SURVEY OF OPHTHALMOLOGY0 VOLUME 32 * NUMBER 3 * NOVEMBER-DECEMBER 1987

THERAPEUTIC REVIEW, JOEL MINDEL, EDITOR

Gonococcal Keratoconjunctivitis
SAUL ULLMAN, M.D., THOMAS J. ROUSSEL, M.D., AND RICHARD K. FORSTER, M.D.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine,
Miami, Florida

Abstract. Gonococcal is a potentially devastating infection, because Neis-

keratoconjunctivitis
seria gonort-hoeae can cause a rapid, severe, ulcerativekeratitis resulting in visual loss. The thera-
peutic decision making process is complicated by the necessity for prompt, effective parenteral
therapy, frequent coinfection with other sexually transmitted diseases, and emergence of antibi-
otic resistance. Because of the evolving problem of antibiotic resistance and the need for cost
containment, the current recommendations of hospitalization for intravenous penicillin may
need to be modified. The third generation cephalosporin, ceftriaxone, has properties that suggest
it may be the best available antimicrobial agent as a single-dose treatment ofgonococcal conjunc-
tivitis. Spectinomycin may be a useful alternative in the penicillin-allergic adult patient. (Surv
Ophthalmol 32:199-208, 1987)

Key words. ceftriaxone l gonococcal keratoconjunctivitis l Neisseria gonorrhoeae l

penicillin l spectinomycin

Despite effective antimicrobial agents, public tracellular gram-negative diplococci on gram stain
health intervention, and improved health education (Figs. 1 and 2). However, since N. meningitidies,
efforts, gonorrhea incidence remains high.‘* In 1986 Branhamella catarrhalis, and Acinetobacter calcoaceticus
over 900,000 cases of gonorrhea in the United States can present with similar clinical and gram stain
were reported to the Centers for Disease Control.23 findings, definitive cultures and sensitivities are
It is estimated that less than half of all cases are mandatory in all cases.‘0~43~60J0gJ’2The laboratory
reported; therefore, a more accurate estimate of the characteristics and diagnostic techniques of gono-
annual incidence is approximately two million coccal infections have been reviewed elsewhere.36J’i
cases. The incidence of gonococcal conjunctivitis in Bacterial keratoconjunctivitis is usually treated
adults is estimated at one per 700-800 cases of with regional antibiotics (both topical and subcon-
gonorrhea. 42Therefore, the incidence of gonococcal junctival) modified by culture results. Gonococcal
conjunctivitis may be as high as 2000 cases keratoconjunctivitis, however, is unique in several
annually. respects. Gonococcal keratoconjunctivitis requires
Gonococcal keratoconjunctivitis is a potentially parenteral antimicrobial agents and its course can
devastating infection because of the ability of N. progress rapidly. g5,‘ooFrequently, coinfection with
gonorrhoeae to cause a rapid, severe, ulcerative kerati- other sexually transmitted diseases is present.35,50*57
tis which may result in a cornea1 perforation.30@ These factors, coupled with emerging antibiotic re-
Studies have shown that with prompt, effective par- sistance, have complicated the therapeutic decision-
enteral antibiotics this infection can be eradicated making process. The rapidity and potential severity
and complications avoided.4’~ggJ08 A presumptive di- of this infection necessitates treatment before cul-
agnosis of gonococcal conjunctivitis is made when a ture and sensitivity results are known. Unfortunate-
hyperpurulent conjunctivitis is associated with in- ly, this initial empiric treatment must be based on
199
 Surv Ophthalmol 32( 3) November-December 1987 ULLMAN ET AL

Fig. 2. Numerous intracellular and extracellular gram-

Fig. 1. Typical clinical appearance of a purulent conjunc- negative diplococci in association with acute inflamma-
tivitis secondary to N. gonorrhoeae. tory cells. (Hematoxylin and Eosin)

inadequate clinical and experimental information. in 1976, and have become important pathogens in
This article will review the historical aspects and many parts of the world. 6,76Chromosomally-medi-
current literature on the medical treatment of gono- ated resistance (CMRNG) to penicillin and tetracy-
coccal keratoconjunctivitis. Only empirically de- cline was first reported in the United States in
rived guides for therapy can be recommended be- 1983.‘6J7 CMRNG is relatively difficult to diagnosis
cause of the paucity of clinical data. Prophylaxis for because it requires performing formal susceptibility
ophthalmia neonatorum and the surgical manage- testing on gonococcal isolates. In 1985, plasmid-
ment of infectious keratitis have been reviewed mediated tetracycline resistance (TRNG) was first
elsewhere and will not be addressed in this described.21@’ The implications of this strain on tet-
article 2,27Z%37~85~~10 racycline prophylaxis of the newborn are unknown.

I. Historical Background II. General Considerations

Allusions to gonorrhea may have been made in In addition to the general criteria ofsafety, ease of
the Book of Leviticus. Galen ( 130 AD), referring to administration, compliance, and cost, three other
the urethral discharge of men with urethritis, first important factors are important in the selection of a
used the term gonorrhea, meaning “a flow of seed.” treatment regimen for gonococcal keratoconjuncti-
In 1879, Neisser identified the gonococcus, and vitis: the prevalence of PPNG and other antibiotic-
Bumm cultivated the bacteria in vitro by 1885. Karl resistant strains in their community, the possibility
Crede’ (early 1880s) experimented with topical sil- of concomitant nongonococcal infection, and the ra-
ver nitrate to prevent gonococcal ophthalmia neo- pidity in which gonococcal keratoconjunctivitis can
natorum. In 1939 sulfonamides were introduced to progress.
the physicians’ armamentarium. During World Because man is the only natural reservoir of N.
War II, sulfonamide resistant strains of gonococcus gonorrhoeae, no reproducible experimental animal
were encountered. Fortunately, penicillin was de- model exists for gonococcal conjunctivitis.“,58 Infec-
veloped at this time and quickly became the drug of tion with the gonococcus results in little, if any,
choice for gonorrhea. Still, the diagnosis of gonor- immunity to reinfection. Reinfection, therefore, is a
rhea was difficult because of the problems in obtain- common cause of apparent treatment failure. Per-
ing a pure culture. In 1964, Thayer and Martin sistence of a concomitant nongonococcal infection
developed an antibiotic selective medium that al- (i.e., Chlamydia trachomatis conjunctivitis) is another
lowed the pathogenic species N. gonorrhoeae and N. cause of apparent treatment failure.ag Treatment
meningitidis to grow.‘O’ failure may be due to antibiotic resistance (PPNG or
In 1972, in response to a precipitous increase in CMRNG), poor compliance, or the inability of the
incidence and relative resistance of the gonococcus antibiotic to reach inhibitory concentrations at the
to penicillin, the federal government financed state site of infection.40,4g,82,g6
efforts to control gonorrhea. Beta-lactamase-pro- The paramount concern in the treatment of gono-
ducing N. gonorrhoeae (PPNG) were first discovered coccal keratoconjunctivitis is the evolution and
GONOCOCCAL KERATOCONJUNCTIVITIS 201

TABLE 1 gonococcal conjunctivitis and conjunctivitis after

Current Recommendations - Centers for Disease Control* ocular contamination with urine support this
hypothesis.‘~‘3~‘07~“6 I n patients with a gonococcal
Gonococcal Ophthalmia in Adults
Aqueous penicillin G 10 million units intravenously daily ocular infection without cornea1 involvement, we
for 5 days believe hospitalization and intravenous therapy
For PPNG Infections: may be unnecessary. Case reports and our own
Cefotaxime 500 mg intravenously 4 times daily for 5 experience indicate that gonococcal conjunctivitis
days
responds promptly to intramuscular antibiotics,
OR
Ceftriaxone 1.O gram intramuscularly or intravenously similar to other localized mucosal gonococcal infec-
daily for 5 days tion (i.e., urethritis, cervicitis) .3g.57,74~‘06.“6
Gonococcal Ophthalmia in Neonates If out-patient therapy is contemplated for gono-
Aqueous penicillin G 100,000 units/kg/day intravenously coccal conjunctivitis, a single dose regimen that en-
in 4 divided doses for 7 days
sures patient compliance is necessary. In addition,
For PPNG infections:
Cefotaxime or gentamicin intravenously in appropriate daily ocular examinations until the infection is
neonatal doses. eradicated is mandatory. If there is doubt about
*From the Centers for Disease Control: 1985 STD Treat- compliance with follow-up examinations, or if dis-
ment Guidelines: MMWR 34:75S, 1985. ease progression is noted (cornea1 involvement), the
patient should be hospitalized. We recommend hos-
pitalization for patients with either preexisting ocu-
lar disease, cornea1 involvement, or immunocom-
spread of strains of N. gonorrhoeae with diminished promised states.
susceptibility to antimicrobial agents.‘*~83~“3~“4~“5~“7
The gonococcus has demonstrated the capacity to III. Topical Therapy
develop relative or absolute resistance to the penicil- After the introduction of penicillin, there were
lins, tetracyclines, sulfonamides, aminoglycosides, enthusiastic reports of gonococcal ocular infections
and other antimicrobial drugs.‘2,g3 Resistance occurs treated solely with topical penicillin.g4 These initial
through a chromosomally mediated mechanism studies were inadequate because clinical and not
(CRMNG) or the acquisition of plasmids bearing microbiologic cure were shown, and extraocular in-
genes coding for beta-lactamase.25,64@ In CMRNG fected sites were not examined. Subsequent studies
strains, the organism’s outer membrane is less per- have found that topical treatment may transiently
meable to the antimicrobial agents. This change alleviate the signs of the conjunctivitis without
often simultaneously confers relative resistance to eradicating the infection.7g,86 Moreover, topical ther-
several antimicrobial agents (penicillins, tetra- apy will not affect any extraocular sites of infection.
cyclines, and erythromycin). Plasmid-mediated Topical antimicrobial agents may be used in ad-
(PPNG) resistance to the penicillins and some dition to parenteral therapy. They have no role in
cephalosporins are noted in the organisms that the primary treatment of gonococcal infections and
produce beta-lactamase which breaks down penicil- some experts feel they are superfluous when appro-
lin extracellularly. 32,33 Plasmid-mediated tetracy- priate parenteral therapy is given.’ Many clinical
cline resistance affects ribosomal binding of studies have shown that topical antimicrobial
tetracycline? agents are not necessary when parenteral therapy is
The recommendations of the Centers for Disease used. However, Fransen and coworkers, in assess-
Control (CDC) for treatment of gonococcal ocular ing the efficacy of single-dose kanamycin therapy for
infections as of April, 1987, are shown in Table 1 .22 gonococcal ophthalmia neonatorum, reported an
These recommendations are not based on con- increased cure rate with the addition of topical gen-
trolled clinical studies and are similar to the treat- tamicin ointment when compared with the kanamy-
ment regimen for disseminated gonococcal infec- cinlsaline eye wash regimen.34
tions.‘03 These treatment recommendations are We recommend adjunctive irrigation with ap-
independent of the severity of the ocular infection proximately 50 cc of saline every hour as needed to
(whether there is cornea1 involvement or not). Most remove the possibly toxic purulent conjunctival dis-
cases of gonococcal conjunctivitis are believed to be charge. Since topical therapy delivers a large con-
due to inoculation of the conjunctiva with infected centration of antibiotic locally without great risk of
genital secretions, either directly or via contaminat- systemic side effects, and some studies suggest that
ed lingers. ‘g.74.‘oo We feel this mechanism differs from it may be of benefit, we recommend the use of an
“classic” hematogenously disseminated gonococcal antibiotic ointment four times daily. Antibiotic se-
disease (arthritis-dermatitis syndrome, endocardi- lection should be based upon the culture results,
tis, meningitis). Reports of laboratory-acquired cost, toxicity, and availability. Topical gentamicin,
202 Surv Ophthalmol 32(3) November-December 1987 ULLMAN ET AL

erythromycin, or bacitracin are reasonable choices. They found that from 1982 thru 1986, seven of the
Because of the frequent bulbar conjunctival chemo- 43 (16%) cases of gonococcal conjunctivitis were
sis, and subsequent cornea1 dellen formation with penicillin resistant.
irritation, we feel an antibiotic ointment may pro- The need for hospitalization and live days of in-
vide more patient comfort than antibiotic drops. travenous penicillin to eradicate gonococcal ocular
Patients with unilateral disease should be cau- infections has never been proven. This infection
tioned not to inoculate the uninvolved eye when generally results from inoculation of the conjunctiva
applying the topical antimicrobial ointment. In pa- with infected genital secretions, not from hema-
tients with severe cornea1 thinning or an actual per- togenously disseminated disease.1g,74J00 Since gono-
foration, the eye should be manipulated as little as coccal conjunctivitis most likely represents a local-
possible. We therefore do not recommend topical ized mucosal infection, similar to goncococcal
antibiotics or saline lavage when the integrity of the urethritis, a single-dose treatment with an effective
globe is in question. antibiotic should be effective. Recent studies in the
treatment of gonococcal ophthalmia neonatorum
and case reports of adult gonococcal ophthalmia
A. PENICILLIN suggest that single-dose therapy is effective.3ga57,74,“6
Until recently, aqueous procaine penicillin G
(APPG), a bactericidal beta-lactam antibiotic, has
been the basis of treatment of gonococcal infections. B. SPECTINOMYCIN
In 1956, only 300,000 units of intramuscular APPG Spectinomycin is an aminocyclitol that differs
cured genital gonorrhea. 26However, over the course structurally from the related aminoglycoside antibi-
of 20 years, N. gonorrhoeae isolates with increasing otics. It is poorly absorbed from the gastrointestinal
resistance to penicillin have been found, necessitat- tract but is well absorbed when given intramuscu-
ing escalation of the penicillin dose to 4.8 million larly. A single intramuscular 2.0 gram dose in an
units in the 1970’s.54 Oral probenecid, which inhib- adult results in blood levels of about 100 micro-
its the active secretion of penicillin by the renal grams/ml one hour after injection.63 Spectinomycin
tubules and therefore results in higher and pro- inhibits protein synthesis in the bacterial cell by
longed concentration of-antibiotic in the plasma, acting at the 30s ribosomal subunit.63
has become a required adjuvant in the treatment of Indications approved by the U.S. Federal Drug
genital gonorrhea.% Administration (FDA) are limited to acute gono-
The current recommendation by the CDC for coccal urethritis and proctitis in men and acute
adult gonococcal ophthalmia is hospitalization for gonococcal cervicitis and proctitis in women. It is
treatment with ten million units of intravenous relatively ineffective in oropharyngeal gonococcal
aqueous penicillin G daily for five days (Table l).” infections.53 The inefficacy of spectinomycin in oro-
This regimen is independent of the severity of the pharyngeal infection may relate to failure of the
ocular disease and has not been subjected to con- antibiotic to be secreted into saliva in inhibitory
trolled clinical studies. Multiple reports, which uti- concentrations. There is no correlation between the
lized various doses and duration of therapy, have in vitro sensitivity to spectinomycin and the results
shown intravenous penicillin to be efficacious for of treatment of gonococcal infection with spectino-
penicillin-sensitive gonococcal keratoconjunctivi- mycin. 45 Gonococcal isolates that are penicillin-re-
tis.7J3~g8J00J08 In addition, this regimen will also cure sistant are no more likely to be resistant to spectino-
incubating syphylis, is not teratogenic, assures com- mycin than isolates that are penicillin-sensitive.70
pliance, and is effective against gonococcal infec- Spectinomycin-resistant N. gonorrhoeae was first not-
tions of all sites.38,87 ed in Denmark in 1973.84 Additional cases have sub-
The paramount concern with the use of intrave- sequently been reported in the United States, but
nous penicillin for the treatment of gonococcal kera- the incidence remains rare.4,20,53,78 In 1985-l 986,
toconjunctivitis is the proliferation of antibiotic re- there were nine confirmed cases of spectinomycin-
sistant isolates.g1 Nationally, the incidence of PPNG resistant gonococcal infections in the United
infection has doubled in each of the past two years; States.‘17
in 1986 the incidence was 1.7% (CDC, unpublished Patients who are penicillin allergic generally tol-
data). Numerous case reports have documented the erate spectinomycin well. Spectinomycin appears to
occurrence of ocular infections secondary to N. gon- be neither ototoxic nor nephrotoxic in single doses
orrhoeae resistant to penicillin. 19,28,31,34,35,39,57,73,74,80,81,85 up to 4 grams. Volunteers receiving 8 grams daily
Ullman and coworkers retrospectively reviewed for 21 days did not develop cochlear, vestibular, or
their cases of gonococcal keratoconjunctivitis from renal abnormalities.71 Adverse reactions have been
south Florida, where PPNG is a major problem.‘5*‘06 uncommon and serious adverse reactions have not
GONOCOCCAL KERATOCONJUNCTIVITIS
been reported. It is not approved for use during
pregnancy; however, available data does not sug-
gest that spectinomycin poses a threat to the fe-
tus.38,65Spectinomycin is not FDA-approved for use
in neonates.
Spectinomycin is not effective against Treponema
pallidurn and has no activity against incubating
syphilis. 8,5gIn addition, it is ineffective against Chla-
mydia trachomatis.50
The use of spectinomycin for gonococcal urethri-
tis has increased in areas where antibiotic-resistant
gonorrhea is prevalent. No studies have been per-
formed regarding the efficacy of spectinomycin in
gonococcal keratoconjunctivitis. Anecdotal reports
of gonococcal conjunctivitis secondary to penicillin
resistant N. gonorrhoeae eradicated by intramuscular
spectinomycin have been reported.lg Ullman and
coworkers successfully treated some of their cases of
adult gonococcal conjunctivitis with intramuscular
spectinomycin although details of these cases were
not reported. ‘06 However, Reed and coworkers re-
ported a case of PPNG conjunctivitis treated unsuc-
cessfully with two grams of intramuscular spectino-
mycin daily for two days; on the fourth day a clinical
relapse was noted, suggesting this therapy was inad-
equate.8’
The high failure rate of spectinomycin in oro-
pharyngeal gonorrhea illustrates the problem of ex-
trapolating the results of urethritis treatment to oth-
er mucosal sites. Although spectinomycin may be
an important antimicrobial agent in the treatment
of gonococcal keratoconjunctivitis, further studies
are needed.
C. THE CEPHALOSPORINS
Recently developed “third generation” semi-
synthetic beta-lactam antibiotics are characterized
by their resistance to beta-lactamases, their broad
spectrum of activity, and relative safety. Their
mechanism of action is similar to that of penicillin,
and involves the inhibition of bacterial cell-wall
synthesis. They are bactericidal. Individual cepha-
losporins differ in their susceptibility to beta-lacta-
mases, antibacterial spectrum, and pharmacokinet-
ic properties. There is no present evidence that the
cephalosporins produce fetal toxicity or teratogeni-
city, but clinical experience has been limited.38@ In
general, first-generation cephalosporins (cephalori-
dine, cephalothin, cefazolin, and cephalexin) are
less active by weight than second-generation cepha-
losporins (cefamandole, cefuroxime, cefonicid, and
cefaclor) against N. gonorrhoeae.67 The third-genera-
tion cephalosporins (ceftriaxone, cefotaxime, cefti-
zoxime, and cefoperazone) are the most active beta-
lactam antibiotics against N. gonorrhoeae.”
203
There is a good correlation between in vitro activ-
ity of the cephalosporins against N. gonorrhoeae and
clinical efficacy. 67 Single-dose therapy with lirst-
generation cephalosporins results in unacceptably
low cure rates (< 90%) in gonococcal urethritis and
should therefore not be used for ocular infections.
The second-generation cephalosporins generally
show good clinical efficacy for gonococcal infec-
tions. Cefoxitin, a semisynthetic cephamycin, has
been studied most extensively and has been shown
to be effective as a single-dose therapy against peni-
cillinase-producing gonococcal urethritis.g,48,75 Ce-
foxiten is, however, no longer recommended for the
treatment of penicillinase-producing gonococcal
urethritis because of increasing resistance. Cases of
gonococcal conjunctivitis treated effectively with
single dose intramuscular cefoxiten have been re-
ported. 74,81Cefoxiten, and the second-generation ce-
phalosporins, are relatively ineffective for gonococ-
cal pharyngitis and incubating syphilis.40 In
addition, they are ineffective against chlamydial
disease.‘j’
Ceftriaxone (Rocephin@), a third-generation ce-
phalosporin, has properties which suggest it may be
the best available antimicrobial agent for gonococ-
cal keratoconjunctivitis. 5’.66,goIts long plasma half-
life (approximately eight hours), beta-lactamase
stability, and excellent in vitro activity against N.
gonorrhoeae are important attributes. N. gonorrhoeae
isolates from Africa, whether beta-lactamase-posi-
tive or -negative, have been sensitive to < 0.12
ug/ml of ceftriaxone. 57A single intramuscular dose
of 500 mg produces a mean peak serum level of
42-56 ug/ml in healthy adults.W After one gram of
intravenous ceftriaxone, a mean peak aqueous hu-
mor concentration of 0.93 micrograms/ml was not-
ed approximately two hours after administration,
with mean levels of 0.88 micrograms/ml about 12
hours after administration.6 Ceftriaxone has been
shown to be a safe and effective agent when admin-
istered intravenously to children with severe infec-
tions.3 Multiple clinical studies have shown the im-
pressive success of ceftriaxone in eradicating N.
gonorrhoeae from all mucosal sites.24 As little as 125
mg of ceftriaxone cured 100% of 52 anorectal gono-
coccal infections and 94% of 32 pharyngeal infec-
tions5* Single-dose ceftriaxone therapy is not effec-
tive against concomitant Chlamydia trachomatis
infection. Allergic or other adverse drug reactions
are not known to occur any more or less frequently
with ceftriaxone than with other cephalosporins.
Ceftriaxone should not be used in any patient with a
history of an allergic reaction to penicillin.
In a preliminary study, Haase and coworkers
showed that ceftriaxone was an effective antimicro-
bial agent for single-dose therapy of gonococcal
204 Surv Ophthalmol 3!2(3) November-December 1987 ULLMAN ET AL

ophthalmia secondary to both penicillinase produc- The potential serious toxicity of kanamycin limits
ing and non-penicillinase producing N. gonorrhoeae.3g its widespread use. Most notable is ototoxicity (both
Laga and coworkers conducted a randomized clini- the auditory and vestibular functions of the eighth
cal trial utilizing a single intramuscular dose of 125 cranial nerve) and nephrotoxicity. Both of these un-
mg of ceftriaxone for gonococcal ophthalmia neona- toward effects are dose and duration dependent and
torum. They demonstrated a 100% cure rate in the would therefore be unlikely in a single-dose regi-
61 infants who received the ceftriaxone. Thirty-one men. In addition, the apparent need for topical
(51%) of the isolates were PPNG. In addition, it treatment with parenteral kanamycin and its rela-
was extremely effective in eradicating extraocular tive ineffectiveness for extraocular gonococcal infec-
gonococcal infections (nasopharyngeal infections). tions (nasopharyngeal) make it less than an ideal
Zajdowicz and coworkers reported a case of labora- regimen. Because of the lack of information avail-
tory acquired adult gonococcal conjunctivitis that able and potential serious toxicity, kanamycin can-
responded dramatically to 1.0 gram of ceftriax- not be recommended for the routine treatment of
one.l16 The efficacy of ceftriaxone in the treatment of gonococcal keratoconjunctivitis.
incubating syphilis is unknown. Johnson and
coworkers have shown that ceftriaxone may be ef-
fective against experimentally induced syphilis in IV. Treatment Recommendations
rabbits.47 Specific therapeutic recommendations for gono-
The high level of in vitro activity against penicil- coccal keratoconjunctivitis must be based on incom-
linase-producing and nonpenicillinase-producing plete information and are therefore empiric and in-
N. gonorrhoeae, along with its prolonged half-life, and tuitive. Initial treatment should be modified by the
safety, make ceftriaxone the preferred drug for the clinical response and culture results. These recom-
treatment of gonococcal keratoconjunctivitis. mendations should not be construed as rules but
rather as general guidelines from which the treating
D. OTHER ANTIMICROBIAL AGENTS ophthalmologist should individualize care. In all
Other antimicrobial agents, including tetracy- cases, cultures prior to antimicrobial therapy and follow-up
cline, doxycycline, thiamphenicol, ampicillin, cultures after treatment to document cure should beperformed.
amoxicillin, erythromycin, trimethoprim/sulfa- Patients should be examined daily until the infec-
methoxazole, amikacin, and tobramycin have been tion has resolved. No patient should be considered
used successfully in the treatment of genital gono- adequately treated until he has been counseled re-
coccal infections.56,62~6g~g7~104 Anecdotal case reports garding his disease and his sexual partners have
have noted success with some of these agents in been properly dispositioned. Pregnancy testing
gonococcal keratoconjunctivitis.g5 However, none of should be routinely performed on all sexually active
these agents have been subjected to controlled clini- females.
cal studies for the treatment of gonococcal kerato- Since other sexually transmitted diseases may fre-
conjunctivitis. In addition, the need for patient quently coexist, all patients should have serology for
compliance with an oral regimen and/or the limited syphilis performed. If serology for syphilis is posi-
efficacy of these antimicrobial agents preclude their tive, the patient should be treated in the customary
use as the initial drug of choice in gonococcal kera- fashion (intramuscular benzathine penicillin G). In
toconjunctivitis. addition, because gonococcal and chlamydial infec-
Kanamycin, an aminoglycoside, has been shown tions commonly coexist (up to 32% of men with
in clinical studies to be efficacious in ophthalmia urethral gonorrhea and 63% of women with endo-
neonatorum due to penicillin-sensitive and penicil- cervical gonorrhea) and isolation techniques for
lin-resistant N. gonorrhoeae.34,57J02 Fransen and co- chlamydia are not readily available, we recommend
workers successfully used single-dose kanamycin in empiric treatment with an oral antimicrobial agent
combination with topical gentamicin in gonococcal effective for Chlamydia trachomatis.35~44~50~72~g2~g7 This
ophthalmia neonatorum. 34Interestingly, they noted oral regimen is in addition to the parenteral therapy
an unacceptable failure rate when topical gentami- for the gonococcal infection. Fransen and cowork-
tin was excluded. Laga and coworkers recently ers, in a series of 117 infants with gonococcal oph-
showed that single dose parenteral kanamycin (75 thalmia neonatorum, noted postgonococcal chla-
mg) plus topical tetracycline or gentamicin was ef- mydial conjunctivitis in 14 (12%) infants.34 Scott
fective in the treatment of gonococcal ophthalmia and coworkers, reported a case in which C. trachoma-
neonatorum.57 They noted this regimen was less tis was the etiologic agent of postgonococcal con-
than optimal for nonocular sites of gonococcal infec- junctivitis in an adolescent female.8g These reports
tion and inferred it was not as effective as parenteral suggest an association between gonococcal and
ceftriaxone. chlamydial ocular infections.
GONOCOCCAL RERATOCONJUNCTIVITIS 205

TABLE 2 TABLE 3

Authors’ Recommendation: Treatment af Comcoccat Ophthalmia in Authors’ Recommendation - Treatment of Gonocwcal ophthalmia
Adults in Neonates
Conjunctivitis: Conjunctivitis:
Ceftriaxone 1.O gram intramuscularly (one dose) Ceftriaxone 50 mg/kg intramuscularly (one dose)
In penicillin allergic patients: In penicillin allergic neonates:
Spectinomycin 2.0 grams intramuscularly (one dose) Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours
Keratoconjunctivitis: for 3 days
Ceftriaxone 1.0 gram intravenously every 12 hours for 3 Keratoconjunctivitis:
days Ceftriaxone 25-40 mg/kg intravenously every 12 hours
In penicillin allergic patients: doses for 3 days
Spectinomycin 2.0 grams intramuscularly every 12 In penicillin allergic neonates:
hours for 2 days. Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours
Concurrent treatment with: for 3 davs
Topical Saline Lavage AND Topical Erythromycin Oint- Concurrent tre6tment with:
ment OR Gentamicin Ointment OR Bacitracin Oint- Topical Saline Lavage AND Topical Erythromycin Oint-
ment 4 times daily. ment OR Gentamicin Ointment OR Bacitracin Oint-
AND Treatment for Chlamydia trachomatis infection with: ment 4 times daily
Tetracycline hydrochloride 500 mg by mouth 4 times daily AND Treatment for Chhmydia trachomatis infection with:
for 14 days Oral erythromycin syrup 50 mg/kg/day in 4 divided doses
OR for 14 davs
Doxycycline 100 mg by mouth twice daily for 14 days

(for patients in whom tetr?&line contraindicated)

Erythromycin base or stearate 500 mg by mouth 4 times
dailv for 14 davs
Our recommendations for the treatment of gono-
coccal ophthalmia in adults is shown in Table 2.
The table does not include antibiotic sensitivities
because initial treatment decisions must be made
without the benefit of these results. Obviously, as
culture results become known, treatment should be
modified accordingly. The possibility of rapid pro-
gression, resulting in a severe ulcerative keratitis
and visual loss, necessitates that the most effective,
safe, parenteral antimicrobial agent be used at all
times in a therapeutically effective dose. Because of
the increasing prevalence of N. gonorrhoeae isolates
resistant to penicillin, erythromycin, tetracycline,
and ampicillin, we do not recommend initial treat-
ment of conjunctivitis with these antimicrobial
agents. In patients with isolated conjunctival dis-
ease, without preexisting ocular disease or immuno-
suppression, we feel that out-patient treatment with
ceftriaxone and daily examinations is sufftcient. The
1.O gram dose of ceftriaxone may seem high consid-
ering the efficacy of 125 mg in gonococcal genital
infections. However, we feel this dose is appropriate
considering the potential complications of gonococ-
cal conjunctivitis, the belief that using “supra-
therapeutic dosages” may inhibit the selection of
drug-resistant mutants, and the few adverse effects
associated with this dose. If compliance with daily
follow-up is in doubt or if disease progression is
noted, the patient should be hospitalized.
In penicillin-allergic patients, since other antimi-
crobial regimens may not be as effective, the treat-
ing ophthalmologist must be as certain as possible
that a penicillin allergy exists before abandoning
ceftriaxone. In penicillin allergic patients, intra-
muscular spectinomycin (2.0 grams) should be
used. Until more experience with spectinomycin in
gonococcal conjunctivitis is obtained, we recom-
mend hospitalization initially until clinical im-
provement is noted and culture and sensitivity re-
sults are known.
Cornea1 involvement is a poor prognostic sign
and requires hospitalization and emergent ther-
apy. “,‘08 Isolated punctate epithelial cornea1 stain-
ing is usually attributed to the toxic effects of the
purulent discharge, not to active cornea1 infection.
Transient marginal subepithelial infiltrates, similar
in appearance to an immune-mediated hypersensi-
tivity phenomenon, have also been described in as-
sociation with gonococcal conjunctivitis.105,‘06 Pa-
tients with an epithelial defect, stromal infiltrate, or
stromal thinning should be considered to have an
infectious keratitis and treated emergently with par-
enteral antibiotics. Intravenous ceftriaxone, which
provides rapid, high peak serum levels is recom-
mended for these patients. The necessary duration
of intravenous therapy has not been established.
Treatment should be based on clinical response and
culture results. Empirically, we recommend at least
three days of intravenous therapy for these patients.
The optimal treatment for penicillin-allergic adults
with gonococcal keratitis is unknown. Treatment
with 2.0 grams of spectinomycin intramuscularly
every twelve hours is recommended. As with intra-
venous ceftriaxone, the optimal duration of therapy
206 Surv Ophthalmol 32(3) November-December 1987 ULLMAN ET AL

is not known and must be individualized. 6. Axelrod JL, Newton JC, Sarakhum C, et al: Ceftriaxone. A
new cephalosporin with aqueous humor levels effective against
Our treatment recommendations of neonatal
Enterobacteriaceae. Arch Ophthalmol103:71-72, 1985
gonococcal conjunctivitis is shown in Table 3. 7. Baker FJ, Wood DR: Adult gonococcal ophthalmia. South Med
These recommendations are based largely on sever- J 77:800-801, 1984
8. Berg SW: Spectinomycin as primary treatment ofgonorrhea in
al studies on the single-dose therapy of gonococcal
areas of high prevalence of penicillinase-producing Neissereia
ophthalmia neonatorum with ceftriaxone.3g,57 Out- gonorrhoeae.Sex Transm Dis 8338-39, 1981
patient single-dose intramuscular ceftriaxone ther- 9. Berg SW, Kilpatrick ME, Harrison WO, McCutchan JA: Ce-
foxitin as a single-dose treatment for urethritis caused by peni-
apy in conjunction with daily examinations is sufli-
cillinase-producing Neisseria gonowhoeae. N Engl J Med 301:
cient in the neonate with uncomplicated gonococcal 509-511, 1979
conjunctivitis. 10. Brook I, Bateman B, Pettit TH: Meningococcal conjunctivitis.
Arch Ophthalmol.97:890-891, 1979
All neonates with cornea1 involvement should be 11. Brown J, Lucas CT, Kuhn USG: Gonorrhoeae in the chimpan-
hospitalized and treated emergently with intrave- zee infection with laboratory-passed gonococci and by natural
nous ceftriaxone (50-80 mg/kg/day in two divided transmission. Br J Vmcr Dis 48: 177-l 78, 1972
12. Brown S, Biddle J, Warnnissorn T, et al: Antimicrobial resis-
doses). The optimal duration of therapy has not tance of Netiseria gonorrhoeaein Bangkok: Is single-drug treat-
been established; however, we empirically suggest a ment passe? Lancet 1:1366-1368, 1982
minimum of three days of therapy (6 doses). Ther- 13. Bruins SC, Tight RR: Laboratory-acquired gonococcal con-
junctivitis. JAMA 241:274, 1979
apy can then be adjusted based on the clinical 14. Centers for Disease Control: Table 1. Summary - Cases of
course and culture results. specified notiticable diseases, United States. MMWR 34:782,
In the extremely rare case of gonococcal ophthal- 1986
15. Centers for Disease Control: Penicillinase-producing Neisseria
mia neonatorum in which ceftriaxone is contraindi- gonowhoeae- United States, Florida. MMWR 3512-14, 1986
cated, we recommend consultation with an infec- 16. Centers for Disease Control: Penicillin-resistant gonorrhea -
tious disease expert. Empirically, we recommend North Carolina. MMWR 32:273-275, 1983
17. Centers for Disease Control: Chromosomally mediated resis-
three days of intravenous gentamicin in appropriate tant Neisscriagonorrhoeae- United States. MMWR33:408-410,
pediatric dosages in these cases. 1984
Additional studies are needed to confirm and re- 18. Centers for Disease Control: Infections due to penicillinase-
producing Neisseriagonowhoeaein the United States: 1976-1980.
line these recommendations for the treatment of JZnfect Dis 144:191-196, 1981
gonococcal keratoconjunctivitis. Considering the 19. Centers for Disease Control: Gonococcal eye infections in
proliferation of N. gonorrhoeae isolates resistant to adults - California, Texas, Germany. MMWR 30:341-343,
1981
various antimicrobial agents, the need for cost con- 20. Centers for Disease Control: Spectinomycin-resistant Neisseria
tainment, and pharmacologic advances, the treat- gonorrhoeae- worldwide. MMWR 31:637-638, 1982
ment regimen of choice has become less clearcut. 21. Centers for Disease Control: Tetracycline-resistant Neisseria
gonorrhoeae - Georgia, Pennsylvania, New Hampshire.
The necessity for periodic review of drug efficacy MMWR 34:563-570, 1985
and toxicity in the treatment of ocular infections 22. Centers for Disease Control: 1985 STD treatment guidelines.
secondary to N. gonorrhoeae cannot be overempha- MMWR 34~8 1S-9OS, 1985
23. Centers for Disease Control: Table 1 Summary- Cases speci-
sized. Undoubtedly, new recommendations will be- lied notifiable diseases, United States. MMWR 3.5~810, 1987
come necessary in the future as antibiotic resistance 24. Collier AC, Judson FN, Murphy VL, et al: Comparative study
problems evolve and new antimicrobial agents be- of ceftriaxone and spectinomycin in the treatment of uncompli-
cated gonorrhea in women. Am J Med 77 (Suppl 4C):6%72,
come available. 1984
25. Coovadia VM, Krarsany A, Ramsaroop U: Antimicrobial sus-
Acknowledgment ceptibility of N&&a gonorrhoeae isolated in Durban, South
The authors are indebted to Dr. Jonathan M. Zenilman Africa. Br J Vener Di.s 60:30&308, 1984
26. Curtis FR, Wilkinson AE: A comparison of the in vitro sensi-
for his editorial assistance and critical review of the manu-
tivity ofgonococci to penicillin with the results of treatment. Br
script.
J Vener Dis 34:70-82, 1958
27. Dillon HC: Prevention ofgonococcal ophthalmia neonatorum.
N Engl J Med 31.5:1414-1415, 1986
28. Doraiswamy
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