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 fluoroquinoloneresistance 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 (www.cdc.gov/std/gisp); 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
Number Number Percent
(mg)
evaluable cured
cured Ref.
Azithromycin
1000
2
2
100
i
Azithromycin
1000
1
1
100
ii
Azithromycin
1000
3
3
100
Azithromycin
2000
19
19
100
Cefixime 400
8
8
Cefixime 800
7
Cefixime 800
Cefixime 800
95%
C.I.
Time serum
concentration
MIC90 is > 4x MIC90
(mg/L)2
(hours)
29.2-100
3
iii
82.3-100
3
100
iv
63.1-100
<0.0010.015
20-34
6
85.7
iv
8
6
75.0
v
15
12
80.0
51.995.7
<0.0010.015
42->70
Cefdinir 300
No
published
data
≤0.06
≥8
Cefdinir 600
No
published
data
≤0.06
≥11
Cefditoren 400
No
published 1 or less
data
0
Cefpodoxime
proxetil 200
54.594.0
0.03-2
0-9
Cefpodoxime
proxetil 400
No
published
data
0.03-2
0-14
Ceftibuten 400
No
published 0.15-0.5
data
19
15
78.9
vi
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
42.270.7
0.06-2
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
7-11
1-8
Table 2. Oral non-quinolone antimicrobials for the treatment of uncomplicated gonococcal
infections of the urethra, cervix, or rectum4
Antimicrobial
and dose
Number Number Percent
(mg)
evaluable cured
cured Ref.
Azithromycin
1000
95
89
93.7
i
Azithromycin
1000
29
29
100
ii
Azithromycin
1000
124
118
95.2
Azithromycin
2000
264
262
99.2%
iii
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
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%
C.I.
Time serum
concentration
MIC90 is > 4x MIC90
(mg/L)2
(hours)
91.498.9
3
97.299.9
3
95.998.6
<0.0010.015
20-34
95.999.6
<0.0010.015
42->70
Cefdinir 300
No
published
data
≤0.06
≥8
Cefdinir 600
No
published
data
≤0.06
≥11
No
published 1 or less
data
Cefditoren 400
Cefpodoxime
proxetil 200
274
264
96.4
vi
Cefpodoxime
proxetil 200
10
10
100
viii
Cefpodoxime
proxetil 200
284
274
96.5
Cefpodoxime
proxetil 400
10
10
100
Ceftibuten 400
112
110
Cefuroxime
axetil 1000
65
Cefuroxime
axetil 1000
0
94.898.9
0.03-2
0-9
xiv
69.1-100
0.03-2
0-14
98.2
xv
93.699.8
0.15-0.5
7-11
62
95.4
viii
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
94.597.3
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
Efficacy (with 95% CL)
Time serum
concentration
is > 4x MIC90 Pharyngeal Rectal/Urogenital
(hours)
Peak serum
concentration
(mg/L)
Elimination
half-life
(hours)
Cefixime 400
3.5
3-4
<0.0010.015
20-34
92.3%
(74.999.1)
97.7% (95.9-98.6)
Cefixime 800
7.1¶
3-4
<0.0010.015
42->70
80.0%
(51.995.7)
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
<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%
(54.594.0)xviii
Cefpodoxime proxetil
400
3.9
2.8
0.03-2
0-14
No
published
data
100% (69.1-100)xx
98.2% (93.6-99.8)
95.9% (94.5-97.3)
Antimicrobial and
dose (mg)
Cefditoren 400
MIC90
(mg/L)
Ceftibuten 400
13.3
2.4
0.15-0.5
7-11
No
published
data
Cefuroxime axetil
1000
13.6
1.3
0.06-2
1-8
56.9%
(42.270.7)
¶extrapolation
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
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i
Lassus A. Comparative studies of azithromycin in skin and soft-tissue
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ii
96.8% (94.8-98.9)xix
iii
Handsfield HH, Dalu ZA, Martin DH, Douglas JM Jr, McCarty JM, Schlossberg
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iv
Handsfield HH, McCormack WM, Hook EW 3rd, Douglas JM Jr, Covino JM,
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v
Megran DW, Lefebvre K, Willetts V, Bowie WR Single-dose oral cefixime
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vi
Upjohn, unpublished
Reichman RC, Nolte FS, Wolinsky SM, Greisberger CA, Trupei MA, Nitzkin J.
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vii
viii
Das RP, Jones K, Robinson AJ, Timmins DJ. Cefuroxime axetil to treat
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x
Thorpe EM, Schwebke JR, Hook EW 3rd, Rompalo A, McCormack WM,
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xi
xii
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xiii
Kuhlwein A, Nies BA. Efficacy and safety of a single 400 mg oral dose of
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xiv
Novak E, Paxton LM, Tubbs HJ, Turner LF, Keck CW, Yatsu J. Orally
administered cefpodoxime proxetil for treatment of uncomplicated gonococcal
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xv
Chong LY, Cheung WM, Leung CS, Yu CW, Chan LY. Clinical evaluation of
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xvi
Gottlieb A, Mills J. Cefuroxime axetil for treatment of uncomplicated
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Kinghorn GR, Spencer RC, Smith TK, Woolley PD, Patel R, Robinson AJ.
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xvii
xviii
Upjohn, unpublished
xix
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xx
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