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Gonorrhea
C. A. Ison and D. A. Lewis
INTRODUCTION
EPIDEMIOLOGY
The clinical syndrome of gonorrhea was described by biblical authors, but the
etiologic agent, Neisseria gonorrhoeae, was not described until 1879, when Albert
Neisser observed the organism in smears of purulent exudates from urethritis,
cervicitis, and ophthalmia neonatorum. N. gonorrhoeae colonizes and infects primarily the mucosa of the lower anogenital tract, the oropharynx and the conjunctivae and occasionally ascends to colonize and infect the normally sterile upper
genital tract or invades the blood to cause disseminated infection. If innappropriately treated, or left untreated, uncomplicated gonorrhea may lead to epididymitis in men and pelvic inflammatory disease (PID) in women. In addition,
epidemiological and biological studies provide strong evidence that gonococcal
infections facilitate HIV transmission, hence effective treatment of gonorrhea
should remain an important part of HIV prevention strategies.
The genus Neisseria includes the pathogenic species N. gonorrhoeae and N.
meningitidis, as well as species that are normal flora of the oropharynx and nasopharynx. The cell envelope of N. gonorrhoeae consists of a cytoplasmic membrane,
a thin peptidoglycan layer and an outer membrane. Colonization of the mucosal
surface by the organism occurs by attachment to the epithelial cell surface, which
is mediated by pili and opacity proteins, followed by internalization and transcytosis, mediated by opacity proteins and porins, to establish an infection in the
subepithelial space. An immune response is elicited resulting in a polymorphonuclear infiltrate containing intracellular gonococci. Sialylation of the lipooligosaccharide results in resistance to the bactericidal action of serum, an
attribute necessary for dissemination into the blood to occur.
N. gonorrhoeae is always considered a pathogen that requires treatment and is
not considered part of the normal flora. However, strains of commensal Neisseria
spp. may occasionally be isolated in clinical specimens from anogenital sites and
observed intracellularly in polymorphonuclear leukocytes, and are morphologically indistinguishable from the pathogenic Neisseriae. Thus, accurate laboratory
identification of the gonococcus is essential because of the social and medicolegal
consequences of misidentifying strains of non-pathogenic Neisseria spp. as N.
gonorrhoeae.
Because of the fastidious growth requirements of N. gonorrhoeae, it was difficult
to culture the organism until the development of chocolatized blood agar supplemented with growth factors. In the 1960s, the development of selective media
containing antimicrobial and antifungal agents (such as ThayerMartin medium),
which enhanced the isolation of the gonococcus by inhibiting not only Grampositive bacteria but also the closely related Neisseria spp., further simplified the
laboratory diagnosis of gonorrhea. Rapid biochemical and serologic tests are
available, allowing identification of the gonococcus within a few hours of its isolation. More recently, nucleic acid amplification technology has shed new light on
the extent of asymptomatic gonococcal infection. All of these innovations have
advanced our knowledge of this common pathogen, its epidemiology and its
clinical manifestations.
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Antimicrobial resistance
Region
Total
62.34
Fig. 2.1 Estimated new cases of gonorrhea. (In millions, 1999, courtesy WHO 2000.)
4500
1200000
Number of epidemiological treatments
4000
1000000
800000
600000
400000
200000
0
1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000 2003 2006
Year
3500
3000
Heterosexual males
Men having sex with men
Females
2500
2000
1500
1000
500
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Fig. 2.2 Reported cases of gonorrhea in the USA, 19702007.
Fig. 2.4 Diagnoses of epidemiological treatment for gonorrhea by gender and sexual
orientation: United Kingdom 19992008.
16000
Heterosexual males
14000
Number of gonorrhea patients
12000
Females
10000
8000
ANTIMICROBIAL RESISTANCE
6000
4000
2000
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Fig. 2.3 Diagnoses of uncomplicated gonorrhea by gender and sexual orientation:
United Kingdom 19992008.
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Gonorrhea
penicillin and tetracycline (PPNG/TRNG) are commonly found. Like the penicillins, tetracyclines are inappropriate sole therapies for gonococcal infections.
Decreased susceptibility and high-level chromosomal resistance to the fluoroquinolones (e.g. ciprofloxacin, ofloxacin), acquired through the acquisition of
point mutations in the DNA gyrase (gyrA) and topoisomerase IV (parC) genes,
are now widespread and have resulted in many regions of the world abandoning
this antibiotic class as first-line therapies for presumptive or confirmed gonorrhea.
It seems probable that strains exhibiting high-levels of resistance also have
changes in membrane permeability that may be associated with an efflux system.
Most countries in the world where fluoroquinolones are no longer effective
have now turned to use of cephalosporins, administered either orally (e.g. cefixime or cefpodoxime) or parenterally (e.g. ceftriaxone). Resistance to oral cephalosporins has recently been described in Japan1 which appears, in the main part,
to be due to the acquisition of mosaic penA genes as the result of genetic exchange
of DNA between N. gonorrhoeae and commensal Neisseria spp.2 The strains
showing decreased susceptibility and resistance to oral cephalosporins remain
susceptible to intramuscular ceftriaxone. However, a drift in the minimum inhibitory concentration (MIC) upwards for both oral cephalosporins and ceftriaxone
Table 2.1 Types of antimicrobial resistance in N. gonorrhoeae.
Type of resistance
Antimicrobial agent
Sulphonamides
Penicillin
Tetracycline
Spectinomycin
Macrolides
Fluoroquinolones
Cephalosporins
Penicillin (PPNG)
Tetracycline (TRNG)
Fig. 2.5 Chemically defined media used for auxotyping: complete medium, without
proline and without arginine. Absence of growth indicates requirement for the
specific amino acid.
tbpB 26
T T T G G A T G C G G T T G A A T T G A C A C CA G AC G G C A A G A A A A T CA A A G A T C T C G A C A A C T T C A G C A A C G C C G C
tbpB 16
T T T G G A T G C G G T C G A G C T G A A A T C G G AC G G T A A G A A A G T G G A A A A T C T C G A C A A C T T C A G C G A C G C T A C
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Antimicrobial
Clinical manifestations
resistance
has been described in longitudinal surveillance programs in both the USA and
the UK, raising concerns about the future viability of cephalosporins in the treatment of gonorrhea. Azithromycin may also be used in the management of gonorrhea, although a single 2g oral dose is required for optimal efficacy. Whilst useful
in the management of individual cases, concerns exist over recommending any
macrolide as first line therapy for gonorrhea, given the ease with which macrolide
resistance may develop in N. gonorrhoeae. Isolates with decreased susceptibility to
azithromycin were identified by the Gonococcal Isolate Surveillance Project
(GISP) in 1999 and isolates with very high MICs were recently reported in the
United Kingdom.3
The continued emergence of resistance to antimicrobial agents used for the
treatment of gonorrhea1,4 is a concern and requires effective surveillance programs
to monitor susceptibility patterns, detect drifts in susceptibility and emergence of
resistance. There are established surveillance programs in the USA, Canada, Australia and The Netherlands which have produced valuable temporal data in these
individual countries. The Gonococcal Antimicrobial Susceptibility Program
(GASP) was established to provide a global surveillance network. GASP is coordinated by the World Health Organization and the aim was to create a series
of networks based on WHO regions. Important elements of GASP are that data
should be comparable between laboratories and this requires the development
of training and quality assurance programs. Currently GASP is most active in the
Americas and the Caribbean, the western Pacific region and the southeast Asian
region although new GASP initiatives are now underway in Africa, the European
Union and Eastern Europe. The GASP team is currently working on definitions
for multi-drug (MDR) and extensively drug-resistant (XDR) N. gonorrhoeae.
CLINICAL MANIFESTATIONS
Symptomatic
Cervix
Asymptomatic
Symptomatic
Rectum
Asymptomatic
Symptomatic
Pharynx
Asymptomatic
Symptomatic
Conjunctiva
Asymptomatic
Symptomatic
Male complications
Female complications
Gonorrhea
The most common symptom of gonorrhea in men is urethral discharge that may
range from a scanty, clear, or cloudy fluid to one that is copious and purulent
(Figs 2.8 and 2.9). Dysuria is usually present and the meatus may be inflamed.
However, men with asymptomatic urethritis may be an important reservoir for
transmission. Although most men with gonorrhea develop symptoms, those who
ignore their symptoms or have asymptomatic infection are at increased risk of
developing complications (see Table 2.2).
Endocervical infection is the most common type of uncomplicated gonorrhea
in women (Figs 2.10 and 2.11). At least one-half of infected women are asymptomatic or have symptoms that are mild to non-specific. Cervical infections may
be accompanied by vaginal discharge, abnormal vaginal bleeding, or dysuria. Local
complications include abscesses in Bartholins and Skenes glands (Fig. 2.12).
Asymptomatic infections are found most often in women who are screened for
gonorrhea in routine gynecologic examinations or who are seen as sexual contacts
of men with gonorrhea. On examination, the cervical os may be erythematous and
friable, with a purulent exudate (Figs 2.11 and 2.13), or may be normal.
Anorectal infections, which occur in 30% of women with cervical gonorrhea,
probably represent secondary colonization from a primary cervical infection and
are symptomatic in less than 5% of women. Infections in MSM, however, result
from both penile-anal and oro-anal intercourse and are more often symptomatic
(1834%). Symptoms and signs range from mild burning on defecation to itching
Penile edema
Tysons glands abscess
Cowpers glands abscess
Seminal vesiculitis
Epididymitis
Endometritis
Salpingitis
Tubo-ovarian abscess
Ectopic pregnancy
Infertility
Bacteremia
Fever
Skin lesions: macular, erythematous,
pustular, necrotic, hemorrhagic
Tenosynovitis
Joints; septic arthritis
Endocarditis
Meningitis
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Gonorrhea
Fig. 2.8 Symptomatic
gonococcal urethritis.
Scanty urethral discharge
obtained after urethral
stripping.
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Clinical manifestations
disease, it is useful to divide patients into two groups: those with suppurative arthritis and those without. The term tenosynovitis-dermatitis syndrome often is applied
to the latter group of patients, because the majority present with, or give a history
of, one or both of tenosynovitis or skin rash. Only a minority of patients with suppurative gonococcal arthritis have tenosynovitis and/or skin lesions at the time of
presentation. It is generally thought that the tenosynovitis-dermatitis syndrome
represents the initial stage which then progresses to a frank septic arthritis.
Patients with the tenosynovitis-dermatitis syndrome may be febrile. The majority will have skin lesions which begin as small erythematous maculopapular
petechial lesions. These lesions usually develop a central pustule which may then
progress to a lesion with central necrosis (Figs 2.172.19). Early on the lesions of
meningococcemia and DGI may be indistinguishable though the former usually
progress to confluent petechial and then hemorrhagic lesions. Patients with DGI
usually have less than 20 lesions, whereas patients with meningococcemia usually
have many more. DGI lesions are located peripherally, with the wrists and ankles
being the most common locations. Polyarthralgia is a common presenting
symptom of DGI regardless of the clinical classification of the patient. Tenosynovitis is characterized as erythema, swelling, and direct tenderness upon palpation
of the affected tendon group (Fig. 2.20). It is found most commonly around the
wrist and dorsum of the hand, and less often at the ankle, including the Achilles
tendon, and the dorsum of the foot. In contrast to those with the tenosynovitisdermatitis syndrome, most patients with gonococcal suppurative arthritis are
afebrile. The arthritis typically affects the wrists, the small joints of the hands and
the knees. The majority of cases will give a history of migratory polyathralgia and
tenosynovitis may be present. About one third have skin lesions as described for
tenosynovitis-dermatitis syndrome. Left untreated, many cases of DGI eventually
resolve without specific therapy, but a significant proportion will suffer serious
morbidity including endocarditis, meningitis, and osteomyelitis. Since the advent
of antibiotics, these complications have been observed only rarely.
The diagnostic method of choice is blood culture although all suspected cases
should be screened for N. gonorrhoeae infection at pharyngeal and anorectal sites,
as well as at urethral and (in women) endocervical sites, prior to commencing
antibiotics as asymptomatic gonococcal colonization is often present. Gonococci
may occasionally be detected by microscopy and culture from pus expressed from
broken skin lesions (Fig. 2.21). Blood cultures are most likely to be positive
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Gonorrhea
among patients with the tenosynovitis-dermatitis syndrome and are rarely positive when taken from septic arthritis cases. Aspiration of pus from joints of septic
arthritis patients should undergo full microbiological investigation, including
microscopy and culture for N. gonorrhoeae. In one-half of DGI cases, gonococci
cannot be isolated from blood, CSF, or synovial fluid, even with the best laboratory techniques.6
DGI must be distinguished from Reiters syndrome, meningococcemia, acute
rheumatoid arthritis, other forms of septic arthritis, and the immune complexmediated arthritides caused by hepatitis B virus and HIV (Box 2.1 and Table 2.3).
In the absence of positive blood or synovial fluid cultures, a presumptive diagnosis of DGI can be made according to Box 2.2.
Sequence of extension
Non-infectious
Bacterial
Adults
Neisseria gonorrhoeae*
Staphylococcus aureus
Streptococcus pneumoniae
Other Streptococcus spp.
Children
Staphylococcus aureus
Streptococcus pneumoniae
Other Streptococcus spp.
Haemophilus influenzae
Gram-negative rods
Tuberculosis
Fungal
Gout, pseudogout*
Rheumatoid arthritis (especially juvenile
rheumatoid arthritis)
Trauma
Tumors
Hemarthrosis
Osteochondritis
Psoriatic arthritis
Pigmented/villonodular synovitis
*Most common.
2. Uterine cavity
3. Fallopian tubes
4. Abdominal cavity
1. Cervix
Clinical Features
Endocervicitis
Endometritis
May be asymptomatic; vaginal discharge,
Menstrual irregularity.
cervical inflammation, or infection; local
tenderness.
Endosalpingitis
Peritonitis
Constant bilateral lower quadrant
Nausea, emesis, abdominal distention,
abdominal pain aggravated by body
rigidity, tenderness. Pelvic or abdominal
motion. Tenderness in one or both adnexal
cavity abscess formation may follow.
areas. Abscess formation may occur.
Fig. 2.22 The evolution of gonococcal pelvic inflammatory disease.
Table 2.4 Etiologic agents of primary and recurrent pelvic inflammatory disease.
Neisseria gonorrhoeae
Chlamydia trachomatis
Group B Streptococci
Escherichia coli and other enterobacteria
Gardnerella vaginalis
Haemophilus spp.
Fusobacterium spp.
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Bacteroides spp.
Peptococcus spp.
Peptostreptococcus spp.
Genital mycoplasmas
Actinomyces israelii
(only with IUD-associated disease)
ClinicalLaboratory
manifestations
tests
Fig. 2.23 Normal
laparoscopic view of the
female genital tract: view
from above the dome of
the uterus.
Fig. 2.25 Gram-stained smear of urethral exudate from a male showing a sheet of
neutrophils (PMNs) and many Gram-negative diplococci within PMNs. This finding is
sufficient for a presumptive diagnosis of gonorrhea in the male.
Fig. 2.24 Uterus and fallopian tubes of a patient with advanced recurrent pelvic
inflammatory disease showing so-called retort tubes.
LABORATORY TESTS
The laboratory diagnosis of gonorrhea has undergone considerable change in
recent years. The presumptive diagnosis by examination of a Gram-stained smear
for the presence of intracellular Gram-negative cocci remains the mainstay in
many clinical settings, particularly for patients with the signs and symptoms of
gonorrhea. However, isolation of N. gonorrhoeae, historically the gold standard,
has been replaced in many settings by molecular detection using nucleic acid
amplification tests (NAATs). Culture is still required to provide a viable organism
for susceptibility testing to monitor the emergence of resistance to current therapies but NAATs offer detection using highly sensitive and specific tests which are
more tolerant of delays or inadequacies in specimen collection or transportation
to the laboratory. It must be remembered that no NAAT is 100% sensitive and
specific and although the commercially available kits will detect both N. gonorrhoeae and Chlamydia trachomatis, often simultaneously, the genetic targets for N.
gonorrhoeae are not as robust as for C. trachomatis because of the extraordinary
ability of the gonococcus for genetic recombination and exchange.
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Gonorrhea
Fig. 2.27 Methylene
blue-stained smear of
urethral exudate from a
man showing neutrophils
and intracellular
organisms.
Concentrations used
Organisms inhibited
Vancomycin
Lincomycin
Colistin
24mg/L
1mg/L
7.5mg/L
Trimethoprim
5mg/L
Nystatin
Amphotericin
12,500IU/L
11.5mg/L
Gram-positive bacteria
Gram-positive bacteria
Gram-negative bacteria
(other than Neisseria)
Gram-negative bacteria
(other than Neisseria)
Candida spp.
Candida spp.
Isolation methods
Specimens should be inoculated onto selective media such as ThayerMartin
(TM) medium, modified ThayerMartin medium (MTM), MartinLewis (ML)
medium, New York City (NYC) medium, or GCLect (GCL) medium, which are
composed of GC base or equivalent media supplemented with growth factors and
antimicrobial and antifungal agents (Table 2.5); some media contain hemoglobin. The addition of the selective agents allows the colonies of N. gonorrhoeae to
grow and bacteria found in the normal flora to be inhibited (Fig. 2.28). If the
specimen is obtained from a site that is normally sterile (e.g. blood, synovial
fluid, conjunctiva), it may be inoculated on a non-selective medium such as
chocolate agar. It should be remembered that other Neisseria and related spp. may
grow on non-selective media and therefore confirmation by identification of
N. gonorrhoeae should be undertaken. Vancomycin-susceptible strains of N. gonorrhoeae occasionally occur and may not grow on selective media containing 4g
vancomycin/mL, which is routinely used for the isolation of the gonococcus.
Selective media have been modified to contain 2g or 3g vancomycin/mL in
order to overcome this problem. Lincomycin has also been used as an alternative
but is less inhibitory than vancomycin and overgrowth, particularly from rectal
specimens, can occur. Vancomycin-susceptible gonococci should be suspected in
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Identification of N. gonorrhoeae
Fig. 2.32 Inoculated plate
after 24 hours of
incubation.
a community when false-negative cultures are obtained, as evidenced by a discrepancy between Gram-stain positivity and culture-positivity rates for urethral
gonorrhea in men; these should agree for at least 95% of cases. In an ideal situation both selective and non-selective media (Fig. 2.29) would be used, however
in most instances resources are only available for a single medium which should
contain selective agents.
The specimen should be inoculated over the entire surface of the plate in a Z
pattern, followed by streak inoculation of the plate (Figs 2.302.31). This inoculation technique yields isolated colonies that can be more easily processed, particularly in pharyngeal specimens, from which strains of N. meningitidis, N. lactamica,
and K. denitrificans may also be isolated.
Inoculated plates should be incubated immediately at 3536.5C in a CO2enriched, humid atmosphere. Gonococci require CO2 for primary isolation; the
supplemental CO2 can be provided in a CO2 incubator, a container with a CO2generating tablet, or a candle-extinction jar with white, unscented, non-toxic
candles.
IDENTIFICATION OF N. GONORRHOEAE
Presumptive identification
Culture plates are examined for growth after incubation for 24 hours; those that
show no growth at this time are reincubated for 2448 hours before being discarded and before a report of negative for N. gonorrhoeae is issued. Translucent,
non-pigmented-to-brownish colonies measuring 0.51.0mm in diameter on
isolation media should be further characterized (Fig. 2.32). Representative colonies are Gram stained and examined for oxidase production. Smears prepared
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Gonorrhea
colonies will turn purple within 10 seconds. The oxidase reagent should not be
placed on all suspect colonies. If few suspect colonies are available, they must be
subcultured to chocolate agar immediately after the application of the oxidase
reagent because of the toxicity of the reagent to the cells. Thin smears of suspect
colonies are Gram stained as described above. If the suspect colonies are oxidasepositive, Gram-negative diplococci, a report of presumptive N. gonorrhoeae may
be made for cervical, urethral, or rectal specimens.
Confirmation of identification
Ideally, when culture is performed, all isolates should be confirmed as N. gonorrhoeae, although this is not always possible when adequate laboratory facilities
and resources are not available. Certainly, pharyngeal isolates must be confirmed
because other Neisseria and related spp. may frequently be isolated on gonococcal
selective media. The aim of identification tests is to distinguish between N. gonorrhoeae and other species of Neisseria, particularly N. meningitidis and N. lactamica.7
Traditonally, N. gonorrhoeae is characterized by its ability to produce acid from
glucose but not from maltose, lactose and sucrose after incubation at 3536.5C
without CO2 for 2448 hours (Figs 2.35 and 2.36) and, from growth on a selective
isolation medium, this may be sufficient. However, many commensal Neisseria
grow on non-selective media and these may produce acid from glucose and
therefore additional tests may be required such as reduction of nitrate and the
production of polysaccharide.7
It is now more usual to use rapid identification kits (Fig 2.37 and 2.38) which
combine the detection of acid production from carbohydrates with that of preformed enzymes such as prolyliminopeptidase which is produced by N. gonorrhoeae, -glutamyl aminopeptidase produced by N. meningitidis, and -galactosidase
produced by N. lactamica; strains of Branlamella catarrhalis produce none of these
enzymes. A biochemical profile is obtained from these kits usually after 24
hours incubation and this gives a precentage likelihood of the identification. A
pure growth of the organism to be identified is required and therefore an overnight subculture is usually required before identification can take place. The use
of tests which only detect the presence of aminopeptidases should be discouraged
as N. gonorrhoeae that lack the ability to produce prolyliminopeptidase have been
reported in many countries in recent years.8
Serologic tests
There are currently no available tests that permit the detection of gonococcal
antibodies in serum. Serologic tests for the identification of N. gonorrhoeae in
primary cultures are commercially available as immunofluorescence (FA), coagglutination or latex tests. Thin smears may be stained with a monoclonal FA
reagent (Fig. 2.39) to confirm the identification of N. gonorrhoeae. Cross-reaction
with non-gonococcal species has not been observed with monoclonal reagents
and reagents containing polyclonal antibodies are no longer commercially available. Occasionally, some gonococcal strains do not react in this test (false
negative).
Coagglutination tests consist of cocktails of monoclonal antibodies directed
toward the major gonococcal porin, Por, which have been adsorbed to protein
A-producing Staphylococcus aureus cells. Suspect colonies are suspended in buffer
or saline and heated in a boiling-water bath. A drop of the cooled suspension is
mixed with a drop each of the antigonococcal reagents and a negative control.
After rotation for 12 minutes, the reactions are interpreted. If a suspension gives
a positive reaction with the antigonococcal reagent and a negative reaction with
Fig. 2.37 API NH identification kit in incubation chamber demonstrating the profile
of N. gonorrhoeae.
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Antimicrobial
Identificationsusceptibility
of n. Gonorrhoeae
testing
the control, the isolate is identified as N. gonorrhoeae and the use of the two
reagents also gives the serogroup WI or WII/III (Fig. 2.40). Cross-reactions
between non-gonococcal Neisseria and related spp. is rare (Fig. 2.41) although
gonococcal strains that do not react with the reagents do occur. Reagents that are
based on latex particles do exist but have little advantage over the co-agglutination
reagents.
The approach to identification of N. gonorrhoeae will depend on the number
and source of isolates obtained in any laboratory but careful consideration should
be taken to the limitations of the tests available9 and where possible it is advisable
to use more than one test, for instance a biochemical kit and immunological
reagent together. The identification of organisms isolated from sexual or child
abuse cases is always difficult and the use of multiple tests is essential.
Preservation
Isolates of N. gonorrhoeae must be subcultured every 2448 hours or suspended
in a solution of trypticase soy broth containing 15% glycerol and frozen at 70C.
Strains cannot be stored at 20C for long periods but can be stored at this temperature for a short time (approximately 2 months).
amplification (TMA; Gen Probe) and real-time PCR (Abbott). A number of inhouse assays have also been reported and two of the most useful of these detect
the pseudo porA gene and the opa gene10 and are particularly useful as confirmatory assays. The use of molecular methods for the diagnosis of gonorrhea has
increased markedly in the last five years and this has been driven by the widespread use of NAATs for chlamydia screening, the opportunity to detect two sexually transmitted infections for little or no extra cost, together with a vast
improvement in the sensitivity and specificity of these tests. The high sensitivity
allows the use of non-invasive specimens such as urine or self-taken vaginal swabs
and hence enables patients to be screened in many different settings, although
there is evidence that urines are not the optimal specimen for women.11 The
increased specificity allows use with extragenital specimens, although these kits
are not approved for use with rectal and pharyngeal specimens, there is increasing
evidence that molecular detection is becoming the method of choice for these
sites as culture is shown to have a low sensitivity.12 However, it is recommended
NAATs should only be used with specimens from individuals at risk of infection
and that all positive results should be confirmed using an alternative target to
avoid misdiagnosis due to cross-reactions with other Neisseria spp., especially with
pharyngeal specimens.
While NAATs offer many advantages for the diagnosis of gonorrhea their use
will be affected by the prevalence of infection in the population being tested. In
low prevalence populations the positive predicitive value (PPV) will be unacceptably low unless a supplementary test is used to confirm using a different genetic
target. For example: in a population with a 1% prevalence using a test with sensitivity of 98% and specificity of 99% the PPV is 50% and the negative predictive
value (NPV) is 100%. If the positive specimens are tested using a supplementary
test of equal sensitivity and specificity (98% and 99% respectively) then the
prevalence becomes 50% and the PPV is 99% and the NPV is 98%. It is generally
recommended that the algorithm for testing should produce a PPV of >90% to
limit misdiagnosis.10
Fig. 2.40 Reaction of two strains (A, wells 1 and 2 and B, wells 5 and 6) of N.
gonorrhoeae with Phadebact coagglutination reagents WI (wells 1 and 5) and WII/III
(wells 2 and 6).
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Gonorrhea
Fig. 2.44 Reactions of
-lactamase-positive (left)
and negative (right) strains
of N. gonorrhoeae in a
nitrocefin test.
Fig. 2.43 Comparison of -lactamase production (*) as detected by API NH (well) for
a positive (top) and negative (bottom) strain of N. gonorrhoeae.
part of the identification profile (Fig 2.43). Several tests for -lactamase are available commercially; these include chromogenic cephalosporin (Fig. 2.44), acidometric, and iodometric tests. The chromogenic cephalosporin (nitrocefin) tests
are preferred because the substrate is stable and the reactions are specific and
highly sensitive for -lactamase. The specificity and sensitivity of the acidometric
and iodometric tests may be affected by several factors, including incorrect storage
of the product, which may result in non-specific hydrolysis of the substrate.
-lactamase-positive and -lactamase-negative strains should be included as controls with each batch of clinical isolates.
antimicrobial agents is measured as the MIC of the agent that inhibits growth of
an isolate. Determination of susceptibilities to antimicrobial agents used for
therapy should be tested such as the third generation cephalosporins, cefixime
and ceftriaxone although other agents, such as ceftobutin, are used in different
parts of the world. The methodology for susceptibility testing of N. gonorrhoeae
can vary between countries, differing primarily in the base medium used; GC agar
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Antimicrobial therapy
In response to the continued emergence of resistant strains in the USA, the current
CDC STD Treatment Guidelines14 recommend treatment of all gonococcal infections presumptively with antibiotic regimens effective against strains resistant to
penicillin, quinolones and/or tetracycline. First line agents recommeded by CDC
are either imtramuscular ceftriaxone (125mg) or oral cefixime (400mg),
although availability of the latter has been a problem in the USA in recent years.
Spectinomycin, 2g intramuscularly, is a useful regimen for the treatment of
patients who have severe allergic reactions to penicillins (e.g. bronchospasm,
anaphylaxis) in whom cephalosporins would be contraindicated due to the 10%
risk of cross-allergy in penicillin-allergic patients. The World Health Organizations (WHO) treatment guidelines15 are very similar to former CDC treatment
guidelines and are currently being updated. Similar to the CDC guidelines, the
UK National Guidelines16 and European guidelines17 recommend either a single
dose cephalosporin (ceftriaxone or cefixime), although the ceftriaxone is used at
the higher 250mg dose, or spectinomycin as first-line therapy. It should be noted
that treatment recommendations for complicated gonococcal infections (Table
2.7) are based on expert opinion, not on therapeutic trials.
Although not listed as a first-line agent in the CDC, WHO or UK treatment
guideline for gonorrhea, azithromycin 2g as a single dose may be a useful agent
in selected individual cases. Like spectinomycin, it may be given to pregnant
women and also to patients with severe penicillin allergies in whom cephalosporins are contraindicated. It is not recommended as a first-line agent as resistance
to azithromycin may develop on treatment and azithromycin-resistant N. gonorrhoeae isolates are already circulating.3 In really difficult cases, use of gentamicin
240mg as a single intramuscular dose may be used. Although there remains
debate over the MIC breakpoints that determine clinical susceptibility and resistance, this agent has been used with success as a first-line agent in Malawi for
treatment of the male urethritis syndrome for over 14 years, and clinical treatment
failures appear to be rare. Given the increasing prevalence of multidrug resistant
gonococci globally, it is likely that future therapy will require multidrug therapy
and a move away from single dose regimens in an attempt to maintain the useful
life of the few antibiotics currently available to reliably treat gonorrhea.
RESISTANT
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Gonorrhea
Recommended therapy
Disseminated gonococcal
infection
Meningitis/endocarditis
Ophthalmia
Neonatal
Adult
*Or cefotaxime 1g i.v. every 8 hours, or ceftizoxime 1g i.v. every 8 hours, or spectinomycin
2g i.m. every 12 hours.
ACKNOWLEDGEMENTS
The authors acknowledge the contribution of David Martin in co-writing the
previous edition of this chapter with Dr C. Ison.
REFERENCES
1.
N. gonorrhoeae isolate
Extract DNA
2.
3.
4.
5.
6.
Trim from a
conserved region
Trim from a
conserved region
7.
8.
Allele number obtained
from NG-MAST
website, e.g. 7
9.
10.
11.
12.
13.
14.
15.
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References
16.
17.
18.
19.
39
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