered to pregnant women who are allergic to cephalosporins.
Azithromycin (Zithromax)
Used to treat mild to moderately severe infections caused by susceptible strains of microorganisms. Indicated for chlamydia and gonorrheal infections of genital tract.
Doxycycline (Dory, Bio-Tab)
Used in treatment of rectal syphilis. Inhibits protein synthesis and bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Tetracycline (Sumycin)
Treats susceptible bacterial infections of both gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Minocycline (Dynacin, Minocin)
Treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to susceptible chlamydial, rickettsial, and mycoplasmal infections.
Erythromycin (E-Mycin, Eryc, Ery-Tab)
Indicated for treatment of infections caused by susceptible strains of microorganisms, including Staphylococcus aureus. Inhibits RNA-dependent protein synthesis, possibly by stimulating dissociation of peptidyl tRNA from ribosomes, thus inhibiting bacterial growth. Twice-a-day dosing not recommended when doses greater than 1 g/d are administered.
Metronidazole (Flagyl)
Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually used in combination with other antimicrobial agents except when used for Clostridium difficile enterocolitis in which monotherapy is appropriate. Active against various anaerobic bacteria and protozoa. Appears to be absorbed into cells, and intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.
Antibiotic, Quinolone
Class Summary
The quinolone class antibiotics are no longer considered effective against GCU due to increasing resistance. However, these antibiotics are useful for NGU as initial alternative to or when refractory to initial treatment with azithromycin.
Moxifloxacin (Avelox)
Inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Useful for refractory NGU secondary to Mycoplasma genitalium infection.
Ofloxacin (Floxin)
Treats GU only. Penetrates prostate well and is effective against N gonorrhea and C trachomatis. A derivative of pyridine carboxylic acid with broad-spectrum bactericidal effect. Useful for the treatment of NGU.
Levofloxacin (Levaquin)
For pseudomonal infections and infections due to multidrug resistant gram-negative organisms as well as atypical infections such as Chlamydia, Mycoplasma and Ureaplasma species.
