However, in 2012, the CDC no longer recommended cefixime as a first-line regimen
because of concerns about declining cefixime susceptibility among urethral N.
gonorrhoeae isolates in the United States during 2006 to 2011.
cephalosporins, such as cefpodoxime and cefuroxime, are not recommended because
of inferior efficacy and less favorable pharmacodynamics; however, they are FDA
approved to treat uncomplicated N. gonorrhoeae.
Fluoroquinolones have been routinely used since the 1990s for the treatment of
gonorrhea; however, the GISP has continuously documented fluoroquinolone
resistance in N. gonorrhoeae isolates, which has necessitated changes in the CDC
Sexually Transmitted Disease treatment guidelines (Fig. 72-3). Because of this
increased resistance, the CDC no longer recommends ciprofloxacin, levofloxacin,
ofloxacin, or other fluoroquinolones for the treatment of gonorrhea. This
recommendation also extends to the treatment of gonorrhea-associated conditions,
The CDC’s 2013 Sexually Transmitted Disease Surveillance Program observed that
96.9% of treated patients received ceftriaxone 250 mg. The number of those treated
with cefixime decreased from 5.3% in 2011 to 0.02% in 2013.
cefixime use was expected as CDC recommendations to avoid use of cefixime at any
dose as first-line therapy was issued in 2012. Other most prescribed medications,
followed in order by ceftriaxone, azithromycin, “other less frequently used drugs,”
and cefixime (Fig. 72-4). Dual therapy with azithromycin or doxycycline was
prescribed in 95.4% and 4% of those treated with ceftriaxone, respectively.
CASE 72-1, QUESTION 7: How should D.S.’s urethritis be treated? Because C.S. is totally asymptomatic
Because D.S. has gonococcal infection limited to the urethra (uncomplicated), a
few treatment regimens are possible, as outlined in Case 72-1, Question 6.
Ceftriaxone is the preferred treatment, with cefixime as an alternative, only if
ceftriaxone is not available. Quinolones should be avoided because of increased
resistance in N. gonorrhoeae and because D.S.’s infection was likely obtained in the
Philippines, where quinolone resistance occurs in more than half of all isolates.
Patients with gonorrhea may also be coinfected with Chlamydia and therefore
presumptive cotreatment with azithromycin 1 g PO as a single dose could be initiated
25 Although single-dose azithromycin 2 g monotherapy
has been used to treat concurrent gonorrhea and Chlamydia, it is more expensive and
poorly tolerated because of increased gastrointestinal (GI) side effects and may lead
to macrolide-resistant N. gonorrhoeae, or treatment failure.
C.S. also should be treated even though she appears asymptomatic. All partners who
have had sexual exposure to patients with gonorrhea within 60 days should be
treated. If the patient has not been sexually active for 60 days, the most recent sexual
partner should be treated. This is especially true when the partner is pregnant
because gonorrhea during pregnancy is associated with chorioamnionitis and
prematurity, as well as neonatal infection. Pregnant women can be treated safely with
cephalosporins and azithromycin for gonorrhea and Chlamydia.
Prevention. 2009 Sexually Transmitted Disease Surveillance. Atlanta, GA: US Dept of Health and Human
CASE 72-1, QUESTION 8: How does one determine whether the drug therapy of gonorrhea has been
If recommended therapies are used for treatment of uncomplicated gonorrhea, a
test-of-cure is not necessary for either C.S. or D.S. because cure rates are close to
2 However, a test-of-cure should be done 14 days after treatment in those with
pharyngeal infection treated with an alternative treatment regimen.
persist in D.S., who was treated with ceftriaxone, cultures should be done to
determine antibiotic susceptibility, and to rule out other causes of urethritis.
Antibiotic-Resistant Neisseria gonorrhoeae
CASE 72-1, QUESTION 9: D.S. states that he was treated with penicillin in the past for a gonococcal
infection. Why are penicillins not prescribed routinely today?
Failure of penicillin to eradicate the gonococcus can be the result of plasmid (e.g.,
PPNG) or chromosomally mediated resistant Neisseria gonorrhea (CMRNG)
antibiotic resistance. PPNG contain plasmids, which determine the production of
lactamase, an enzyme that hydrolyzes the lactam ring of penicillin G or ampicillin.
Chromosomally mediated resistance does not involve β-lactamase production and
often is associated with increased resistance to other β-lactams. The clinical
significance of CMRNG is questionable because serum levels of approved
antibiotics are achieved far above the minimum inhibitory concentration, such that
treatment failure is unlikely. However, to date, CMRNG remain largely susceptible
to ceftriaxone. High-level tetracycline resistance is defined by gonococci that carry
plasmid-encoded resistance to 16 g/mL or more of tetracycline. These strains are
known as TRNG. Although not of major concern in the United States, development of
resistance to alternative therapies is a continuing concern.
The first cases of PPNG infection were reported in the United States in 1976.
PPNG are especially prevalent in Southeast Asia, the Far East, and West Africa,
where the prevalence often exceeds 50%. In the United States, the percent of PPNG
strains reached a peak of about 11% in 1991; since then, cases have steadily declined
to 0.4% in 2007, according to the CDC’s GISP (Fig. 72-2).
1985 and penicillin was abandoned in 1987. In the late 1990s, the number of TRNG
and PPNG plus TRNG cases plateaued at about 5% and 1%, respectively. Therefore,
because approximately 21% of gonococcal isolates are resistant to tetracycline
and/or penicillin within the United States, it is not acceptable to use these agents in
the initial management of uncomplicated genital gonorrhea; IM ceftriaxone remains
the drug of choice. Antibiotic susceptibility testing is recommended in cases of
persistent infection after treatment.
QRNG was first reported in 1990 and was reported to be 0.2% of isolates in the
In the 2013 GISP report, 11% of isolates from
Honolulu, Hawaii, were QRNG, whereas among California sites, 31.8% to 44.4% of
27 N. gonorrhoeae resistance to quinolones has increased almost
every year since reporting began in 1990 and has become widespread in the United
States, resulting in the CDC recommending against using quinolones for the treatment
of gonococcal or related conditions (e.g., PID) acquired in the United States.
2013, 16.1% of all isolates collected by the GISP demonstrated resistance to
4 Resistance to fluoroquinolones is associated with mutations of GyrA
and is commonly identified in strains that produce β-lactamase and strains exhibiting
chromosomally mediated resistance to penicillin and tetracycline.
strains may therefore exhibit decreased susceptibility or complete resistance to the
recommended dose of quinolones, and the clinical importance of strains with
decreased susceptibility is unknown.
frequently used drugs (<0.1%).
D.S. was likely infected with N. gonorrhoeae in the Philippines, and QRNG is
highly likely; thus, an appropriate cephalosporin antibiotic such as IM ceftriaxone
should be recommended. If he had been initially treated with ceftriaxone, the
expectation would be that he would be free of gonococcal infection within 3 days. To
date, ceftriaxone-resistant strains of N. gonorrhoeae have not been reported in the
United States, but GISP data has documented decreased cefixime susceptibility
among urethral N. gonorrhoeae isolates.
Anorectal and Pharyngeal Gonorrhea
negative and a Venereal Disease Research Laboratory (VDRL) test was nonreactive. Both rectal and
pharyngeal cultures revealed N. gonorrhoeae. How does gonorrhea in homosexual men compare with
gonorrhea in heterosexual men?
Rectal infection occurs rarely in strictly heterosexual men, whereas in the male
homosexual population, anorectal (25%) and pharyngeal (10%–25%) gonococcal
infections are often asymptomatic, a large reservoir of carriers in the homosexual
male population may exist and annually screening should be done if they have
engaged in receptive oral or anal intercourse in the preceding year. By comparison,
very few urethral gonococcal infections are asymptomatic. In addition, data indicate
that pharyngeal infections may be an important source of urethral gonorrhea in
homosexual men, spread by fellatio.
CASE 72-2, QUESTION 2: Are M.B.’s signs and symptoms consistent with gonorrhea?
Rectal gonorrhea produces the syndrome of proctitis with anorectal pain,
mucopurulent anorectal discharge, constipation, tenesmus, and anorectal bleeding.
The differential diagnosis of proctitis in the homosexual male includes rectal
infection with N. gonorrhoeae, C. trachomatis, HSV, and syphilis. Proctitis, limited
to the distal rectum, should be differentiated from proctocolitis, which is often
caused by Shigella species, Campylobacter species, or Entamoeba histolytica in
homosexual men. The incidence of rectal gonorrhea and Chlamydia has risen
33 Rectal Chlamydia is often asymptomatic and observed
more often than gonorrhea, necessitating testing for both pathogens.
pharyngeal gonorrhea is often asymptomatic, a review of system and physical exam
may reveal a sore throat, pharyngeal exudates, or cervical lymphadenitis.
CASE 72-2, QUESTION 3: How should M.B.’s diagnosis be managed?
The treatment of choice for patients such as M.B. with anorectal or pharyngeal
gonorrhea is ceftriaxone 250 mg IM as a single dose (Table 72-1).
should also be given to treat possible coexisting rectal chlamydial infection. Patients,
such as M.B., with either anorectal or pharyngeal gonorrhea should be advised to
avoid further unprotected sexual activity and should be counseled and tested for
Patients with anorectal gonorrhea alone should be treated with ceftriaxone. Oral
cefixime is a recommended alternative, but it should not be used as a first-line agent.
unavailable, patients with anorectal gonorrhea, who are allergic to penicillin or
cephalosporins, should be desensitized before treatment is initiated. Patients with
gonococcal infections of the pharynx should be treated with ceftriaxone; however,
infections of this nature are more difficult to eradicate than infections at urogenital
and anorectal sites. Treatment for gonorrheal infections at these sites should also be
treated with azithromycin for presumptive Chlamydial coinfection.
CASE 72-2, QUESTION 5: What measures have been used to prevent the sexual transmission of infection?
Condoms, when used properly, seem to provide a high degree of protection against
the acquisition and transmission of STDs.
35 Previous studies indicated that the use
of the spermicide nonoxynol-9 had activity against gonorrhea and Chlamydia;
however, in light of recent evidence suggesting that nonoxynol-9 might actually
increase the risk of acquiring HIV and other STDs, the FDA currently requires
manufacturers of nonoxynol-9 products to include a warning statement on the
product’s label that it does not protect against HIV or other STDs.
antibacterial agents, urinating, and washing after intercourse are of little value in
preventing the transmission of STDs. Douching may increase the risk of other STDs,
The prophylactic administration of antibiotics immediately before or soon after
sexual intercourse is not recommended owing to increased costs and antimicrobial
resistance. Use of rapid, specific tests and empiric symptomatic management
enhances detection and treatment of gonorrhea.
The term PID refers to a variety of inflammatory disorders of the upper female
reproductive tract. This term does not denote the primary infection site (the fallopian
tubes) nor the causative microorganisms. PID also has been used to connote an
infection that occurs acutely when either vaginal or cervical micro-organisms
traverse the sterile endometrium and ascend to the fallopian tubes. Acute salpingitis
may also be used to describe an acute infection of the fallopian tubes. Therefore, the
terms PID and salpingitis are used interchangeably in this discussion to denote an
acute infection involving the fallopian tubes.
PID affects approximately 1 million women annually in the United States.
However, the National Disease and Therapeutic Index (NDTI) estimates that from
2002 to 2012, the number of initial visit to physicians for PID for women aged 15 to
4 Many cases of acute PID occur by sexual transmission,
especially in young women 16 to 24 years, who are more likely to have multiple
39 Risk factors for the development of PID include unprotected sexual
intercourse before age 15, douching, BV, sex while menstruating, and smoking.
unclear whether an intrauterine device (IUD) increases the risk of PID, but it may be
prudent to avoid placement when the patient has chlamydial or gonococcal
41 Two-thirds of PID cases resulting in infertility are asymptomatic, and up
to one-third are incorrectly diagnosed owing to low specificity of diagnostic
techniques. In the United States, infertility occurs in about 12.1% of women after the
42 The estimated costs for treatment of PID and its sequelae
exceeds $4.2 billion annually.
Most cases of PID are caused by C. trachomatis and N. gonorrhoeae. Some
microorganisms that make up the vaginal flora are also associated with PID,
including Gardnerella vaginalis, H. influenzae, and Streptococcus agalactiae.
Mycoplasma hominis, Ureaplasma urealyticum, M. genitalium, and cytomegalovirus
(CMV) have also been associated with PID, but a causative role is unclear.
70% of cases may be polymicrobial and include M. genitalium and BV.
enteric gram-negative bacilli and a variety of anaerobic bacteria have also been
isolated from the upper genital tract of up to 70% of women with acute PID.
Women diagnosed with acute PID should be tested for C. trachomatis and N.
gonorrhoeae using NAAT and screened for HIV.
The variations in presentation and nonspecific signs and symptoms of PID make it a
complex disease to diagnosis. The onset of symptoms of abdominal pain attributable
to PID caused by either gonococci or chlamydia often occurs soon after the menstrual
period. Symptoms of PID, if present, are often nonspecific, which can create a delay
in or failure of diagnosis. Vaginal discharge, menorrhagia, dysuria, and dyspareunia
are commonly associated with PID. Pelvic examination findings include cervical
motion tenderness, uterine tenderness, or adnexal tenderness. Temperatures greater
than 101°F, abnormal cervical or vaginal mucopurulent discharge, white blood cells
(WBC) on saline microscopy of vaginal secretions, elevated erythrocyte
sedimentation rate, an elevated C-reactive protein, or laboratory documentation of
cervical infection with N. gonorrhoeae or C. trachomatis support a diagnosis of PID.
Clinical diagnosis has sensitivity for PID of about 65% to 90%, whereas
laparoscopy and a newer technique, transvaginal Doppler ultrasound, are about
100% specific, resulting in the combination of laparoscopy and clinical impression
45 Unfortunately, laparoscopy and Doppler ultrasound
are costly and often not readily available for acute cases and they are not diagnostic
for endometritis; thus, clinical impression is critical. A key to reducing the incidence
of PID may be through active screening of Chlamydia in young, sexually active
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