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Epidemiology, clinical
features, diagnosis and
treatment of Haemophilus
ducreyi a disappearing
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by CDL-UC San Diego on 12/31/14
pathogen?
Expert Rev. Anti Infect. Ther. 12(6), 687696 (2014)
David A Lewis Chancroid, caused by Haemophilus ducreyi, has declined in importance as a sexually transmitted
Centre for HIV and STIs, National
pathogen in most countries where it was previously endemic. The global prevalence of
Institute for Communicable Diseases, chancroid is unknown as most countries lack the required laboratory diagnostic capacity and
National Health Laboratory Service, surveillance systems to determine this. H. ducreyi has recently emerged as a cause of chronic
1 Modderfontein Road, Sandringham
skin ulceration in some South Pacific islands. Although no antimicrobial susceptibility data for
2131, Johannesburg, South Africa
H. ducreyi have been published for two decades, it is still assumed that the infection will
For personal use only.
and
Department of Internal Medicine, respond successfully to treatment with recommended cephalosporin, macrolide or
Faculty of Health Sciences, University fluoroquinolone-based regimens. HIV-1-infected patients require careful follow-up due to
of the Witwatersrand, Johannesburg,
South Africa
reports of treatment failure with single dose regimens. Buboes may need additional treatment
and with either aspiration or excision and drainage.
Division of Medical Microbiology,
University of Cape Town, Cape Town, KEYWORDS: azithromycin ceftriaxone chancroid ciprofloxacin erythromycin genital ulcer Haemophilus
South Africa ducreyi HIV-1
Tel.: +27 115 550 468
davidl@nicd.ac.za
Chancroid, also known as soft chancre (ulcus
molle), is caused by the fastidious Gram- Epidemiology
negative bacillus Haemophilus ducreyi [1]. The Chancroid is more prevalent among individu-
organism is usually spread through sexual als from lower socioeconomic groups as well
intercourse and it is believed that microabra- as among female commercial sex workers
sions are required to be present before infec- (CSWs) and their male partners [9]. Impor-
tion can be established in the genital tantly, men have a much higher incidence of
epithelium and underlying tissue [2,3]. Chan- chancroid than women, while uncircumcised
croid usually presents as multiple painful males are more susceptible than circumcised
superficial genital ulcers and may be associated men [10,11]. A link has also been described
with suppurated regional lymphadenopathy [4]. between chancroid in men and sexual exposure
Chancroid used to be one of the most preva- to crack cocaine-using CSWs [12].
lent sexually transmitted infections (STIs), par- Although two studies have reported asymp-
ticularly so in several resource-poor countries tomatic carriage rates of 24% in female CSWs,
of Africa, Asia, Latin America and the Carib- it is generally believed that asymptomatic car-
bean [5]. Several prospective and cross-sectional riage of H. ducreyi plays little or no role in dis-
casecontrolled studies, undertaken in coun- ease transmission [2,13,14]. The cross-sectional
tries where chancroid used to be a common design of these two studies, one culture-based
cause of genital ulcer disease (GUD) and and the other based on the use of nucleic acid
where analyses were appropriately adjusted for amplification tests (NAATs), made it impossible
differences in sexual behavior, have highlighted to determine if asymptomatic carriage of
the importance of GUD as a risk factor for H. ducreyi does indeed exist or contribute signif-
the transmission of HIV-1 [68]. icantly to chancroid transmission. Specifically,
these studies were unable to differentiate persistent asymptomatic in period 20022005. Likewise, a total of only 24 cases of
infection from transient carriage following sexual inoculation or chancroid were detected in the USA in 2010, which represents
either the incubation or recovery phases of true H. ducreyi a 99.4% decline in the number of reported cases since
infection. 1990 [29].
For chancroid, the reproductive rate (Ro) is critically depen-
Chancroid enhances HIV-1 transmission dent on the average number of exposed sexual contacts per
Men and women with genital ulceration have been shown to be unit time [11]. Accordingly, any intervention that reduces the
substantially more likely to be co-infected with HIV-1 infection, number of sexual exposures will have a profound effect on Ro
with odds and risk ratios being higher than for non-ulcerative and the number of new chancroid cases will rapidly decline
STIs [6,15]. A re-analysis of data from longitudinal studies of once Ro falls below unity. Such interventions include better
female CSWs and men in Nairobi showed that GUD can pro- health-seeking behavior, improved access to services, improved
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by CDL-UC San Diego on 12/31/14
duce high co-factor effects per sexual exposure for male-to-female quality of sexual health services through the introduction of
(10- to 50-fold) and for female-to-male (50- to 300-fold) trans- STI syndromic management, high levels of treatment, a reduc-
mission of HIV-1 [16]. These estimates suggest that GUD may tion in high-risk sexual behavior and increased condom use as
have been responsible for a high proportion of heterosexually well as better sexual healthcare for sex workers and their
acquired HIV-1 infections in sub-Saharan Africa during the time partners [23,30,31].
when chancroid was highly prevalent. Strong correlations have As a result of the painful nature of the genital ulcers, as well
also been reported between HIV-1 seropositivity and serological as the belief that persistent asymptomatic carriage of H. ducreyi
evidence of previous chancroid [17,18]. Further supportive evi- is of limited or of no importance in transmission, chancroid
dence for the epidemiological synergy between chancroid and may continue to exist only among those individuals who
HIV-1 infection comes, first, from the observations that belong to sexual networks characterized by high turnover
HIV-1 infection rates are the highest in the world in those Afri- of sexual partners in resource-poor communities with limited
can countries where chancroid was previously common and, sec- access to healthcare services. As an example, surveillance
ond, from reports that those Asian countries with early studies undertaken in other Southern African Development
For personal use only.
generalized HIV-1 epidemics had co-existent endemic levels of Community countries since 2004 suggest that chancroid still
chancroid [5]. remains an important cause of GUD in some parts of Lesotho
[LEWIS D, UNPUBLISHED DATA], Madagascar [LEWIS D, UNPUBLISHED DATA] and
Decline in chancroid Malawi [32].
Over the past 1020 years, there has been a substantial decline There are some key challenges in interpreting data on the
in the prevalence of chancroid in several countries in Southeast prevalence of chancroid. First, genital herpes cases are easily
Asia and Africa [5]. At the same time, several authors have misdiagnosed as chancroid on clinical examination and so
reported a rise in the relative prevalence of genital herpes sim- reports based on clinical diagnosis alone can be erroneous [3335].
plex virus type 2 (HSV-2), and to a lesser extent, HSV Second, laboratory culture is technically difficult as well as
type 1 (HSV-1) infections, which now account for the vast insensitive, while NAATs are rarely available outside of national
majority of GUD cases in these countries [1921]. reference laboratory of specialized STI research settings; this
In Thailand, a 95% reduction was reported in the incidence makes it difficult to confirm clinical diagnoses. Determination
of chancroid between 1987 and 1994 [22,23]. Within Africa, of the true global burden of chancroid is made even more diffi-
chancroid virtually disappeared in Kenyas capital city by the cult given that those countries that use the syndromic approach
end of the 1990s and has been followed by a marked reduction for STI management report, at best, only total numbers of
in the HIV-1 prevalence among Nairobis sex workers [24,25]. In GUD presentations and genital ulcer etiological surveys are
Uganda, H. ducreyi was detected in only 1% of genital ulcer rarely, if ever, carried out. These include those resource-poor
swabs obtained from the Rakai Community cohort between countries where chancroid is most likely to occur.
2002 and 2006 [26]. Within Southern Africa, several molecular-
based GUD etiological studies have demonstrated similar Clinical features
reductions. In South Africa, several surveys undertaken since After initiation of infection at sites of microabrasions, H.
2007 have repeatedly demonstrated that chancroid now ducreyi infection may first manifest as tender erythematous pap-
accounts for <1% of genital ulcers [LEWIS D, UNPUBLISHED DATA]. ules within 47 days. These papules may subsequently progress
Likewise, no H. ducreyi infections were detected among almost to a pustular stage and then an ulcerative stage (FIGURE 1) [4].
200 GUD cases recruited in two cities in Namibia in Human studies of experimental H. ducreyi infection have dem-
2007 [27]. As chancroid prevalence has plummeted in resource- onstrated that a delivery dose of approximately 30 colony form-
poor countries, diagnoses have also fallen in Europe, as exem- ing units (CFU) of the pathogen results in a papule formation
plified by the results of a prospective study of 278 GUD cases rate of 95% and a pustule formation rate of 69% [36]. Charac-
enrolled between 1995 and 2005 at a STI clinic in France [28]. teristically, the ulcers of chancroid are multiple, painful, puru-
In this study, only eight bacteriologically confirmed cases of lent and deep with ragged undermined edges and evidence of
chancroid were detected up until 2001, in contrast to no cases bleeding points in the base [4].
of H. ducreyi [40]. In purulent ulcers, it is recommended that the The pathogen has fastidious growth requirements and optimal
superficial inflammatory exudate is first removed using a swab or recovery is obtained through the use of freshly made media
by flushing the ulcer with sterile physiological saline. As the path- and attention to the incubation conditions.
ogen only survives on swabs for 24 h, it is recommended that Ideally, a minimum of two different media should be
inoculation of selective enriched H. ducreyi culture media is per- employed to improve the sensitivity of culture as a diagnostic
formed at the time of specimen collection [41,42]. Alternatively, method [45,46]. Several media have been described and recom-
but less ideal, swabs with ulcer-derived material may be placed in mended media options have been reviewed in detail else-
Amies transport medium and sent immediately to the local labo- where [3]. The most widely used media require either
ratory for culture [40]. An in-house thioglycolate hemin-based Gonococcal agar or Mueller-Hinton agar as the base to which
TM
transport media has been described, which retained viability of is added, first, a nutritional supplement (e.g., IsoVitaleX
H. ducreyi for up to 4 days, but this transport medium is not enrichment) and, second, either 1% hemoglobin with 5% fetal
commercially available [43]. If diagnosis is to be undertaken using calf serum or 5% chocolatized blood [3]. Overgrowth of com-
molecular assays, the ulcer swab should be placed in an empty mensal Gram-positive bacteria on the ulcer swab is prevented
sterile tube and sent as a dry swab to the laboratory [40]. Bubo through use of vancomycin (3 mg/ml); however, some clinical
pus is an alternative diagnostic sample and may be the only H. ducreyi strains are inhibited by vancomycin at this concen-
option in the absence of associated GUD. However, culture of tration and additional non-selective plates may require inocula-
bubo pus is quite often negative and published experience with tion to ensure recovery of the pathogen [47]. In an attempt to
molecular diagnostic assays is extremely limited. reduce the cost of culture media for H. ducreyi, an activated
charcoal-containing medium has been used in some resource-
Bacteriological diagnostic techniques poor settings with success [48].
H. ducreyi is a Gram-negative bacillus and organisms tend to Once inoculated, agar plates should be incubated at 3335C
clump together, a phenomenon that gives rise to the character- in a humidified incubator, ideally in a microaerophilic or strict
istic schools of fish, fingerprints or railroad track morpholo- anaerobic environment [1]. It is important to note that the opti-
gies described in the literature [2]. However, as these mal temperature for H. ducreyi is 33C and that viability is
morphological features lack both sensitivity and specificity, compromised if the incubator temperature exceeds 35C [40].
microscopy should not be used as a means to diagnose Identification of presumptive H. ducreyi colonies typically
chancroid [1,42]. relies upon colony morphology, the fact that colonies can be
For many years, culture was the gold standard method for pushed across the plate intact due to bacterial adherence
diagnosing H. ducreyi infection. Molecular methods (see below) (clumping), as well as Gram staining of single colonies [40].
have now replaced culture as the diagnostic method of choice Presumptive identification can be assisted with demonstration of
and it has been reported that culture is at best only 75% a positive oxidase reaction and a negative catalase reaction [49].
informahealthcare.com 689
Review Lewis
Figure 2. Right-sided inguinal bubo and penile ulcer in a Other non-culture-based methods of detection
man with chancroid.
Given the technical challenges of H. ducreyi culture and the
Reproduced with permission from [4].
general unavailability of molecular diagnostic assays, there is a
need to develop other non-culture modalities to assist with the
Full biochemical identification is hampered by the fact that diagnosis of chancroid cases. Matrix assisted laser desorption/
H. ducreyi cannot grow on the media used in commercially ionisation/TOF-mass spectrometry can enable rapid identifica-
available biochemical test strips and demonstration of tion of bacteria (within 10 min) and this technique has been
X-factor dependence relies on a negative porphyrin test [40]. evaluated as a diagnostic and typing tool using H. ducreyi colo-
Additional biochemical tests that may be helpful include nies [64]. A large number of monoclonal antibodies (mAb)
For personal use only.
demonstration of alkaline phosphatase production and nitrate against H. ducreyi have been generated in research laboratories
reduction [1]. and some of these have been harnessed for potential diagnostic
use [65,66]. An anti-lipo-oligosaccharide mAb was used with suc-
Molecular-based detection cess in an immunolimulus system, which enabled detection of
Several molecular diagnostic approaches have been evaluated as few as 103 CFU of cultured H. ducreyi per ml of buffer as
and employed in research and reference laboratories. well as detection of this pathogen in experimental rabbit
32
P-labeled DNA probes reliably detect 104 CFU of H. ducreyi lesional material [65]. Patterson et al. developed a rapid
in both pure and mixed cultures, but this technology lacks the immunochromatographic-based diagnostic test for chancroid
sensitivity associated with NAATs [50]. Several PCR assays have using mAb directed against the H. ducreyi hemoglobin recep-
been described that amplify DNA sequences from a number of tor [66]. However, although the test only took 15 min to per-
targets on the H. ducreyi genome, including the 16S rRNA form, it required at least 2 106 CFU of H. ducreyi to
gene, the rrs (16S rRNA)/rrl (23S rRNA) intergenic spacer generate a positive reaction and would therefore be an insensi-
region, an anonymous fragment of cloned H. ducreyi DNA, tive tool to detect this pathogen in genital ulcer swabs.
the gene encoding a 27 kDa H. ducreyi-specific protein and the
groEL gene and the recD gene [44,5158]. Although PCR assays Serological detection
for H. ducreyi may perform well using bacterial colonies as the The humoral immune response to H. ducreyi infection only
source of DNA template, the sensitivity of these assays can be starts to develop as the disease progresses through the ulcerative
reduced by the presence of Taq polymerase inhibitors in the stage [42,67]. This is supported by the observed lack of IgG anti-
GUD swab specimen, particularly if a sodium phosphate- body responses to either H. ducreyi lipo-oligosaccharide or
containing transport medium is used [59]. In such situations, ultrasonicated whole cell antigen in subjects experimentally
the assay sensitivity may be improved through the use of deter- infected with the pathogen up to the pustular stage [67]. Due to
gents in preparing nucleic acid from clinical specimens and the their low sensitivity compared with PCR, serological techniques
inclusion of a dialysis step prior to amplification [59]. have no place in the diagnosis of chancroid among GUD
Given the rarity of H. ducreyi as an etiological cause of patients [57]. However, they may be useful as a tool to perform
GUD, the most useful PCR assays are those which are available sero-epidemiological studies within communities [17,68,69].
in a multiplex format. The first multiplex PCR (M-PCR) to
detect multiple GUD pathogens (HSV-1/2, Treponema pal- Antimicrobial susceptibility testing
lidum and H. ducreyi) was developed by Roche in the 1990s, As one would expect from the fastidious nature of H. ducreyi
although it was never made available on a commercial basis [44]. and its tendency to clump, antimicrobial susceptibility testing
This assay has been used to study the etiology of GUD in a presents a technical challenge and there is no standardized pro-
number of geographic locations, including the USA, India, cedure for this activity. Minimum inhibitory concentrations of
antimicrobial agents may be determined by conventional agar Ernst et al. reported that patients with buboes who received
dilution or through use of Etest methodology, although this incision and drainage required no further intervention, whereas
is rarely performed in practice [70,71]. approximately half of those who received aspiration required
Although historically susceptible to a wide range of antimi- further attempts at aspiration [84]. There has been some debate
crobial agents, H. ducreyi has acquired a variety of resistance as to which of these two options should be recommended in
mechanisms over time. Plasmid-mediated resistance has been resource-poor settings and, currently, WHO only recommends
described for tetracycline, chloramphenicol, sulfonamides, peni- aspiration for the management of suppurated buboes [79,86]. In
cillin and aminoglycosides [2,7276]. Different antimicrobial comparison with bubo aspiration, incision and drainage may
resistance-encoding plasmids may exist in the same bacterial take longer to heal, which may lead to secondary infection, par-
cell and some plasmids contain genes that encode resistance to ticularly in immunosuppressed HIV-1-infected patients.
more than one antimicrobial agent. In addition, chromosomally
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by CDL-UC San Diego on 12/31/14
resistance data for this pathogen for approximately two decades. lance for GUDs in many countries means that we have little or
Despite this, chancroid may still be treated effectively with no recent prevalence data for chancroid. Now is surely the time
macrolides (azithromycin, erythromycin) cephalosporins (ceftri- to call for public health investment in setting up a task team to
axone) and fluoroquinolones (ciprofloxacin) (TABLE 1) [79]. document where we have got to in terms of chancroid elimina-
Although the combination of amoxicillin with clavulanic acid tion through targeted surveillance activities. Such an exercise
may be effective in some countries, it is no longer recom- would highlight those countries where efforts should be focused
mended in the USA due to concerns over chromosomally over the next decade in order to achieve the reality of chan-
mediated b-lactam resistance [78]. As advocated by WHO, geni- croid eradication on a global scale.
tal ulceration is normally treated syndromically in most
resource-poor countries where chancroid is still, or has recently Expert commentary & five-year view
been, endemic. Typically, GUD treatment flow charts contain The substantial decline in chancroid ulcers and buboes within
additional treatment to cover syphilis and, in many countries, many countries of Africa and Southeast Asia over the past two
also genital herpes and lymphogranuloma venereum [80]. decades has been remarkable. This decline, which followed the
Treatment failures to single dose oral fleroxacin, intramuscu- implementation of the syndromic approach for STI manage-
lar ceftriaxone and oral azithromycin therapies for proven chan- ment and control, has been cited by proponents of this
croid cases have been reported among HIV-1 co-infected approach as strong supporting evidence for the impact of STI
patients [8183]. These treatment failures appear to be due to syndromic management in resource-poor settings. Syndromic
causes other than antimicrobial resistance and it is believed that management for STIs, a tool established to improve the man-
single-dose therapies are not always sufficient to cure chancroid agement of symptomatic STIs and which can be delivered by
in the context of HIV-1-associated immunosuppression [81]. nurses in a variety of urban and rural settings, has certainly
Accordingly, HIV-1 seropositive patients may require repeated improved the quality of sexual health service provision in many
or longer courses of treatment than those normally prescribed countries. The approach works best for those STIs that are
for HIV-1 seronegative patients. All patients, particularly those mostly or exclusively symptomatic as well as those that are
infected with HIV, should be carefully followed-up by the severe enough to motivate a patient to seek early STI care. It is
attending clinician to ensure that clinical cure is achieved with therefore entirely predictable that syndromic management
currently recommended antimicrobial therapies [79]. would exert its strongest effect on an STI such as chancroid,
Both chancroid and lymphogranuloma venereum may result which is characterized by multiple, deep and painful genital
in inguinal bubo formation and this complication requires at ulcerations and for which asymptomatic carriage is not thought
least 2 weeks antimicrobial therapy. Large suppurated buboes to play a major role in transmission.
may require aspiration or incision and drainage in order to However, it is important to note that there are several other
avoid spontaneous rupture [84,85]. In a US-based study, additional factors that may also have made significant
informahealthcare.com 691
Review Lewis
Table 1. Summary of recommended regimens for the treatment of chancroid in various international
guidelines.
Guideline (year) WHO (2003) [86] CDC (2010) [87] European (2011) [88] BASHH (2013, draft) [89]
as a single dose OR
Erythromycin base,
500 mg orally,
6 or 8 h for 7 days
Specific Follow patients up Monitor patients closely as more No specific The erythromycin regimen is
recommendations weekly until likely to experience treatment recommendations recommended for HIV-infected
for treating clear evidence of failure with any of stated patients rather than any of
HIV-infected improvement the above regimens the single-dose therapies
individuals Azithromycin and ceftriaxone
regimens to be used only when
follow-up can be assured
BASHH: British Association for Sexual Health and HIV.
contributions to the reported decline in chancroid during the presumptive therapy and ongoing sexual health education.
same time period. The rise of the HIV-1 epidemic in chan- Finally, the magnitude of the effect of the roll-out of medical
croid endemic areas of the world, from the late 1980s onward, male circumcision programs within sub-Saharan Africa is
was accompanied by changes in sexual behavior within commu- unknown, but this mass HIV-1 prevention strategy has also
nities and key populations as a result of the perceived fears for likely played, and will continue to play a role in the demise
personal health and implementation of a number of general of chancroid.
and targeted HIV-1 prevention programs. Public health While it is clear that chancroid has declined as a cause of
responses to the HIV-1 epidemic included efforts to change sexually acquired GUD in many countries, the recent reports
sexual behavior in terms of promoting abstinence, faithfulness of chronic lower limb ulceration in individuals from the South
and/or condom use within the general population. Very rele- Pacific islands is of particular interest [37,38]. These ulcers, which
vant to chancroid, an STI strongly associated with exposure to may be clinically misdiagnosed as yaws without appropriate
or practice of commercial sex work, sexual health and investigation using sensitive and specific diagnostic assays, are a
HIV-1 prevention programs targeted at CSWs are thought to relatively newly described presentation for H. ducreyi, and are
have been very important in curtailing the transmission of H. most likely transmitted non-sexually between individuals. Fur-
ducreyi [23]. Such programs are characterized by use of peer ther ulcerative lesions may occur on the limb though the pro-
educators, provision of CSW-focused sexual health services in cess of auto-inoculation. Further clinical and epidemiological
the workplace or through mobile outreach services, marketing research is required to improve our understanding of this der-
and distribution of male and female condoms, appropriate matological manifestation of H. ducreyi infection using appro-
management of STI syndromes, provision of periodic priate diagnostic tools. It is unclear, at the present time, as to
mended cephalosporins, macrolides and fluoroquinolones should alence chancroid exists in those countries which lack data. It is
still be effective. It is, however, important for clinicians to be possible that chancroid could be the first bacterial STI to be
aware that HIV-1 immunosuppressed patients may not respond eradicated. This would be a huge achievement, given that it
to single dose oral or intramuscular treatments and that all would have been achieved by improving the quality of sexual
HIV-1-infected patients treated for suspected chancroid should healthcare, sexual behavior change and use of appropriate anti-
be followed-up at 1 week to assess the degree of ulcer healing. microbial agents in the absence of an effective vaccine.
Chancroid has become so rare in some countries that there
is now discussion regarding removing antimicrobial therapy for Financial & competing interests disclosure
H. ducreyi from first-line GUD treatment algorithms and The author has a PEPFAR grant from the US Centers for Disease Control
reserving it instead for second-line therapy. For example, in and Prevention (CDC) to support STI surveillance activities in South
South Africa, now that chancroid accounts for less than 1% of Africa, although this is not relevant to the current review. The author has no
GUD cases, it has been recently debated as to whether first-line other relevant affiliations or financial involvement with any organization or
GUD therapy should be dispensed for only genital herpes and entity with a financial interest in or financial conflict with the subject matter
For personal use only.
syphilis, with single-dose azithromycin being reserved for or materials discussed in the manuscript apart from those disclosed.
second-line treatment of non-healing ulcers [LEWIS D, UNPUBLISHED No writing assistance was utilized in the production of this manuscript.
Key issues
A number of studies and surveillance reports have reported marked declines in the prevalence of chancroid in many countries where it
was previously endemic.
There have been some recent reports of Haemophilus ducreyi causing chronic skin ulceration in patients visiting or from the South
Pacific islands.
The current prevalence of chancroid is unknown for most countries as they lack the required laboratory diagnostic capacity and
surveillance systems to report on this.
The optimal diagnostic method involves H. ducreyi-specific nucleic acid amplification, but few molecular assays are commercially available.
H. ducreyi culture is technically challenging and requires freshly made specialized vancomycin-containing media and strict incubation conditions.
It is still assumed that chancroid will usually respond successfully to treatment with recommended cephalosporin, macrolide or
fluoroquinolone-based regimens, despite the absence of recent antimicrobial susceptibility data for H. ducreyi.
HIV-1-infected patients require careful follow-up due to reports of treatment failure with single-dose regimens.
Fluctuant buboes may require aspiration or excision and drainage.
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