Clinics in Dermatology (2014) 32, 275–281

Gonorrhea: New challenges

Mihael Skerlev, MD, PhD a,⁎, Ivana Čulav-Košćak, MD b
a
Department of Dermatology and Venereology, Zagreb University School of Medicine and Zagreb University Hospital,
Šalata 4, 10000 Zagreb, Croatia
b
Division of Dermatovenereology, General Hospital “Dr Ivo Pedišić,” J.J. Strossmayera 59, 44000 Sisak, Croatia

Abstract As “a paradigm of the classical Venereology” for many decades, gonorrhea appears to be the
second most common sexually transmitted infection of bacterial origin today. In spite of its mostly
uncomplicated clinical course, gonorrhea may sometimes result with serious complications such as
pelvic inflammatory disease, ectopic pregnancy, infertility, epididymitis, gonococcemia, and
disseminated gonococcal infection. Perhaps the most important challenge today is the emergence of
multidrug-resistant gonorrhea, which is currently the main reason for public concern. Eventually,
Neisseria gonorrhoeae turned out to be one of the most “evolutionarily successful” pathogens. Effective
treatment of gonorrhea providing that N gonorrhoeae might also facilitate the transmission of HIV is a
complex task and almost an imperative in the “sexually transmitted infection world” today.
© 2014 Elsevier Inc. All rights reserved.

Introduction and conjunctival mucosa, making this infection a bit

Gonorrhea is defined as a sexually transmitted
infection (STI), caused by Gram-negative bacteria
Neisseria gonorrhoeae. According to the results of recent
epidemiologic studies, it is the second most common STI of
bacterial origin.1-3 In spite of the fact that N gonorrhoeae has
affinity for the lower urogenital tract mucosa leading to
uncomplicated gonococcal infection, there is a relatively small
but definite risk of evolving into an ascending infection of the
upper genital tract with complications such as pelvic
inflammatory disease (PID), ectopic pregnancy, and infertility
in women and epididymitis in men. Another peculiar (but,
fortunately, comparatively rare) phenomenon concerning
N gonorrhoeae is its potential to invade the bloodstream,
resulting in gonococcemia and disseminated gonococcal
affliction of the joints (especially knees), cardiovascular
system, and skin. Other (than lower genital tract mucosa)
possible ports of entry of N gonorrhoeae are oral, anal,
⁎ Corresponding author. Tel.: +385-1-2368981; fax: +385-1-2379925.
E-mail address: mskerlev@kbc-zagreb.hr (M. Skerlev).
more complex than usually expected.
Perhaps the most important challenge today is the
emergence of multidrug-resistant gonorrhea, which is
currently the main reason for public concern. Effective
treatment of gonorrhea, providing that N gonorrhoeae might
also facilitate the transmission of the HIV, is the complex
task and almost an imperative in the “STIs World” today.
Etiology and pathogenesis
Gram-negative bacterium, human obligatory pathogen
N gonorrheae, is the causative agent of gonorrhea.
Gonococcal infection usually results from the transmission
of N gonorrhoeae through sexual contact. The pathogenetic
hallmark of gonococcal infection is a host innate immune-
driven inflammatory response, characterized by a potent
neutrophil influx. The subsequent tissue damage enables
bacterial access to secondary anatomic sites, which promotes
much of the morbidity and mortality associated with
neisserial infections.2 Discharge displays an inflammatory

0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clindermatol.2013.08.010
276
response elicited by gonococcal antigens resulting from
recruitment of neutrophils, which have potent intracellular
and extracellular antimicrobial activities.1-3 Despite this
massive inflammatory response, neutrophils do not clear the
infection, which suggests that the recruitment of neutrophils
by this pathogen may not be especially deleterious to the
bacteria and may, in fact, enhance the disease-causing
potential of these pathogens.2,3 The pathogenic Neisseriae
avoid phagocytosis by neutrophils in three ways: (1) by
preventing their binding to the neutrophil surface, (2) by
limiting the deposition of opsonic antibody or complement
on the bacterial surface, and (3) by varying antigenic surface
structures to evade humoral immunity.2,4-7 When inside
neutrophils, the bacteria reside within phagosomes, which
protect the pathogens from humoral immune surveillance.8
Neutrophils are not supposed to function as antigen-
presenting cells, so persistence inside neutrophils may also
protect the bacteria from potentially toxic sources of cell-
mediated immunity, such as cytotoxic T lymphocytes. Of
course, phagocytosis of a dead, infected neutrophil by a
macrophage would represent a dead end for the bacteria
inside and would amplify the humoral immune response;
however, infection by pathogenic Neisseriae can prolong the
neutrophil life span, and these bacteria provide a general
immune suppression to dampen adaptive immune responses.
These two features would contribute to the persistence of the
pathogens when in association with neutrophils.2,9,10
The fact that N gonorrhoeae avoids the host’s protective
immune response by varying the expression of its major
outer membrane proteins plays an important role in
pathogenesis because it prolongs infection, prevents immu-
nity to reinfection, and changes the functional properties of
the organism. A small fraction of the pathogenic Neisseriae
transits across epithelial and endothelial monolayers, but in
general, these bacteria are not particularly motile.
The presence of neutrophils would facilitate bacterial
access to secondary sites of infection in two ways. First, the
influx of neutrophils and the associated inflammatory milieu
produces local tissue damage, creating breaches in epithelial
integrity through which the bacteria could pass. Second, as
recently suggested, neutrophils themselves may carry viable
bacteria to new sites.2,11 Neutrophil-driven movement of
Neisseriae has not yet been visualized, but it would promote
disseminated gonococcal infection and associated arthritis,
endocarditis, and dermatitis.2 N gonorrhoeae survives
poorly, if at all, outside the human body.
It is tempting to speculate that neutrophils serve as a
conduit for transfer of meningococci and gonoccoci to
receptive hosts. Although there is no direct evidence for
transfer of neutrophils between individuals, there is a
possibility that mechanisms in addition to the transfer of
free bacteria are important for the high frequencies of
transmission between hosts, for instance, in the transfer of N
gonorrhoeae from women to men. Taking this into account,
the acute inflammation associated with gonorrhea could be a
response to foreign neutrophils as well as to the bacteria.2,12
M. Skerlev, I. Čulav-Košćak
Still, some questions regarding the exact mechanisms remain
unanswered and, therefore, pose a future challenge for the
academic community.
Epidemiologic aspects
Gonorrhea notifications have been on the rise in several
European countries since the early 2000s, particularly in
populations with higher frequency of spread of STIs, such as
men who have sex with men and young heterosexual
individuals of both sexes (younger than 25 years).13-19 The
increase of gonorrhea could most likely be attributed to
multiple factors like increased screening, use of more
sensitive diagnostic methods, particularly nucleic acid
amplification tests, improved reporting, and also high levels
of unsafe sexual behavior among certain subpopulations.
Across Europe, 32,000 cases of gonorrhea were reported in
2010.13 The increases of gonorrhea are of particular concern
because they coincide with decreasing susceptibility of N
gonorrhoeae to currently used antimicrobial drugs across
Europe.20-22
In the United States, gonorrhea is the second most
commonly notifiable disease reported to the Centers for
Disease Control and Prevention (CDC),23,24 next to the
chlamydial infection. Rates of gonococcal infection steadily
declined from 1975 to 1997 in the United States after
implementation of a national gonorrhea control program but
have remained stable since that time. CDC estimates the
actual incidence of gonorrhea at 600,000 to 800,000 cases
per year, with less than half being reported. An estimated
700,000 new gonococcal infections occur annually in the
United States, with less than half being reported.24-26
According to the US CDC data, 301.174 cases of gonorrhea
were reported in 2009.24,26-28 The national average in 2009
was 99.1 cases per 100,000 inhabitants, which represents a
10.5% decrease from 2008.24,29
The highest incidence of gonococcal infection in the
United States is among persons aged 15 to 24 years.24,29 This
is likely due to the increased numbers of sexual partners,
decreased access to health care providers, physiologic ectopy
of the squamocolumnar junction in women, and decreased
use of barrier contraceptives.
Although the frequency data are unknown in most
developing nations, these countries are considered to have
the highest rates of gonorrhea estimated as 400 to 10,000
cases/100,000 population, including the complications.30-32
Infection in children is considered a marker for child
sexual abuse and should be reported as such, although a 2007
review provided some support for nonsexual transmission
between children and for transmission from adults to
children related to poor hand hygiene.33,34
High prevalence of gonorrhea is found among some
subgroups of women with HIV infection, particularly among
those who take illicit drugs or who practice sex for drugs.
Gonorrhea
Increases in gonorrhea prevalence, particularly rectal
gonorrhea, have been noted recently among male homosex-
uals, partially because of the large number of cases of
asymptomatic rectal and oropharynx gonorrhea in men.35
In men, the risk for infection after a single exposure to an
infected person is around 20%, increasing to 60% to 80%
after four or more exposures. Transmission is more efficient
from men to women than from women to men, particularly
when men with symptomatic urethritis continue to have
unprotected sex. Disseminated gonococcal infection occurs
in 1% to 2% of all mucosal infections.
More than 60% of gonococcal infections occur in people
younger than 25 years. As far as women are concerned,
teenagers (15-19 years of age) have rates of infection similar
to those in adults 20 to 24 years of age. Men 20 to 24 years of
age have the highest infection rate. From 2004 to 2008,
increase in the gonorrhea rates was observed in the 15 to 24
years old age group.
Teenage girls remarkably underestimate their risk for
acquiring gonorrhea infection even after being treated for a
prior STI. Professional sex workers still form a reservoir of
infection, especially in the economically low-income
countries. In the United States, black patients have a rate
of infection 10 to 20 times greater than their white and
Hispanic counterparts.35
Clinical aspects
N gonorrhoeae is known to have affinity for columnar
epithelium; hence the most frequent clinical presentation is
urethritis in men and cervicitis in women. Other possibilities
involve rectal and oropharyngeal mucosa, which can
sometimes be the only presenting site of infection, justifying
a search for N gonorrhoeae in extragenital sites in everyone
suspected of being infected. Aside from those practicing anal
(receptive) intercourses, rectal involvement can result from
contamination/autoinoculation, as can urethritis in women
(although rarely). Another point of entry is conjunctiva,
resulting in conjunctivitis, which is due to autoinoculation of
the bacteria from genitalia by hands in adults. Neonatal
gonococcal conjunctivitis (ophthalmia gonorrhoica neona-
torum; gonoblennorrhea neonatorum) is a consequence of
perinatal/intrapartal/vertical transmission from untreated or
unrecognized gonorrhea from mother to child.
Acute gonococcal urethritis in men is most likely to be
symptomatic in the majority of cases, typically presenting
with abundant purulent urethral discharge (green to yellow),
dysuria, and macerated skin and mucosa of the external
orifice. Accordingly, some alternative names for gonorrhea
in the past have been clap or drip, because of abundant
discharge often seen in acute infection. Quite seldom, the
discharge can be scant and, therefore, difficult to separate
from the nongonococcal (eg, chlamydial; however, both
pathogens might sometimes be verified simultaneously). The
277
symptoms typically present after short incubation period of 3
to 7 days, but the incubation period might be sometimes
longer according to the most recent reports.1,36,37
Unlike men, approximately only 50% of women with
acute gonorrhea are symptomatic, and the most prominent
symptom is vaginal discharge.
Rectal gonorrhea presents with symptoms such as
pruritus, pain, tenesmi, constipation, and discharge in only
a third of infected men, whereas it is asymptomatic in
majority of women and may represent an unrecognized
source of infection. Oropharyngeal gonorrhea is vastly
asymptomatic in both men and women. Conjunctival
gonorrhea presents with edema of the eyelid and purulent
exudate. All asymptomatic or oligosymptomatic infections
represent a long-standing reservoir for transmission, and this
is why health care providers should bear this possibility in
mind very seriously when approaching a patient with an STI.
Untreated or inadequately treated gonococcal infection
has the potential to evolve into an ascending infection of the
upper genital tract: epididymitis in men and endometritis,
adnexitis, and PID in women, with the risk for development
of sequelae including infertility or ectopic pregnancy, or
both. As opposed to developing countries where PID is more
commonly caused by N gonorrhoeae, in Europe, Chlamydia
trachomatis is still the main cause; nevertheless, complica-
tions of PID are the same regardless of the initial pathogen
and include ovarian abscesses, pelvic peritonitis, and
perihepatitis.37 Regarding oropharyngeal gonorrhea, several
studies have demonstrated the lower cure rate when
compared with anogenital gonococcal infections, presum-
ably because of the inconsistent tissue levels of cephalospo-
rins in pharyngeal mucosa. 38-41 Further investigations
concerning oropharyngeal involvement are still in progress.
The most feared complications of gonococcal eye infection
are corneal scarring and blindness.
Diagnostic aspects
The simplest and the quickest way to verify the diagnosis of
gonorrhea in a routine setting is a direct microscopy of urethral
or cervical smear stained with Gram or methylene blue (the
latter has similar sensitivity but lower specificity than Gram
stain). In a case of acute gonococcal infection, intracellular
Gram-negative diplococci within the neutrophils can be seen
by either of these methods, which remain important diagnostic
tools especially when confronted by a critical and experienced
eye. Unfortunately, it is the most sensitive in men with typical
signs, whereas it is much less sensitive in asymptomatic men
and in women. Rectal and oropharyngeal smears are not very
sensitive because these sites are abundant with other Gram-
negative cocci; therefore, these methods are not routinely
recommended for these specific cases.
Isolation of N gonorrhoeae by culture continues to be an
important diagnostic method despite the other highly
278
sensitive and specific tools currently available. The biggest
value of culture is in providing viable organisms to detect
antibiotic resistance. Appropriate media for this purpose are
Thayer-Martin or modified New York City medium or
equivalents, with addition of antimicrobial and antifungal
agents to prevent overgrowth of normal flora. Blood agar
preheated to 60 °C to 70 °C (so-called chocolate agar
because of its brownish color) might be sometimes used for
the N gonorrhoeae cultivation as well.
In recent years, nucleic acid amplification tests have
revolutionized detection of N gonorrhoeae. They are now
widely used in a variety of settings because of convenience
of allowing noninvasive and/or self-taken specimens. Main
reasons for their breakthrough is high sensitivity and
specificity, as well as commercially available kits for
detecting both N gonorrhoeae and C trachomatis using
different methods of nucleic acid amplification including
polymerase chain reaction, strand displacement amplifica-
tion, transcription-mediated amplification, and real-time
polymerase chain reaction; however, detection of gonorrhea
in women’s urine specimen is not recommended,38,42-44
and there is ongoing investigation for their use in
extragenital specimens.
Treatment challenges
One of the most puzzling facts regarding N gonorrhoeae is
its ability to acquire and develop resistance to antimicrobial
agents. So far, various treatment options have been abandoned
one after another because of this fascinating, yet frustrating,
adaptive mechanism.45-48 The most recent cause of concern is
the emergence of resistance to the third-generation cephalo-
sporins, which have been currently recommended for treatment
of gonorrhea in most countries. Among them, first-line
monotherapy is still parenteral ceftriaxone 250 mg single
dose or cefixime 400 mg orally as a single dose45; however,
higher doses of ceftriaxone are now being used, up to one-time
1 g dose or even a one-time 2 g dose. Increased doses of
cefixime are not approved because of its gastrointestinal
adverse effects.45,49 Alternative approach is dual therapy with
adding azithromycin 1 g orally once to the ceftriaxone 250 mg
intramuscularly, which has been proposed in the UK for
uncomplicated gonorrhea.50 The same scheme has been
recommended in the United States, offering alternatively
doxycycline 100 mg bid for 7 days instead of azithromy-
cine.51,52 This approach relies on in vitro–proven synergistic
effects and is also considered appropriate for frequent
coinfection with C trachomatis (see earlier Clinical Aspects
section).45 Such a regimen might also inhibit future develop-
ment of antimicrobial resistance.45 Still, decreased suscepti-
bility to ceftriaxone as well as common resistance to
doxycycline and emerging resistance to azithromycin have
been more frequently observed, especially in South Africa,
Japan, and the Caribbean.53-56 For this reason, susceptibility
M. Skerlev, I. Čulav-Košćak
testing offers more accurate insight into the growing problems
and raises our chances to provide better quality health care.1
Results of such testing are categorized as susceptible,
intermediate or decreased susceptibility, or resistant, and
there are several means of testing susceptibility.1 Surveil-
lance programs have been established to get more objective-
ness in global trends.57 National and international guidelines
are assembled according to these records. In addition, the
World Health Organization has published the “Global Action
Plan to Control the Spread and Impact of Antimicrobial
Resistance in Neisseria gonorrhoeae” addressing the need to
slow and/or counteract ceftriaxone resistance and untreatable
gonorrhea.58
Effective vaccine, however, still has not been developed
because of several obstacles. Several recent advances may
enable future gonococcal vaccine research: development of
transgenic mouse models expressing human genes required
for gonococcal infection; better definition of the course of
natural infection through the use of experimental infection in
male volunteers59; enhanced knowledge regarding develop-
ment of polyvalent vaccines (which might be required for
gonorrhea) gained from the reverse vaccinology technology
used for meningococcal vaccine 60 modern molecular
biology, including genome sequencing for the identification
of novel single or multiple vaccine candidate antigens;
recombinant protein vaccines; discoveries in genital mucosal
immunology; and intranasal immunization for increased
local mucosal immune responses.61-63
Important keys in future perspectives
The European CDC and the US CDC have published region-
specific response plans for the European Union/European
Economic Area countries and the United States.22-24 Some of
the important keys in these future perspectives are:
• It is crucial to culture more isolates, examine
antimicrobial resistance (AMR), and identify specific
extended-spectrum cephalosporins (ESC) resistance
determinants, to facilitate AMR surveillance and
develop sensitive and specific genetic ESC resistance
testing assays.
• It is also crucial to optimize and, as much as feasible,
harmonize the methods, interpretative criteria (break-
points), and internal and external quality assurance used
globally. This is essential to be able to compare validated
and quality-assured AMR data internationally.
• Accordingly, crucial actions also include encouraging
increased awareness of gonococcal AMR; correct use
of antimicrobials; effective early prevention (eg,
information, counseling, and safe sex), diagnosis and
management of gonorrhea; effective drug regulation
and prescription policies (using only ideal antimicro-
bials of appropriate quality and optimized doses);
Gonorrhea
development of molecular methods for detecting and
monitoring ESC resistance; and, most importantly,
research (basic science, in vitro and in vivo studies) to
identify new effective treatment strategies, novel
antimicrobials, and ideally a vaccine.46,57 An in-
creased focus on preventing, diagnosing, and treating
pharyngeal gonorrhea, with special attention to
pharmacokinetic/pharmacodynamic considerations, is
also crucial. This includes increasing the sampling of
pharyngeal specimens and promoting condom use
when practicing oral sex. Pharyngeal infections are
more difficult to treat than urogenital infections.
Pharyngeal infections are relatively common and
represent an asymptomatic reservoir for infection and
emergence of resistance.38,40,46,48,50,51,64-69 Finally,
widespread implementation of test-of-cure is important
to identify treatment failures and reinfection, particu-
larly, but not only, for pharyngeal infections.
• Accumulating knowledge regarding ESC resistance
determinants combined with recent advances in
genome sequencing, nanotechnology, and other
molecular approaches might enable sensitive and
specific genetic ESC resistance assays (ideally at
point of care), as well as genetic point-of-care
diagnostic tests, which might substantially improve
early detection, particularly in less resourced settings
worldwide. These point-of-care tests should be able
to detect not only ESC resistance/susceptibility, but
also resistance/susceptibility to many of the antimi-
crobials previously recommended for treatment of
gonorrhea, and the results should be available in a
timely manner and used not only for gonococcal
AMR surveillance, but also to direct the treatment of
the individual patient.
• Unfortunately, the aforementioned action/response
plans will only delay and limit, but not halt, the
inevitable spread of ceftriaxone resistance globally. It is
essential to develop novel treatment strategies and
antimicrobials in a timely manner. Using an increased
dose of ceftriaxone will provide a short-term solution,
but introduction of dual antimicrobial therapy (currently
ceftriaxone and azithromycin) covering concurrent
chlamydial infection,40,50,51 is recommended for most
settings and, hopefully, will also inhibit future develop-
ment of gonococcal AMR. Additional research is needed
regarding which antimicrobials (and at what dosage) to
combine, and to document efficacy, negative side
effects, pharmacokinetic/pharmacodynamic parameters,
resistance development (in gonococci and bystander
organisms), in vitro methods for synergy testing, and
microbiologic resistance breakpoints.
• Dual antimicrobial therapy, especially with injectable
antimicrobials, might not be feasible and/or affordable
in less-resourced settings (with a substantial gonorrhea
burden), and thus may not significantly mitigate AMR
emergence and global spread.
279
Currently, there are ongoing clinical trials to evaluate the
efficacy and safety profile of gentamicin 1 × 240 mg
intramuscularly plus azithromycin 1 × 2 g orally and
gemifloxacin 1 × 320 mg orally plus azithromycin 1 × 2 g
orally.70
A potential candidate for future treatment for gonorrhea is
the new fluoroketolide, solithromycin, which has proved its
efficacy against gonococci in vitro; it also may be suitable
for monotherapy and as dual therapy of gonorrhea.45,70 It
also appears to be effective against C trachomatis and My-
coplasma genitalium.45,71,72 Another potential future candi-
date is ertapenem, which has proved its antigonococcal
efficacy in vitro primarily against ceftriaxone-resistant and
multidrug-resistant isolates.45,73
Last, but not least, clinicians can help prevent sequelae
and spread of gonorrhea by eliciting sexual histories from
their patients, screening sexually active risk group(s) for
gonorrhea at least annually at exposed anatomic sites, and
treating appropriately.74
Conclusions: an alternative
An era of untreatable gonorrhea may be approaching,
which might represent a serious public health problem. It is
crucial to implement action plans at global and national
levels, focus research and funding on enhanced surveillance
of gonococcal AMR (phenotypic and genetic) and treatment
failures, and improve the prevention, early diagnosis, and
effective treatment of gonorrhea. Novel effective treatment
strategies, new antimicrobials (or other compounds), and,
ideally, a gonococcal vaccine should be developed; mean-
while, any clinician dealing with STIs should be aware of the
usual and unusual aspects of gonorrhea in both men and
women to not miss the true diagnosis and to give the patient
the best chance of cure.
Pearls and take-home messages
• Gonorrhea appears to be the second most common STI
of bacterial origin today, especially in the low-income
developing countries.
• Gonorrhea might sometimes result with serious
complications such as PID, ectopic pregnancy, infer-
tility, epididymitis, gonococcemia, and disseminated
gonococcal infection.
• The most important challenge today is the emergence
of the multidrug-resistant gonorrhea, which is current-
ly the main reason for public concern.
• Alternative treatment approach is dual therapy with
adding azithromycin 1 × 1 g orally or doxycycline 2 ×
100 mg daily to the ceftriaxone 250 mg intramuscu-
larly. Hopefully, it might also inhibit future develop-
ment of gonococcal antimicrobial resistance.
280
• Clinicians can help prevent sequelae and spread of
gonorrhea by eliciting detailed sexual histories from
their patients, screening sexually active risk group(s) for
gonorrhea at exposed anatomic sites, and treating
appropriately.
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