1. No category

Treatment of chancroid.
Y Dangor, R C Ballard, S D Miller and H J Koornhof
Antimicrob. Agents Chemother. 1990, 34(7):1308. DOI:
10.1128/AAC.34.7.1308.
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Vol. 34, No. 7
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1990, p. 1308-1311
0066-4804/90/071308-04$02.00/0
Copyright © 1990, American Society for Microbiology
Treatment of Chancroid
YUSUF DANGOR,* RONALD C. BALLARD, STEVEN D. MILLER, AND HENDRIK J. KOORNHOF
Emergent Pathogen Research Unit of the South African Medical Research Council, School of Pathology, University of
the Witwatersrand, and South African Institute for Medical Research, P.O. Box 1038, Johannesburg 2000, South Africa
The finding that sexually acquired genital ulcer disease, in
particular chancroid, is a major cofactor in the heterosexual
transmission of human immunodeficiency virus (HIV) (14,
35) has increased the urgency for the implementation of
simple, effective, and inexpensive treatment regimens for
chancroid which could be incorporated into HIV-control
programs in developing countries.
Prior to the Vietnam war, the sulfonamides, tetracycline,
and, in some regions, penicillin were accepted as adequate
therapy for chancroid (43). Treatment failures with these
antimicrobial agents which correlated with in vitro resistance were subsequently recorded in both the Far East (24)
and Africa (11). At the present time, multidose therapy with
either erythromycin or co-trimoxazole is regarded as the
treatment of choice for the disease in most endemic areas.
However, recently, single-dose therapies with compounds
exhibiting suitable pharmocokinetic properties and good in
vitro activity against Haemophilus ducreyi have yielded cure
rates in excess of 90% (34, 38).
THERAPEUTIC TRIALS
The results of therapeutic trials of various antimicrobial
agents in which cure rates of _90% have been obtained are
summarized in Table 1. The emergence of P-lactamaseproducing strains of H. ducreyi (16) suggests a limited role
for the treatment of chancroid with penicillin or other
P-lactamase-susceptible antibiotics. However, treatment of
chancroid with amoxicillin plus clavulanic acid has yielded
cure rates of over 90% in patients in Kenya (12, 30). Among
the other beta-lactam antibiotics tested, cefotaxime was
shown to be effective after multidose but not single-dose
therapy (29), while ceftriaxone, which has a long half-life,
gave excellent results following single-dose administration in
two studies in Kenya and Thailand (5, 40) and was recently
accepted as one of the treatments of choice for the disease
by the Centers for Disease Control (7).
Erythromycin has proved to be consistently effective in
the treatment of chancroid (6, 9, 20, 28) and has been
accepted as one of the treatments of choice for chancroid
worldwide. However, no significant difference in cure rates
could be detected when patients in Johannesburg, South
Africa, were treated with erythromycin stearate (500 mg four
times daily) for 7, 14, or 21 days (9), indicating that a shorter
duration of therapy could be effective. In a subsequent
dose-finding study, single-dose erythromycin (1,500 mg) and
other short-course regimens proved to be unsatisfactory in
the treatment of the disease but good clinical and microbiological responses were recorded (>90% cure rates) when
patients were treated with 500 mg three times daily for 3 days
(3). Later in an open, controlled, comparative study, no
treatment failures were recorded among 57 patients treated
with such a 5-day course of erythromycin base (Miller et al.,
15th ICC).
The quinolones rosoxacin, ciprofloxacin, enoxacin, norfloxacin, and fleroxacin have all proved to be effective in the
treatment of chancroid (1, 3, 4, 15, 23, 25, 26). Although
some of these agents have been found to be effective
following single-dose administration, the efficacy of such
CORRELATION OF IN VITRO TEST RESULTS WITH
IN VIVO EFFICACY
Although animal models for chancroid infection have been
described (33, 41), they have not been used routinely for
evaluating the efficacy of various treatments for the disease.
Thus, the validity of in vitro susceptibility testing techniques
has to be confirmed almost exclusively by human clinical
trials. Lack of standardization of methodology for antimicrobial susceptibility testing of H. ducreyi is potentially an
important variable. However, despite inconsistencies in the
techniques used, a good correlation between in vitro results
and clinical outcome has been obtained by using conventional breakpoint values (5, 8, 11; R. C. Ballard, H. G.
Fehler, and B. S. Msikinya, Proc. 13th Int. Congr. Chemother., p. 16/21-16/24, 1983). However, occasional treatment
failures, e.g., with spectinomycin, have occurred, even
when the organism appears to be fully susceptible to the
antimicrobial agent used (S. D. Miller, M. 0. Duncan, H. G.
Fehler, R. C. Ballard, and H. J. Koornhof, Proc. 15th Int.
Congr. Chemother., p. 1338-1340, 1987).
CRITERIA FOR CLINICAL RESPONSES
Important objectives that have been found to correlate
best with clinical outcome include rapid sterilization of the
ulcer and early epithelialization of the ulcer base. Ideally,
cultures of ulcer material should become sterile within 72 h
(3, 25, 26) and clinical cure should ultimately be based on
reepithelialization, which is usually complete by day 10 (5)
but may be delayed up to 28 days (2). The majority of
patients who do not show improvement of ulcers within 7
*
Corresponding author.
1308
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days (4, 5, 26, 40) should be regarded as treatment failures
and therefore require therapy with an alternative agent. In
general, clinical improvement has been associated with a
decrease in pain at the ulcer site, disappearance of the
purulent base of the ulcers, onset of epithelialization, and
failure to reisolate H. ducreyi. Apart from the action of the
antimicrobial agent, the rate of healing of ulcers appears to
be affected by the initial size and site of the lesions (3, 9, 19).
In contrast, resolution of inguinal buboes should not be used
as a criterion for the clinical efficacy of an antimicrobial
agent since temporary progression of existing buboes with or
without fluctuation may occur during the course of adequate
antimicrobial chemotherapy. Aspiration of fluctuant buboes
is frequently required to prevent spontaneous rupture and
formation of inguinal or femoral ulcers. In such cases,
culture of bubo material should be performed to exclude
microbial persistence.
INTRODUCTION
MINIREVIEWS
VOL. 34, 1990
1309
TABLE 1. Treatment of culture-proven chancroid with antimicrobial agents with cure rates of -90%
Country
Kenya
Yr
Antibiotica
Dosageb
Cure
rate
(%)
Reference
Cefotaxime
1 g i.m.i. + 1 g of probenecid for 3 days
95
29
1986
Amoxicillin-clavulanic acid
500/250 mg t.i.d. for 3 days
95
27
Thailand
1984
Ceftriaxone
250 mg i.m.i., single dose
100
40
Kenya
South Africa
1983
1983
1987
Erythromycin
Erythromycin
Erythromycin
500 mg q.i.d. for 10 days
500 mg q.i.d. for 7 days
500 mg t.i.d. for 5 days
100
98
97
28
9
Miller et al.,
15th ICC
Kenya
South Africa and Zimbabwe
1981
1983
1985
1987
1989
TMP-SMX
TMP-SML
TMP-SMO
TMP-SMX
TMP-SMP
160/800 mg b.i.d. for 7 days
160/800 mg b.i.d. for 5 days
160/800 mg b.i.d. for 5 days
160/800 mg b.i.d. for 3 days
1,000/800 mg, single dose
100
96
100
96
93
12
30
10
26
3
Kenya
Thailand
1984
1987
Rosoxacin
Ciprofloxacin
South Africa
1988
Ciprofloxacin
Thailand
Kenya
1987
1983
1987
1981
1982
Norfloxacin
Rifampin
Spectinomycin
Thiamphenicol
Minocycline
150 mg b.i.d. for 3 days
500 mg, single dose
500 mg, two doses, 12 h apart
500 mg, single dose
1,000 mg, single dose
800 mg, single dose
600 mg daily for 3 days
2 g i.m.i., single dose
2.5 g followed by 1.25 g 1 wk later
100 mg b.i.d. for 10 days
95
100
98
96
100
94
100
94
94
91
15
4
4
3
3
1
31
13
21
Ballard et al.,
13th ICC
Zimbabwe
South Africa
a Abbreviations: TMP, trimethoprim; SMX, sulfamethoxazole; SML, sulfametrole; SMO, sulfamoxole; SMP, sulfamethopyrazine.
b Abbreviations:
i.m.i., intramuscular injection; t.i.d., three times a day; q.i.d., four times a day; b.i.d., two times a day.
single-dose regimens in populations with high rates of HIV
type 1 infection remains to be confirmed. Recently, fleroxacin in a single oral dose was found to be effective therapy
for microbiologically proven chancroid in Kenya in the
absence of HIV infection. However, among HIV-infected
men, a single dose of 200 or 400 mg of the antibiotic proved
to be inadequate therapy for the disease (3 of 11 HIVinfected men [27%] had bacteriological failures) (23).
Sulfonamide-trimethoprim combinations have also become established as one of the treatments of choice for the
disease in many areas. In particular, multidose therapy with
sulfamethoxazole-trimethoprim has been widely used (12,
19). Single-dose administration of combinations containing
longer-acting sulfonamides was also evaluated in Kenya (30)
and South Africa and Zimbabwe (3) with encouraging results. However, failure rates of 22 and 45% with sulfonamide-trimethoprim combinations were recently recorded in
Kenya (25) and Thailand, where in vitro trimethoprim resistance has become widespread (39, 40). Sulfonamides alone
are no longer recommended for the treatment of the disease
in Africa or the Far East (12, 40).
The clinical efficacy of rifampin alone (600 mg once daily
for 3 days) or combined with trimethoprim (600/160 mg as a
single dose or daily for 3 days) was evaluated in Nairobi,
Kenya (31). The respective cure rates recorded were 100, 91
and 94%.
Single-dose therapy with spectinomycin gave encouraging
results in Kenya (13), but somewhat less favorable responses
were recorded in South Africa (Miller et al., 15th ICC).
Interestingly, spectinomycin appears to prevent progression
of buboes more efficiently than either erythromycin base
(Miller et al., 15th ICC) or co-trimoxazole (13), but the
mechanism remains unknown. Although kanamycin and
streptomycin have also been used successfully for the treatment of the disease (24, 42), treatment failures with these
agents have been reported in Singapore (32), and failures
with gentamicin have also been recorded in The Netherlands
(37).
Thiamphenicol was found to be effective for the treatment
of chancroid in Harare, Zimbabwe, where one initial oral
dose of 2.5 g followed by 1.25 g given 7 days later yielded a
cure rate of 94% (21). Subsequently, two doses of 2.5 g given
on consecutive days were found to be equally effective (22).
The results obtained following tetracycline therapy have
varied from good to poor (2, 17, 18, 24, 36). The longeracting tetracycline derivatives minocycline and doxycycline
have also been evaluated in a comparative study in South
Africa. Significantly higher cure rates were obtained following treatment with minocycline than with doxycycline given
at the same dosage (Ballard et al., 13th ICC). In this study,
treatment outcome showed good correlation with in vitro
susceptibilities of the isolates to the two tetracycline analogs.
SUMMARY AND PROSPECTS
Since the emergence of resistance to penicillin, tetracycline, and sulfanomides, erythromycin (500 mg three times
daily for 7 days) or trimethoprim-sulfamethoxazole (160/800
mg twice daily for 7 days) has become established as the
treatment of choice for chancroid. However, the duration of
treatment with these agents could be shortened to 5 and 3
days, respectively, with a substantial saving in costs. Based
on in vitro susceptibility testing, the most active drugs
against H. ducreyi are ceftriaxone, ciprofloxacin, and
roxithromycin. The former two agents are effective in single-
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1981
1310
MINIREVIEWS
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dose regimens, while the optimal dosage and duration of
treatment of roxithromycin remain to be established. These
agents may well emerge as acceptable alternatives for routine use, but problems may be encountered in populations
with high rates of HIV infection. Other considerations, such
as cost, patient compliance, and toxicity, are important
factors in the choice of future regimens. The possibility of
emergence of resistance to rifampin and the fact that this
very active drug should probably be reserved for use in
patients with tuberculosis mitigate against its acceptance for
routine use in the treatment of chancroid. In the light of the
experience of emergence of resistance in H. ducreyi, antimicrobial susceptibilities to drugs used routinely at present
or in the future should be monitored closely
With regard to the assessment of prospective antimicrobial agents, standardization of the criteria used for bacteriologic and clinical cure is desirable. Based on the experience
of several workers (3, 26, 31), sterilization of the ulcer within
72 h should constitute a bacteriologic cure and persistence of
viable organisms in ulcers or subsequent aspirates of fluctuant buboes should constitute evidence treatment failure.
Although complete epithelialization of primary ulcerations
may take up to 28 days, in the majority of cases it is achieved
within 10 days. Lack of improvement with regard to pain at
the ulcer site, purulence of the ulcer base, and lack of
epithelialization by day 7 after the onset of therapy also
constitute evidence for treatment failure. Allowance should
also be made for temporary progression in size of buboes
and development of fluctuation despite initiation of effective
therapy. In rare cases, concomitant infection with herpes
simplex virus may result in apparent clinical relapse.
While nontherapeutic measures, such as elective circumcision, may play an important role in control of chancroid,
the prompt use of effective affordable therapy for the disease
should be a high priority among measures which could be
introduced to control the heterosexual transmission of HIV
in developing countries.
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VOL. 34, 1990
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1311