Oral Alternatives to Cefixime for the Treatment of Uncomplicated Neisseria gonorrhoeae Urogenital Infections

As referenced in: MMWR 53(16); 335-338 and MMWR 51(46);1052

The CDC Sexually Transmitted Diseases Guidelines 2002, recommend several single dose treatment options for uncomplicated Neisseria gonorrhoeae urogenital and rectal infections: cefixime 400 mg orally, ceftriaxone 125 mg intramuscularly, ciprofloxacin 500 mg orally, ofloxacin 400 mg orally, or levofloxacin 250 mg orally. Ceftriaxone provides sustained, high bactericidal levels in the blood, and has, based on data from published trials using a 125 mg dose, a treatment efficacy of 98.9% (95%CI 97.9-99.8%) for treating urogenital and rectal infections and 94.1% (95% CI 85.6-98.4%) for pharyngeal infection. However, ceftriaxone must be given by injection and is relatively expensive. Ciprofloxacin and ofloxacin also provide sustained bactericidal levels, and in published clinical trials the recommended regimens have produced cure rates >98% for treating urogenital infection and >88% for pharyngeal infection. Several other fluoroquinolone regimens (gatifloxacin, norfloxacin, lomefloxacin) appear safe and effective, but limited data suggest no advantage over the recommended fluoroquinolones. Ceftriaxone or spectinomycin are the options recommended by CDC for treating pregnant women with urogenital and rectal gonorrhea; in pregnant women with pharyngeal infection ceftriaxone is recommended. The only other regimen studied in pregnancy is cefixime 400 mg with a treatment efficacy of 96.2% for uncomplicated cervical and rectal infections (95% CI 88.8-99.6%).

Besides the fluoroquinolones, cefixime, whose manufacture was discontinued in 2002, is the only currently CDC-recommended oral agent for treating gonorrhea. Although Lupin, Ltd. (Baltimore, MD) received FDA approval to market cefixime in February 2004, the 400 mg tablets to treat gonorrhea are not yet available; the suspension (100mg/5mL) is available. The limited availability of cefixime in the United States has prompted further examination of alternative oral treatment options for Neisseria gonorrhoeae urogenital and pharyngeal infections. To be recommended as a treatment for uncomplicated gonorrhea, an antimicrobial regimen should cure >95% of urogenital infections (treatment efficacy for anorectal infection is typically comparable to that for urogenital infection). Studies documenting efficacy should have sufficient sample size so that the lower limit of the confidence interval (CI) of the cure rate is also >95%. The available data do not demonstrate that any single dose oral antimicrobial regimen, other than cefixime or the fluoroquinolones, meet these efficacy criteria for gonococcal urogenital or pharyngeal infection (Tables 1,2). Evaluation of efficacy by specific anatomic site is essential because all antimicrobial regimens are less efficacious against pharyngeal infection; thus antimicrobial efficacy against gonococcal pharyngeal infection must be demonstrated in clinical trials. In this context, providers can evaluate if pharyngeal exposure has occurred; if treatment of pharyngeal infection is not an issue, some of the oral alternative regimens, although not recommended, appear marginally effective.

Several alternative oral cephalosporin regimens have been evaluated for the treatment of uncomplicated gonococcal urogenital infection but have not been recommended by CDC because, based upon the available published data, they have not met the above efficacy criteria for treating urogenital infection, have undocumented or unacceptable efficacy for treating pharyngeal infection, or because of safety concerns (Table 1, 2). Treatment with cefuroxime axetil 1 g does not quite meet the minimum efficacy criteria for urogenital and rectal infection 95.9% (95%CI 94.5-97.3); furthermore, its efficacy in treating pharyngeal infection is unacceptable, 56.9% (95%CI 42.2-70.7%). Cefpodoxime proxetil 200 mg is less active against N. gonorrhoeae in vitro than cefixime and also does not quite meet the minimum efficacy criteria with cure rates, 96.5% (95%CI 94.8-98.9%) for urogenital and rectal infection; efficacy in treating pharyngeal infection is also unsatisfactory, 78.9% (95%CI 54.5-94%). Cefpodoxime 400 mg has not been well studied. Ceftibuten 400 mg is not as active as cefixime in vitro, and has been evaluated in only one clinical trial limited to men with uncomplicated urethritis; efficacy does not meet the criteria for treating urogenital infection, 98.2% (95% CI 93.6-99.8%), and no data are available with regard to treatment of pharyngeal infection. Although data from in vitro studies suggest cefdinir, at 300 mg and 600 mg, might be an effective therapy for gonorrhea, there are no published clinical data addressing treatment efficacy.

Azithromycin 2 g, as a single oral dose, has demonstrated an efficacy of 99.2% (95%CI 97.2%-99.9%) for urogenital and rectal infections, and treatment efficacy of 100% for pharyngeal infection (95%CI 82.3-100%) but has not been recommended because of expense and frequency of gastrointestinal intolerance. Anecdotal data from an ongoing clinical treatment trial of early syphilis suggest the 2 g dose may be better tolerated if the recently available 500 mg tablet is used instead of the capsule or sachet formulations that were used in previous evaluations, especially if the tablets are administered with food. However, efficacy data related to treatment of Neisseria gonorrhoeae utilizing this 500 mg tablet formulation, at a 2 gram dose, are not available. Treatment with 1 g of azithromycin is insufficiently effective and is not recommended.

Fluoroquinolones are not recommended for treatment of gonococcal infections acquired in Hawaii, California, Asia, the Pacific, and in other areas with increased prevalence of fluoroquinolone resistance. There has been a recent increase in prevalence of fluoroquinolone-resistant gonococci in Massachusetts, Michigan, New York City, and Seattle. The emergence of these fluoroquinolone resistant isolates should alert providers to the possible appearance of fluoroquinolone-resistant Neisseria gonorrhoeae in their community. Additionally, recent local and national data suggest that the prevalence of fluoroquinolone-resistance among men who have sex with men (MSM) is substantial (probably over 5%). As such, fluoroquinolones should no longer be used to treat proven or suspected gonococcal infection in MSM. Ceftriaxone 125 mg IM remains the regimen of choice when fluoroquinolone-resistant Neisseria gonorrhoeae is a concern. Recently, due to local increases in fluoroquinolone-resistant gonorrhea and the unavailability of cefixime, several locales (King County, Washington and California) have suggested alternative oral gonococcal treatment regimens; these alternative regimens have not been fully evaluated, however an evaluation of cefpodoxime 400 mg by the California Department of Health Services is planned. Therefore, as part of effective gonorrhea control programs, health departments should evaluate their current fluoroquinolone-resistant gonococcal surveillance activities and consider plans to monitor for the emergence of resistant isolates among heterosexual populations at risk for gonorrhea.

Patients with urogenital gonococcal infections often are coinfected with Chlamydia trachomatis; if chlamydial infection has not been ruled out, co-treatment with doxycycline or azithromycin should be provided. Individuals with uncomplicated gonococcal infection who are treated with a regimen recommended by CDC need not return for a test of cure. However, if treatment regimens are utilized which are not CDC- recommended, providers should consider performing a test of cure. In addition, local data concerning efficacy of any alterative treatment regimen should be collected.

References:

CDC. Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR 51(RR-6):1-80.

CDC. Antibiotic-resistant strains of Neisseria gonorrhoeae policy guidelines for detection, management, and control. MMWR 1987;36(noS-5).

The following reference summarizes the results of 87 regimens and cites 171 reports related to treatment of gonorrhea:
Moran JS, Levine WC. Drugs of choice for the Treatment of uncomplicated gonococcal infections. Clin Infect Dis 1995;20(Suppl 1):S47-65.

The following references for relevant clinical trials published after 1993 (excluding trials of antimicrobials restricted or not approved by the FDA) provided the data used to update the calculations of treatment efficacy which were included in the above reference (i.e., Moran 1995):

Crabbe F, Grobbelaar TM, van Dyck E, Dangor Y, Laga M, Ballard RC. Cefaclor, an alternative to third generation cephalosporins for the treatment of gonococcal urethritis in the developing world? Genitourin Med. 1997 Dec;73(6):506-9.

Ekwere PD. An open study of procaine penicillin G, clavulanate-potentiated amoxycillin and probenecid in the treatment of acute gonorrhoea. J Int Med Res 1994 Jul-Aug;22(4):236-43.

Gruber F, Brajac I, Jonjic A, Grubisic-Greblo H, Lenkovic M, Stasic A. Comparative trial of azithromycin and ciprofloxacin in the treatment of gonorrhea. J Chemother. 1997 Aug;9(4):263-6.

Hellmann NS, Nsubuga PS, Baingana-Baingi DJ, Desmond-Hellmann SD, Mbidde EK, Granowitz CB, Sande MA. Single-dose ampicillin/sulbactam versus ceftriaxone as treatment for uncomplicated gonorrhoea in a Ugandan STD clinic population with a high prevalence of PPNG infection. J Trop Med Hyg. 1995 Apr;98(2):95-100.

Lule G, Behets FM, Hoffman IF, Dallabetta G, Hamilton HA, Moeng S, Liomba G, Cohen MS. STD/HIV control in Malawi and the search for affordable and effective urethritis therapy: a first field evaluation. Genitourin Med 1994 Dec;70(6):384-8.

Mogabgab WJ, Lutz FB. Randomized study of cefotaxime versus ceftriaxone for uncomplicated gonorrhea. South Med J. 1994 Apr;87(4):461-4.

Moi H, Morel P, Gianotti B, Barlow D, Phillips I, Jean C. Comparative efficacy and safety of single oral doses of sparfloxacin versus ciprofloxacin in the treatment of acute gonococcal urethritis in men. J Antimicrob Chemother. 1996 May;37 Suppl A:115-22.

Stoner BP, Douglas JM Jr, Martin DH, Hook EW 3rd, Leone P, McCormack WM, Mroczkowski TF, Jones R, Yang J, Baumgartner. Single-dose gatifloxacin compared with ofloxacin for the treatment of uncomplicated gonorrhea: a randomized, double-blind, multicenter trial. Sex Transm Dis. 2001;28:136-42

Table 1. Oral non-quinolone antimicrobials for the treatment of uncomplicated gonococcal infections of the pharynx¹

Antimicrobial and dose (mg)	Number evaluable	Number cured	Percent cured	Ref.	95% C.I.	MIC90 (mg/L)2	Time serum concentration is > 4x MIC90 (hours)
Azithromycin 1000	2	2	100	i
Azithromycin 1000	1	1	100	ii
Azithromycin 1000	3	3	100		29.2-100		3
Azithromycin 2000	19	19	100	iii	82.3-100		3
Cefixime 400	8	8	100	iv	63.1-100	<0.001-0.015	20-34
Cefixime 800	7	6	85.7	iv
Cefixime 800	8	6	75.0	v
Cefixime 800	15	12	80.0		51.9-95.7	<0.001-0.015	42->70
Cefdinir 300					No published data	≤0.06	≥8
Cefdinir 600					No published data	≤0.06	≥11
Cefditoren 400					No published data	1 or less	0
Cefpodoxime proxetil 200	19	15	78.9	vi	54.5-94.0	0.03-2	0-9
Cefpodoxime proxetil 400					No published data	0.03-2	0-14
Ceftibuten 400					No published data	0.15-0.5	7-11
Cefuroxime axetil 1000	2	1	50.0	vii
Cefuroxime axetil 1000	2	0	0	viii
Cefuroxime axetil 1000	25	15	60.0	ix
Cefuroxime axetil 1000	22	13	59.1	x
Cefuroxime axetil 1000	51	29	56.9		42.2-70.7	0.06-2	1-8

1. Cure rates for pharyngeal infections are lower than for urethral, cervical, or rectal infections except for the most effective regimens (Moran JS "Treating Uncomplicated Neisseria gonorrhoeae Infections: Is the Anatomic Site of Infection Important?" Sex Transm Dis 1995;22:39-47)

2. Range of published MIC₉₀s from Moran JS, Handsfield HH. Neisseria gonorrhoeae. In: Yu VL, Weber R, Raoult F, et al., eds. Antimicrobial Therapy and Vaccines. 2nd ed. New York: Apple Trees Productions, 2002;1:457-69.

3. Not applicable; plasma concentration may lower than tissue concentration

Table 2. Oral non-quinolone antimicrobials for the treatment of uncomplicated gonococcal infections of the urethra, cervix, or rectum⁴

Antimicrobial and dose (mg)	Number evaluable	Number cured	Percent cured	Ref.	95% C.I.	MIC90 (mg/L)2	Time serum concentration is > 4x MIC90 (hours)
Azithromycin 1000	95	89	93.7	i
Azithromycin 1000	29	29	100	ii
Azithromycin 1000	124	118	95.2		91.4-98.9		3
Azithromycin 2000	264	262	99.2%	iii	97.2-99.9		3
Cefixime 400	92	91	98.9	xi
Cefixime 400	101	97	96.0	iv
Cefixime 400	121	118	97.5	xii
Cefixime 400	30	30	100	xiii
Cefixime 400	344	336	97.7		95.9-98.6	<0.001-0.015	20-34
Cefixime 800	54	52	96.3	xi
Cefixime 800	94	92	97.9	iv
Cefixime 800	98	97	99.0	v
Cefixime 800	246	241	98.0		95.9-99.6	<0.001-0.015	42->70
Cefdinir 300					No published data	≤0.06	≥8
Cefdinir 600					No published data	≤0.06	≥11
Cefditoren 400					No published data	1 or less	0
Cefpodoxime proxetil 200	274	264	96.4	vi
Cefpodoxime proxetil 200	10	10	100	viii
Cefpodoxime proxetil 200	284	274	96.5		94.8-98.9	0.03-2	0-9
Cefpodoxime proxetil 400	10	10	100	xiv	69.1-100	0.03-2	0-14
Ceftibuten 400	112	110	98.2	xv	93.6-99.8	0.15-0.5	7-11
Cefuroxime axetil 1000	65	62	95.4	viii
Cefuroxime axetil 1000	29	26	89.7	xvi
Cefuroxime axetil 1000	78	77	98.7	xvii
Cefuroxime axetil 1000	297	289	97.3	vii
Cefuroxime axetil 1000	315	298	94.6	x
Cefuroxime axetil 1000	784	752	95.9		94.5-97.3	0.06-2	1-8

4. Cure rates are similar for infections of the cervix, male and female urethra, and male and female rectum (Moran JS "Treating Uncomplicated Neisseria gonorrhoeae Infections: Is the Anatomic Site of Infection Important?" Sex Transm Dis 1995;22:39-47)

Table 3. Pharmacokinetics and efficacy of candidate oral cephalosporins

Antimicrobial and dose (mg)	Peak serum concentration (mg/L)	Elimination half-life (hours)	MIC90 (mg/L)	Time serum concentration is > 4x MIC90 (hours)	Efficacy (with 95% CL)
					Pharyngeal	Rectal/Urogenital
Cefixime 400	3.5	3-4	<0.001-0.015	20-34	92.3% (74.9-99.1)	97.7% (95.9-98.6)
Cefixime 800	7.1¶	3-4	<0.001-0.015	42->70	80.0% (51.9-95.7)	98.4% (95.9-99.6)
Cefdinir 300	1.6	2.9	≤0.06	≥8	No published data	No published data
Cefdinir 600	2.9	3.0	≤0.06	≥11	No published data	No published data
Cefditoren 400	<3.6	1.6	1 or less	0	No published data	No published data
Cefpodoxime proxetil 200	2.3	2.1	0.03-2	0-9	78.9% (54.5-94.0)xviii	96.8% (94.8-98.9)xix
Cefpodoxime proxetil 400	3.9	2.8	0.03-2	0-14	No published data	100% (69.1-100)xx
Ceftibuten 400	13.3	2.4	0.15-0.5	7-11	No published data	98.2% (93.6-99.8)
Cefuroxime axetil 1000	13.6	1.3	0.06-2	1-8	56.9% (42.2-70.7)	95.9% (94.5-97.3)

¶extrapolation

---

ⁱ Waugh MA. Open study of the safety and efficacy of a single oral dose of azithromycin for the treatment of uncomplicated gonorrhoea in men and women. J Antimicrob Chemother. 1993;31 Suppl E:193-8.

ⁱⁱ Lassus A. Comparative studies of azithromycin in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species J Antimicrob Chemother. 1990;25 Suppl A:115-21.

ⁱⁱⁱ Handsfield HH, Dalu ZA, Martin DH, Douglas JM Jr, McCarty JM, Schlossberg D. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis. 1994;21:107-11.

^iv Handsfield HH, McCormack WM, Hook EW 3rd, Douglas JM Jr, Covino JM, Verdon MS, Reichart CA, Ehret JM. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The Gonorrhea Treatment Study Group. N Engl J Med. 1991;325:1337-41.

^v Megran DW, Lefebvre K, Willetts V, Bowie WR Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1990;34:355-7.

^vi Upjohn, unpublished

^vii Reichman RC, Nolte FS, Wolinsky SM, Greisberger CA, Trupei MA, Nitzkin J. Single-dose cefuroxime axetil in the treatment of uncomplicated gonorrhea: a controlled trial. Sex Transm Dis 1985;12:184-7.

^viii Das RP, Jones K, Robinson AJ, Timmins DJ. Cefuroxime axetil to treat gonorrhea. Genitourin Med 1988;64:394.

^ixBaddour LM, Gibbs RS, Mertz G, Cocchetto DM, Noble RC. Clinical comparison of single-oral-dose cefuroxime axetil and amoxicillin with probenecid for uncomplicated gonococcal infections in women. Antimicrob Agents Chemother 1989;33:801-4.

^x Thorpe EM, Schwebke JR, Hook EW 3rd, Rompalo A, McCormack WM, Mussari KL, Giguere GC, Collins JJ. Comparison of single-dose cefuroxime axetil with ciprofloxacin in treatment of uncomplicated gonorrhea caused by penicillinase-producing and non-penicillinase-producing Neisseria gonorrhoeae strains. Antimicrob Agents Chemother 1996;40:2775-80.

^xi Portilla I, Lutz B, Montalvo M, Mogabgab WJ. N Sex Transm Dis. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. 1992;19:94-8.

^xii Plourde PJ, Tyndall M, Agoki E, Ombette J, Slaney LA, D'Costa LJ, Ndinya-Achola JO, Plummer FA. Single-dose cefixime versus single-dose ceftriaxone in the treatment of antimicrobial-resistant Neisseria gonorrhoeae infection. J Infect Dis. 1992;166:919-22.

^xiii Kuhlwein A, Nies BA. Efficacy and safety of a single 400 mg oral dose of cefixime in the treatment of uncomplicated gonorrhea Eur J Clin Microbiol Infect Dis. 1989;8:261-2.

^xiv Novak E, Paxton LM, Tubbs HJ, Turner LF, Keck CW, Yatsu J. Orally administered cefpodoxime proxetil for treatment of uncomplicated gonococcal urethritis in males: a dose-response study. Antimicrob Agents Chemother 1992 Aug;36(8):1764-5.

^xv Chong LY, Cheung WM, Leung CS, Yu CW, Chan LY. Clinical evaluation of ceftibuten in gonorrhea. A pilot study in Hong Kong. Sex Transm Dis. 1998;25:464-7.

^xvi Gottlieb A, Mills J. Cefuroxime axetil for treatment of uncomplicated gonorrhea. Antimicrob Agents Chemother 1986;30:333-4.

^xvii Kinghorn GR, Spencer RC, Smith TK, Woolley PD, Patel R, Robinson AJ. Comparative study of cefuroxime axetil and procaine penicillin in the treatment of uncomplicated gonorrhoea. Int J STD AIDS 1990;1:285-7.

^xviii Upjohn, unpublished

^xix Upjohn, unpublished, and Novak E, Paxton LM, Tubbs HJ, Turner LF, Keck CW, Yatsu J. Orally administered cefpodoxime proxetil for treatment of uncomplicated gonococcal urethritis in males: a dose-response study. Antimicrob Agents Chemother 1992 Aug;36(8):1764-5

^xx Novak E, Paxton LM, Tubbs HJ, Turner LF, Keck CW, Yatsu J. Orally administered cefpodoxime proxetil for treatment of uncomplicated gonococcal urethritis in males: a dose-response study. Antimicrob Agents Chemother 1992 Aug;36(8):1764-5