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Gonococcal keratoconjunctivitis
SURVEY OF OPHTHALMOLOGY0
VOLUME 32 * NUMBER 3 * NOVEMBER-DECEMBER
THERAPEUTIC
REVIEW,
1987
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 Neiskeratitis resulting in visual loss. The therapeutic decision making process is complicated by the necessity for prompt, effective parenteral therapy, frequent coinfection with other sexually transmitted diseases, and emergence of antibiotic 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 conjunctivitis. Spectinomycin may be a useful alternative in the penicillin-allergic adult patient. (Surv Ophthalmol 32:199-208, 1987) keratoconjunctivitis
seria gonort-hoeae can cause a rapid, severe, ulcerative
Key words. penicillin l
ceftriaxone spectinomycin
l
gonococcal
keratoconjunctivitis
Despite effective antimicrobial agents, public health intervention, and improved health education efforts, gonorrhea incidence remains high.‘* In 1986 over 900,000 cases of gonorrhea in the United States were reported to the Centers for Disease Control.23 It is estimated that less than half of all cases are reported; therefore, a more accurate estimate of the annual incidence is approximately two million cases. The incidence of gonococcal conjunctivitis in adults is estimated at one per 700-800 cases of gonorrhea. 42Therefore, the incidence of gonococcal conjunctivitis may be as high as 2000 cases annually. Gonococcal keratoconjunctivitis is a potentially devastating infection because of the ability of N. gonorrhoeae to cause a rapid, severe, ulcerative keratitis which may result in a cornea1 perforation.30@ Studies have shown that with prompt, effective parenteral antibiotics this infection can be eradicated and complications avoided.4’~ggJ08 A presumptive diagnosis of gonococcal conjunctivitis is made when a hyperpurulent conjunctivitis is associated with in-
l
Neisseria gonorrhoeae
l
tracellular gram-negative diplococci on gram stain (Figs. 1 and 2). However, since N. meningitidies, Branhamella catarrhalis, and Acinetobacter calcoaceticus can present with similar clinical and gram stain findings, definitive cultures and sensitivities are mandatory in all cases.‘0~43~60J0gJ’2The laboratory characteristics and diagnostic techniques of gonococcal infections have been reviewed elsewhere.36J’i Bacterial keratoconjunctivitis is usually treated with regional antibiotics (both topical and subconjunctival) modified by culture results. Gonococcal keratoconjunctivitis, however, is unique in several respects. Gonococcal keratoconjunctivitis requires parenteral antimicrobial agents and its course can progress rapidly. g5,‘ooFrequently, coinfection with other sexually transmitted diseases is present.35,50*57 These factors, coupled with emerging antibiotic resistance, have complicated the therapeutic decisionmaking process. The rapidity and potential severity of this infection necessitates treatment before culture and sensitivity results are known. Unfortunately, this initial empiric treatment must be based on 199
Surv Ophthalmol
32( 3) November-December
1987
ULLMAN
Fig. 2. Numerous Fig. 1. Typical clinical appearance of a purulent tivitis secondary to N. gonorrhoeae.
conjunc-
inadequate clinical and experimental information. This article will review the historical aspects and current literature on the medical treatment of gonococcal keratoconjunctivitis. Only empirically derived guides for therapy can be recommended because of the paucity of clinical data. Prophylaxis for ophthalmia neonatorum and the surgical management of infectious keratitis have been reviewed elsewhere and will not be addressed in this article 2,27Z%37~85~~10
I. Historical
Background
Allusions to gonorrhea may have been made in the Book of Leviticus. Galen ( 130 AD), referring to the urethral discharge of men with urethritis, first used the term gonorrhea, meaning “a flow of seed.” In 1879, Neisser identified the gonococcus, and Bumm cultivated the bacteria in vitro by 1885. Karl Crede’ (early 1880s) experimented with topical silver nitrate to prevent gonococcal ophthalmia neonatorum. In 1939 sulfonamides were introduced to the physicians’ armamentarium. During World War II, sulfonamide resistant strains of gonococcus were encountered. Fortunately, penicillin was developed at this time and quickly became the drug of choice for gonorrhea. Still, the diagnosis of gonorrhea was difficult because of the problems in obtaining a pure culture. In 1964, Thayer and Martin developed an antibiotic selective medium that allowed the pathogenic species N. gonorrhoeae and N. meningitidis to grow.‘O’ In 1972, in response to a precipitous increase in incidence and relative resistance of the gonococcus to penicillin, the federal government financed state efforts to control gonorrhea. Beta-lactamase-producing N. gonorrhoeae (PPNG) were first discovered
intracellular
and extracellular
ET AL
gram-
negative diplococci in association with acute inflammatory cells. (Hematoxylin and Eosin)
in 1976, and have become important pathogens in many parts of the world. 6,76Chromosomally-mediated resistance (CMRNG) to penicillin and tetracycline was first reported in the United States in 1983.‘6J7 CMRNG is relatively difficult to diagnosis because it requires performing formal susceptibility testing on gonococcal isolates. In 1985, plasmidmediated tetracycline resistance (TRNG) was first described.21@’ The implications of this strain on tetracycline prophylaxis of the newborn are unknown.
II. General
Considerations
In addition to the general criteria ofsafety, ease of administration, compliance, and cost, three other important factors are important in the selection of a treatment regimen for gonococcal keratoconjunctivitis: the prevalence of PPNG and other antibioticresistant strains in their community, the possibility of concomitant nongonococcal infection, and the rapidity in which gonococcal keratoconjunctivitis can progress. Because man is the only natural reservoir of N. gonorrhoeae, no reproducible experimental animal model exists for gonococcal conjunctivitis.“,58 Infection with the gonococcus results in little, if any, immunity to reinfection. Reinfection, therefore, is a common cause of apparent treatment failure. Persistence of a concomitant nongonococcal infection (i.e., Chlamydia trachomatis conjunctivitis) is another cause of apparent treatment failure.ag Treatment failure may be due to antibiotic resistance (PPNG or CMRNG), poor compliance, or the inability of the antibiotic to reach inhibitory concentrations at the site of infection.40,4g,82,g6 The paramount concern in the treatment of gonococcal keratoconjunctivitis is the evolution and
GONOCOCCAL
201
KERATOCONJUNCTIVITIS TABLE
Current Recommendations -
1
Centers for Disease Control*
Gonococcal Ophthalmia in Adults Aqueous penicillin G 10 million units intravenously daily for 5 days For PPNG Infections: Cefotaxime 500 mg intravenously 4 times daily for 5 days OR Ceftriaxone 1.O gram intramuscularly or intravenously daily for 5 days Gonococcal Ophthalmia in Neonates Aqueous penicillin G 100,000 units/kg/day intravenously in 4 divided doses for 7 days For PPNG infections: Cefotaxime or gentamicin intravenously in appropriate neonatal doses. *From the Centers for Disease Control: ment Guidelines: MMWR 34:75S, 1985.
1985 STD Treat-
spread of strains of N. gonorrhoeae with diminished susceptibility to antimicrobial agents.‘*~83~“3~“4~“5~“7 The gonococcus has demonstrated the capacity to develop relative or absolute resistance to the penicillins, tetracyclines, sulfonamides, aminoglycosides, and other antimicrobial drugs.‘2,g3 Resistance occurs through a chromosomally mediated mechanism (CRMNG) or the acquisition of plasmids bearing genes coding for beta-lactamase.25,64@ In CMRNG strains, the organism’s outer membrane is less permeable to the antimicrobial agents. This change often simultaneously confers relative resistance to several antimicrobial agents (penicillins, tetracyclines, and erythromycin). Plasmid-mediated (PPNG) resistance to the penicillins and some cephalosporins are noted in the organisms that produce beta-lactamase which breaks down penicillin extracellularly. 32,33 Plasmid-mediated tetracycline resistance affects ribosomal binding of tetracycline? The recommendations of the Centers for Disease Control (CDC) for treatment of gonococcal ocular infections as of April, 1987, are shown in Table 1 .22 These recommendations are not based on controlled clinical studies and are similar to the treatment regimen for disseminated gonococcal infections.‘03 These treatment recommendations are independent of the severity of the ocular infection (whether there is cornea1 involvement or not). Most cases of gonococcal conjunctivitis are believed to be due to inoculation of the conjunctiva with infected genital secretions, either directly or via contaminated lingers. ‘g.74.‘oo We feel this mechanism differs from “classic” hematogenously disseminated gonococcal disease (arthritis-dermatitis syndrome, endocarditis, meningitis). Reports of laboratory-acquired
gonococcal conjunctivitis and conjunctivitis after ocular contamination with urine support this hypothesis.‘~‘3~‘07~“6 I n patients with a gonococcal ocular infection without cornea1 involvement, we believe hospitalization and intravenous therapy may be unnecessary. Case reports and our own experience indicate that gonococcal conjunctivitis responds promptly to intramuscular antibiotics, similar to other localized mucosal gonococcal infection (i.e., urethritis, cervicitis) .3g.57,74~‘06.“6 If out-patient therapy is contemplated for gonococcal conjunctivitis, a single dose regimen that ensures patient compliance is necessary. In addition, daily ocular examinations until the infection is eradicated is mandatory. If there is doubt about compliance with follow-up examinations, or if disease progression is noted (cornea1 involvement), the patient should be hospitalized. We recommend hospitalization for patients with either preexisting ocular disease, cornea1 involvement, or immunocompromised states.
III. Topical Therapy After the introduction of penicillin, there were enthusiastic reports of gonococcal ocular infections treated solely with topical penicillin.g4 These initial studies were inadequate because clinical and not microbiologic cure were shown, and extraocular infected sites were not examined. Subsequent studies have found that topical treatment may transiently alleviate the signs of the conjunctivitis without eradicating the infection.7g,86 Moreover, topical therapy will not affect any extraocular sites of infection. Topical antimicrobial agents may be used in addition to parenteral therapy. They have no role in the primary treatment of gonococcal infections and some experts feel they are superfluous when appropriate parenteral therapy is given.’ Many clinical studies have shown that topical antimicrobial agents are not necessary when parenteral therapy is used. However, Fransen and coworkers, in assessing the efficacy of single-dose kanamycin therapy for gonococcal ophthalmia neonatorum, reported an increased cure rate with the addition of topical gentamicin ointment when compared with the kanamycinlsaline eye wash regimen.34 We recommend adjunctive irrigation with approximately 50 cc of saline every hour as needed to remove the possibly toxic purulent conjunctival discharge. Since topical therapy delivers a large concentration of antibiotic locally without great risk of systemic side effects, and some studies suggest that it may be of benefit, we recommend the use of an antibiotic ointment four times daily. Antibiotic selection should be based upon the culture results, cost, toxicity, and availability. Topical gentamicin,
202
Surv Ophthalmol
32(3) November-December
erythromycin, or bacitracin are reasonable choices. Because of the frequent bulbar conjunctival chemosis, and subsequent cornea1 dellen formation with irritation, we feel an antibiotic ointment may provide more patient comfort than antibiotic drops. Patients with unilateral disease should be cautioned not to inoculate the uninvolved eye when applying the topical antimicrobial ointment. In patients with severe cornea1 thinning or an actual perforation, the eye should be manipulated as little as possible. We therefore do not recommend topical antibiotics or saline lavage when the integrity of the globe is in question.
A. PENICILLIN
1987
ULLMAN
ET AL
They found that from 1982 thru 1986, seven of the 43 (16%) cases of gonococcal conjunctivitis were penicillin resistant. The need for hospitalization and live days of intravenous penicillin to eradicate gonococcal ocular infections has never been proven. This infection generally results from inoculation of the conjunctiva with infected genital secretions, not from hematogenously disseminated disease.1g,74J00 Since gonococcal conjunctivitis most likely represents a localized mucosal infection, similar to goncococcal urethritis, a single-dose treatment with an effective antibiotic should be effective. Recent studies in the treatment of gonococcal ophthalmia neonatorum and case reports of adult gonococcal ophthalmia suggest that single-dose therapy is effective.3ga57,74,“6
Until recently, aqueous procaine penicillin G (APPG), a bactericidal beta-lactam antibiotic, has B. SPECTINOMYCIN been the basis of treatment of gonococcal infections. 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 antibiof 20 years, N. gonorrhoeae isolates with increasing otics. It is poorly absorbed from the gastrointestinal resistance to penicillin have been found, necessitattract but is well absorbed when given intramuscuing 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 inhibadult results in blood levels of about 100 microits the active secretion of penicillin by the renal grams/ml one hour after injection.63 Spectinomycin tubules and therefore results in higher and proinhibits 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 gonoThe 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 oroThis regimen is independent of the severity of the pharyngeal infection may relate to failure of the ocular disease and has not been subjected to conantibiotic to be secreted into saliva in inhibitory trolled clinical studies. Multiple reports, which uticoncentrations. 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 spectinopenicillin-sensitive gonococcal keratoconjunctiviisolates that are penicillin-remycin. 45 Gonococcal tis.7J3~g8J00J08 In addition, this regimen will also cure sistant are no more likely to be resistant to spectinoincubating syphylis, is not teratogenic, assures commycin than isolates that are penicillin-sensitive.70 pliance, and is effective against gonococcal infecSpectinomycin-resistant N. gonorrhoeae was first nottions of all sites.38,87 ed in Denmark in 1973.84 Additional cases have subThe paramount concern with the use of intravesequently been reported in the United States, but nous penicillin for the treatment of gonococcal kerathe incidence remains rare.4,20,53,78 In 1985-l 986, toconjunctivitis is the proliferation of antibiotic rethere were nine confirmed cases of spectinomycinsistant 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 toldata). Numerous case reports have documented the erate spectinomycin well. Spectinomycin appears to occurrence of ocular infections secondary to N. gonbe 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 suggest that spectinomycin poses a threat to the fetus.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 Chlamydia trachomatis.50 The use of spectinomycin for gonococcal urethritis has increased in areas where antibiotic-resistant gonorrhea is prevalent. No studies have been performed 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 reported a case of PPNG conjunctivitis treated unsuccessfully with two grams of intramuscular spectinomycin daily for two days; on the fourth day a clinical relapse was noted, suggesting this therapy was inadequate.8’ The high failure rate of spectinomycin in oropharyngeal gonorrhea illustrates the problem of extrapolating the results of urethritis treatment to other 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” semisynthetic 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 cephalosporins differ in their susceptibility to beta-lactamases, antibacterial spectrum, and pharmacokinetic properties. There is no present evidence that the cephalosporins produce fetal toxicity or teratogenicity, but clinical experience has been limited.38@ In general, first-generation cephalosporins (cephaloridine, cephalothin, cefazolin, and cephalexin) are less active by weight than second-generation cephalosporins (cefamandole, cefuroxime, cefonicid, and cefaclor) against N. gonorrhoeae.67 The third-generation cephalosporins (ceftriaxone, cefotaxime, ceftizoxime, and cefoperazone) are the most active betalactam antibiotics against N. gonorrhoeae.”
203 There is a good correlation between in vitro activity of the cephalosporins against N. gonorrhoeae and clinical efficacy. 67 Single-dose therapy with lirstgeneration 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 infections. Cefoxitin, a semisynthetic cephamycin, has been studied most extensively and has been shown to be effective as a single-dose therapy against penicillinase-producing gonococcal urethritis.g,48,75 Cefoxiten 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 reported. 74,81Cefoxiten, and the second-generation cephalosporins, are relatively ineffective for gonococcal pharyngitis and incubating syphilis.40 In addition, they are ineffective against chlamydial disease.‘j’ Ceftriaxone (Rocephin@), a third-generation cephalosporin, has properties which suggest it may be the best available antimicrobial agent for gonococcal keratoconjunctivitis. 5’.66,goIts long plasma halflife (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-positive 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 humor concentration of 0.93 micrograms/ml was noted 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 administered intravenously to children with severe infections.3 Multiple clinical studies have shown the impressive success of ceftriaxone in eradicating N. gonorrhoeae from all mucosal sites.24 As little as 125 mg of ceftriaxone cured 100% of 52 anorectal gonococcal infections and 94% of 32 pharyngeal infections5* Single-dose ceftriaxone therapy is not effective 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 antimicrobial agent for single-dose therapy of gonococcal
204
Surv Ophthalmol
3!2(3) November-December
ophthalmia secondary to both penicillinase producing and non-penicillinase producing N. gonorrhoeae.3g Laga and coworkers conducted a randomized clinical trial utilizing a single intramuscular dose of 125 mg of ceftriaxone for gonococcal ophthalmia neonatorum. They demonstrated a 100% cure rate in the 61 infants who received the ceftriaxone. Thirty-one (51%) of the isolates were PPNG. In addition, it was extremely effective in eradicating extraocular gonococcal infections (nasopharyngeal infections). Zajdowicz and coworkers reported a case of laboratory acquired adult gonococcal conjunctivitis that responded dramatically to 1.0 gram of ceftriaxone.l16 The efficacy of ceftriaxone in the treatment of incubating syphilis is unknown. Johnson and coworkers have shown that ceftriaxone may be effective against experimentally induced syphilis in rabbits.47 The high level of in vitro activity against penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae, along with its prolonged half-life, and safety, make ceftriaxone the preferred drug for the treatment of gonococcal keratoconjunctivitis. D. OTHER
ANTIMICROBIAL
AGENTS
Other antimicrobial agents, including tetracythiamphenicol, ampicillin, cline, doxycycline, trimethoprim/sulfaamoxicillin, erythromycin, methoxazole, amikacin, and tobramycin have been used successfully in the treatment of genital gonococcal infections.56,62~6g~g7~104 Anecdotal case reports have noted success with some of these agents in gonococcal keratoconjunctivitis.g5 However, none of these agents have been subjected to controlled clinical studies for the treatment of gonococcal keratoconjunctivitis. In addition, the need for patient compliance with an oral regimen and/or the limited efficacy of these antimicrobial agents preclude their use as the initial drug of choice in gonococcal keratoconjunctivitis. Kanamycin, an aminoglycoside, has been shown in clinical studies to be efficacious in ophthalmia neonatorum due to penicillin-sensitive and penicillin-resistant N. gonorrhoeae.34,57J02 Fransen and coworkers successfully used single-dose kanamycin in combination with topical gentamicin in gonococcal ophthalmia neonatorum. 34Interestingly, they noted an unacceptable failure rate when topical gentamitin was excluded. Laga and coworkers recently showed that single dose parenteral kanamycin (75 mg) plus topical tetracycline or gentamicin was effective in the treatment of gonococcal ophthalmia neonatorum.57 They noted this regimen was less than optimal for nonocular sites of gonococcal infection and inferred it was not as effective as parenteral ceftriaxone.
1987
ULLMAN
ET AL
The potential serious toxicity of kanamycin limits its widespread use. Most notable is ototoxicity (both the auditory and vestibular functions of the eighth cranial nerve) and nephrotoxicity. Both of these untoward effects are dose and duration dependent and would therefore be unlikely in a single-dose regimen. In addition, the apparent need for topical treatment with parenteral kanamycin and its relative ineffectiveness for extraocular gonococcal infections (nasopharyngeal) make it less than an ideal regimen. Because of the lack of information available and potential serious toxicity, kanamycin cannot be recommended for the routine treatment of gonococcal keratoconjunctivitis.
IV. Treatment
Recommendations
Specific therapeutic recommendations for gonococcal keratoconjunctivitis must be based on incomplete information and are therefore empiric and intuitive. Initial treatment should be modified by the clinical response and culture results. These recommendations should not be construed as rules but rather as general guidelines from which the treating ophthalmologist should individualize care. In all cases, cultures prior to antimicrobial therapy and follow-up cultures after treatment to document cure should beperformed. Patients should be examined daily until the infection has resolved. No patient should be considered adequately treated until he has been counseled regarding his disease and his sexual partners have been properly dispositioned. Pregnancy testing should be routinely performed on all sexually active females. Since other sexually transmitted diseases may frequently coexist, all patients should have serology for syphilis performed. If serology for syphilis is positive, the patient should be treated in the customary fashion (intramuscular benzathine penicillin G). In addition, because gonococcal and chlamydial infections commonly coexist (up to 32% of men with urethral gonorrhea and 63% of women with endocervical gonorrhea) and isolation techniques for chlamydia are not readily available, we recommend empiric treatment with an oral antimicrobial agent effective for Chlamydia trachomatis.35~44~50~72~g2~g7 This oral regimen is in addition to the parenteral therapy for the gonococcal infection. Fransen and coworkers, in a series of 117 infants with gonococcal ophthalmia neonatorum, noted postgonococcal chlamydial conjunctivitis in 14 (12%) infants.34 Scott and coworkers, reported a case in which C. trachomatis was the etiologic agent of postgonococcal conjunctivitis in an adolescent female.8g These reports suggest an association between gonococcal and chlamydial ocular infections.
GONOCOCCAL
205
RERATOCONJUNCTIVITIS TABLE
2
TABLE
3
Authors’ Recommendation: Treatment af Comcoccat Ophthalmia in Adults
Authors’ Recommendation -
Conjunctivitis: Ceftriaxone 1.O gram intramuscularly (one dose) In penicillin allergic patients: Spectinomycin 2.0 grams intramuscularly (one dose) Keratoconjunctivitis: Ceftriaxone 1.0 gram intravenously every 12 hours for 3 days In penicillin allergic patients: Spectinomycin 2.0 grams intramuscularly every 12 hours for 2 days. Concurrent treatment with: Topical Saline Lavage AND Topical Erythromycin Ointment OR Gentamicin Ointment OR Bacitracin Ointment 4 times daily. AND Treatment for Chlamydia trachomatis infection with: Tetracycline hydrochloride 500 mg by mouth 4 times daily for 14 days OR Doxycycline 100 mg by mouth twice daily for 14 days
Conjunctivitis: Ceftriaxone 50 mg/kg intramuscularly (one dose) In penicillin allergic neonates: Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours for 3 days Keratoconjunctivitis: Ceftriaxone 25-40 mg/kg intravenously every 12 hours doses for 3 days In penicillin allergic neonates: Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours for 3 davs Concurrent tre6tment with: Topical Saline Lavage AND Topical Erythromycin Ointment OR Gentamicin Ointment OR Bacitracin Ointment 4 times daily AND Treatment for Chhmydia trachomatis infection with: Oral erythromycin syrup 50 mg/kg/day in 4 divided doses for 14 davs
(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 gonococcal 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 progression, 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 treatment of conjunctivitis with these antimicrobial agents. In patients with isolated conjunctival disease, without preexisting ocular disease or immunosuppression, we feel that out-patient treatment with ceftriaxone and daily examinations is sufftcient. The 1.O gram dose of ceftriaxone may seem high considering the efficacy of 125 mg in gonococcal genital infections. However, we feel this dose is appropriate considering the potential complications of gonococthe belief that using “supracal conjunctivitis, 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-
Treatment of Gonocwcal ophthalmia in Neonates
crobial regimens may not be as effective, the treating ophthalmologist must be as certain as possible that a penicillin allergy exists before abandoning ceftriaxone. In penicillin allergic patients, intramuscular spectinomycin (2.0 grams) should be used. Until more experience with spectinomycin in gonococcal conjunctivitis is obtained, we recommend hospitalization initially until clinical improvement is noted and culture and sensitivity results are known. Cornea1 involvement is a poor prognostic sign and requires hospitalization and emergent therapy. “,‘08 Isolated punctate epithelial cornea1 staining 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 hypersensitivity phenomenon, have also been described in association with gonococcal conjunctivitis.105,‘06 Patients with an epithelial defect, stromal infiltrate, or stromal thinning should be considered to have an infectious keratitis and treated emergently with parenteral antibiotics. Intravenous ceftriaxone, which provides rapid, high peak serum levels is recommended 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 intravenous ceftriaxone, the optimal duration of therapy
206
Surv Ophthalmol
32(3) November-December
1987
is not known and must be individualized. Our treatment recommendations of neonatal gonococcal conjunctivitis is shown in Table 3. These recommendations are based largely on several studies on the single-dose therapy of gonococcal ophthalmia neonatorum with ceftriaxone.3g,57 Outpatient single-dose intramuscular ceftriaxone therapy in conjunction with daily examinations is suflicient in the neonate with uncomplicated gonococcal conjunctivitis. All neonates with cornea1 involvement should be hospitalized and treated emergently with intravenous ceftriaxone (50-80 mg/kg/day in two divided doses). The optimal duration of therapy has not been established; however, we empirically suggest a minimum of three days of therapy (6 doses). Therapy can then be adjusted based on the clinical course and culture results. In the extremely rare case of gonococcal ophthalmia neonatorum in which ceftriaxone is contraindicated, we recommend consultation with an infectious disease expert. Empirically, we recommend three days of intravenous gentamicin in appropriate pediatric dosages in these cases. Additional studies are needed to confirm and reline these recommendations for the treatment of gonococcal keratoconjunctivitis. Considering the proliferation of N. gonorrhoeae isolates resistant to various antimicrobial agents, the need for cost containment, and pharmacologic advances, the treatment regimen of choice has become less clearcut. The necessity for periodic review of drug efficacy and toxicity in the treatment of ocular infections secondary to N. gonorrhoeae cannot be overemphasized. Undoubtedly, new recommendations will become necessary in the future as antibiotic resistance problems evolve and new antimicrobial agents become available. Acknowledgment The authors are indebted to Dr. Jonathan M. Zenilman for his editorial assistance and critical review of the manuscript.
References 1. Alfonso E, Friedland B, Hupp S, et al: Ncicscria gonowhocac conjunctivitis. An outbreak during an epidemic of acute hemorrhagic conjunctivitis. JAMA 250:794-795, 1983 and treatment 2. American Academy of Pediatrics: Prophylaxis of neonatal gonococcal infections. Pediatrics 6.5:1047-1048, 1980 3. Aronoff SC, Murdell D, O’Briend CA, et al: Eficacy and safety of ceftriaxone in serious pediatric infections. Antimicro Agents Chcmother24:663-665, 1983 4. Ashford WA, Adams HJ, Johnson SR, et al: Spectinomycinresistant penicillinase-producing Neisseria gononhocae. Lancet 1:1035-1037, 1981 5. Ashford WA, Golash RG, Hemming VG: Penicillinase-producing Neisseria gonorrhoeae. Lancet 2:657-658, 1976
ULLMAN
ET AL
6. Axelrod JL, Newton JC, Sarakhum C, et al: Ceftriaxone. A new cephalosporin with aqueous humor levels effective against Enterobacteriaceae. Arch Ophthalmol103:71-72, 1985 7. Baker FJ, Wood DR: Adult gonococcal ophthalmia. South Med J 77:800-801, 1984 8. Berg SW: Spectinomycin as primary treatment ofgonorrhea in areas of high prevalence of penicillinase-producing Neissereia gonorrhoeae.Sex Transm Dis 8338-39, 1981 9. Berg SW, Kilpatrick ME, Harrison WO, McCutchan JA: Cefoxitin as a single-dose treatment for urethritis caused by penicillinase-producing Neisseria gonowhoeae. N Engl J Med 301: 509-511, 1979 10. Brook I, Bateman B, Pettit TH: Meningococcal conjunctivitis. Arch Ophthalmol.97:890-891, 1979 11. Brown J, Lucas CT, Kuhn USG: Gonorrhoeae in the chimpanzee infection with laboratory-passed gonococci and by natural transmission. Br J Vmcr Dis 48: 177-l 78, 1972 12. Brown S, Biddle J, Warnnissorn T, et al: Antimicrobial resistance of Netiseria gonorrhoeaein Bangkok: Is single-drug treatment passe? Lancet 1:1366-1368, 1982 13. Bruins SC, Tight RR: Laboratory-acquired gonococcal conjunctivitis. JAMA 241:274, 1979 14. Centers for Disease Control: Table 1. Summary - Cases of specified notiticable diseases, United States. MMWR 34:782, 1986 15. Centers for Disease Control: Penicillinase-producing Neisseria gonowhoeae- United States, Florida. MMWR 3512-14, 1986 16. Centers for Disease Control: Penicillin-resistant gonorrhea North Carolina. MMWR 32:273-275, 1983 17. Centers for Disease Control: Chromosomally mediated resistant Neisscriagonorrhoeae- United States. MMWR33:408-410, 1984 18. Centers for Disease Control: Infections due to penicillinaseproducing Neisseriagonowhoeaein the United States: 1976-1980. JZnfect Dis 144:191-196, 1981 19. Centers for Disease Control: Gonococcal eye infections in adults - California, Texas, Germany. MMWR 30:341-343, 1981 Neisseria 20. Centers for Disease Control: Spectinomycin-resistant gonorrhoeae- worldwide. MMWR 31:637-638, 1982 Neisseria 21. Centers for Disease Control: Tetracycline-resistant gonorrhoeae Georgia, Pennsylvania, New Hampshire. MMWR 34:563-570, 1985 22. Centers for Disease Control: 1985 STD treatment guidelines. MMWR 34~8 1S-9OS, 1985 Cases speci23. Centers for Disease Control: Table 1 Summarylied notifiable diseases, United States. MMWR 3.5~810, 1987 study 24. Collier AC, Judson FN, Murphy VL, et al: Comparative of ceftriaxone and spectinomycin in the treatment of uncomplicated gonorrhea in women. Am J Med 77 (Suppl 4C):6%72, 1984 25. Coovadia VM, Krarsany A, Ramsaroop U: Antimicrobial susceptibility of N&&a gonorrhoeae isolated in Durban, South Africa. Br J Vener Di.s 60:30&308, 1984 26. Curtis FR, Wilkinson AE: A comparison of the in vitro sensitivity ofgonococci to penicillin with the results of treatment. Br 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 B, Hammerschlag MR, Pringle GF, Bouchet L: Ophthalmia neonatorum caused by beta-lactamase-producing Neisseria gonowhoeae.JAMA 250:790-79 1, 1983 29. Du NJ, Chen JW, Gong XM, et al: Therapeutic keratoplasty in the management of purulent cornea1 ulceration - Report of 100 cases. Jpn J Ophthalmol23:412-420, 1979 30. Duke-Elder S: Diseases of the Outer Eye, System of Ophthalmology, Vol8, Part 2. St. Louis, CV Mosby, 1965, pp 167-174 31. Dunlop EM, Rodin P, Seth AD, Kolator B: Ophthalmia neonatorum due to beta-lactamase producing gonococci. Br Med J 1:281-483, 1980 32. Eisenstein BI, Sox T, Biswas G, et al: Conjugal transfer of the gonococcal penicillinase plasmid. Scicace 195:99&999, 1977 33. Elwell LP, Roberts M, Mayer LW, Falkow S: Plasmid-mediated beta-lactamase production in Neisseria gonowhoeac. Antimicrob Agents Chemother11:52%533, 1977
CONOCOCCAL
34. Fransen L, D’Costa L, Ronald AR, et al: Single-dose kanamytin therapy of gonococcal ophthalmia neonatorum. Lancet 2:1234-1236, 1984 35. Fransen L, Nsanze H, Klauss V, et al: Ophthalmia neonatorum in Nairobi, Kenya: The roles of Neisseria gonorrhocat and Chlamydia trachomatis. J Infect Dis 153:862-869, 1986 36. Freeman BA: Neisseria: The gram-negative pathogenic cocci, in Burrow (ed): Textbook of Microbiology. Philadelphia, WB Saunders, 1979, ed 21, pp 480-499 37. Friendly DS: Gonorrhea1 ophthalmia. Reappearance of an old problem. Tram Am Acad Ophthalmol Otolaryngol 74:97>983, 1970 38. Goodrich JT: Treatment of gonorrhea in pregnancy. Sex Transm Dis 6:168-173, 1979 39. Haase DA, Nash RA, Nsanze
gonococcal
ophthalmia
Med 315: 1382-1385,
H, et al: Single-dose therapy of neonatorum with ceftriaxone. N Engl J
1986
40. Handsfield
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43. 44.
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HH: Problems in the treatment of bacterial sexually transmitted diseases. Sex Transm Dis 13:17%184, 1986 Harbin T, Curran RE: Gonococcal conjunctivitis. Ann Ophthalmol5:221-224, 1974 Hausen T, Burns RP, Allen A: Gonorrhea1 conjunctivitis, an old disease revisited. JAMA 195: 1156, 1966 Heidemann DG, Alfonso E, Forster RK, et al: Branhamella Catarrhalis Keratitiis. Am J Ophthalmol 103:576-581, 1987 Hilton AL, Richmond SJ, Mime JD, et al: Chlamydia A in the female genital tract. Br J Vener Dis .50:1-9, 1974 Jaffe HW, Biddle JW, Thornsberry C, et al: National gonorrhea therapy monitoring study. In vitro susceptibility and its correlation with treatment results. N Engf JMed 294:>9, 1976 Jensen PE, Kvorning SA, Norredam K: Probenecid as an adjuvant in the treatment of gonorrhoeae with penicillin. Br J Vener
Dis 39:23%240, 1963 47. Johnson RC, Bey RF, Wolgamot
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SJ: Comparison of the activities of ceftriaxone and penicillin G against experimentally induced syphilis in rabbits. Antimicrob Agents Chemother 21:984989, 1982 Jones RB, Stimson J, Counts GW, Holmes KK: Cefoxitin in the treatment of gonorrhea. Sex Transm Dis 6:23%242, 1979 Jordan WC: Doxycycline vs. tetracycline in the treatment of men with gonorrhoeae: The compliance factor. Sex Transm Dis 8:105-109, 1981 Judson FN: The importance of coexisting syphilitic, chlamydial, mycoplasmal, and trichomonal infections in the treatment of gonorrhea. Sex Tranrm Dis 6: 112-l 19, 1979 Judson FN: Treatment of uncomplicated gonorrhea with ceftriaxone: A review. Sex Transm Dis 13:199-202, 1986 Judson FN, Ehret JM, Handslield HH: Comparative study of ceftriaxone and spectinomycin for treatment ofpharyngeal and anorectal gonorrhea. JAMA 253:1417-1419, 1985 Karney WW, Pedersen AF, Nelson M, et al: Spectinomycin versus tetracycline for the treatment of gonorrhea. N Engl J Med 296:889-893, 1977 Kaufman RE, Johnson RE, Jaffe HW, et al: National gonorrhea therapy monitoring study. Treatment results. N Engl J Med 294: l-4, 1976 Knapp JS, Zenilman JM, Biddle JW, et al: Frequency and distribution in the United States of strains of Neisseria gonorrhoeac with plasmid-mediated, high-level resistance to tetracycline. JZnfect Dis (in press) Kvale PA, Keys TF, Johnson DW, Holmes KK: Single oral dose ampicillin-probenecid treatment of gonorrhea in the male. JAMA 215:144!&1453, 1971 Laga M, Naamara W, Brunham RC, et al: Single-dose therapy ofgonococcal ophthalmia neonatorum with ceftriaxone. NEngl J Med 315:1382-1385, 1986 Lucas CT, Chandler F, Martin JE, Schmale JD: Transfer of gonococcal urethritis from man to chimpanzee. JAMA 216: 1612-1614, 1971 Lucas JB, Price EV: Co-operative evaluation of treatment for early syphilis. Preliminary report with special reference to spectinomycin sulphate. Br J Vener Dis 43:244-248, 1967 Mark DB, Gaynon MW: Trauma-induced endophthalmitis caused by Acinetobacter anitratus. Br J Ophthalmol 67: 124-126, 1983
61. Martin DH, Pastorek JG, Faro S: In-vitro of parenterally administered beta-lactam
and in-vivo activity antibiotics against
Chlamydia trachomatis. Sex Transm Dis 13:81-87, 62. Masterton G, Schofield CB: Doxycycline HCL
1986
(Vibramycin) as a single dose oral treatment of gonococcal and nonspecific urethritis in men. Br J Vener Dis 48:121-125, 1972 63. McCormack WM, Finland M: Spectinomycin. Ann Znt Med 84:712-716, 1976 64. McNicol PJ, Albritton WL, Ronald AR: Transfer of plasmidmediated ampicillin resistance from Haemophilus to Neisseria gonorrhocae requires an intervening organism. Sew Transm Dis 13:145-159, 1986 65. Medical Letter: Safe9 of antimicrobial drugs in pregnancy 27:93-94, 1985 66. Medical Letter: Cefriaxone Sodium (Rocephin). 27:37-39, 1985
67. Mills J, Gottheb A, Harrison WO: Treatment of gonorrhea with first and second-generation cephalosporins and other new beta-lactam antibiotics. Sex Trarum Dis 13:203-206, 1986 68. Morse SA, Johnson SR, Biddle JW, Roberts MC: High level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of Streptococcal tetM determinant. Antimicrob Agents Chemother 30:664-670, 1986 69. Munday PE, Bingham JS, Ison CA, et al: Treatment
of gonorrhea with clavulanate-potentiated amoxicillin (Augmentin@). Sex Transm Dir 12:163-165, 1985 70. Ng WS, Anton P, Arnold K: Neisseriagonorrhoeae strains isolated in Hong Kong: In vitro susceptibility to 13 antibiotics. Antimicrab Agents Chemother 19: 12-17, 1981 7 1. Novak E, Gray JE, Pfeifer RT: Animal and human tolerance of highdose intramuscular therapy with spectinomycin. J Znfect Dis 130:5&55, 1974 72. Oriel JD, Reeve P, Thomas BJ, Nicol CS: Infection with Chlamydia group A in men with urethritis due to Neisseria gonorrhaeae. J It&t Dis 131:376-382, 73. Pang R, Teh LB, Rajan
74. 75. 76. 77.
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1975
VS: Gonococcal ophthalmia neonatorum caused by beta-lactamose-producing Neisseria gonorrhoeae. Br Med J 1:381, 1979 Pareek SS: Conjunctivitis caused by beta-lactamase-producing Neisseria gonorrhocae. Sex Transm Dis 12: 159-160, 1985 Phillips I: The susceptibility of Neisseria gonorrhoeae to cefoxitin sodium. J Antimicro Chemo 4:(Su@ B) 6164, 1978 Phillips I: Beta-lactamase producing penicillin resistant gonococcus. Lancet 2~656-657, 1976 Piot P, Dyck EV, Colaert J, Ursi JP: In vitro activity ofcefotaxime and other cephalosporins against Neisseria gonorrhoeae. J Antimicro Chrmo 6~47-50, 1980 Pon E, Batachelor RA, Howell HB, et al: An unusual case of penicillinase-producing Neisseria gonorrhoeae resistant to spectinomycin in California. Sex Transm Dir 13:47-49, 1986 Rajan VS, Pang R, Sing EH: An evaluation of treatment in gonococcal ophthalmic neonatorum. Singapore Med J 29:86-88, 1978 Raucher HS, Newton MJ, Stern RH: Ophthalmia neonatorum caused by penicillinase-producing Neisseriagonorrhoeae. JPediatrics 100:92%926,
1982
81. Reed K, Jones MW: PPNG conjunctivitis. J Am Optom Assoc 55:425-427, 1984 82. Rein MF: Therapeutic decisions in the treatment of sexually transmitted diseases: An overview. Sex Transm Dis 8:93-99, 1981 83. Reyn A: Sensitivity
84.
85.
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87.
88.
of N. Gonorrhocae to antibiotics. Br J Vener Dis 37:145-156, 1961 Reyn A, Schmidt H, Trier M, et al: Spectinomycin hydrochloride (Trobicin) in the treatment of gonorrhoeae. Br J Vener Dis 49:54-59, 1973 Rothenberg R: Ophthalmia neonatorum due to Neissereia gonorrhoeae: Prevention and treatment. Sex Transm Dis 6: 187-191, 1979 Schofield BS, Shanks RA: Gonococcal ophthalmia neonatorum despite treatment with antibacterial eye drops. Br Med J 1:257-259, 1971 Schroeter AL, Turner RH, Lucas JB, Brown WJ: Therapy for incubating syphilis. Effectiveness of gonorrhea treatment. JAMA 218:711-713, 1971 Schwab L, Tizazu T: Destructive epidemic Neissereia gonor-
208
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32(3) November-December
rhoeae in African adults. Br J Ophthalmol69:525--528, 1985 89. Scott BD, Fortenberry JD: Postgonococcal conjunctivitis due to Chlamydia trachomatis. Sex Tranrm Dis 13: 172-173, 1986 90. Seddon M, Wise R, Gillett Ap, Livingston R: Pharmacokinetits of Ro 13-9904, a broad-spectrum cephalosporin. Antimicrob Agents Chcmother 18:24Q-242, 1980 91. Siegel MS, Thornsberry C, Biddle JW, et al: Penicillinaseproducing Netiseria goaorrhocac: Results of surveillance in the United States. J In&t Die 137:17O-175, 1978 92. Singal SS, Reichman RC, Graman PS, et al: Isolation of Chlam$ia trachomatis from men with urethritis: Relative value ofone vs. two swabs and influence of concomitant gonococcal infection. Sex Transm Dis 13:5&52, 1986 93. Sng EH, Lim AL, Yeo KL: Susceptibility to antimicrobials of Neisseria gonorrhoeac isolated in Singapore: Implications on the need for more effective treatment regimens and control strategies. Br J Vener Dis 60:374-379, 1984 94. Sorsby A: Local penicillin therapy in ophthalmia neonatorum. Br Med J 1:903-906, 1945 95. Spaeth GL: Treatment of penicillin-resistant gonococcal conjunctivitis with ampicillin. Am J O@hthalmol66:427-429, 1968 96. Sparling PF: Treatment of gonorrhea: What. effect will antibiotic resistance have in the future? Sex Transm Dis 6: 120-125, 1979 97. Stamm WE, Guinan ME, Johnson C, et al: Effect of treatment regimens for Neisseriagonorrhoeae on simultaneous infection with Chlamydia trachomatie. N Engl J Med 310:545549, 1984 98. Strand CL, Arango VA: Gonococcal ophthalmia neonatorum after delivery by cesarean section: Report of a case. Sex Transm Dis 6:77-78, 1979 99. Thatcher RW: Treatment of acute gonococcal conjunctivitis. Ann Ophthalmol10:445-449, 1978 100. Thatcher RW, Petitt TH: Gonorrhea1 conjunctivitis. JAMA 215:1494-1496, 1971 101. Thayer JD, Martin JE: A selective medium for the cultivation of N. gonorrhocae and N. meningitidi~. Public Health Rep 79:49, 1964 102. Thirumoorthy T, Rajan VS, Goh C: Penicillinase-producing Neissetia gonorrhoeac in Singapore. Br J Vensr Dis .58:308310, 1982 103. Thompson SE: Treatment of disseminated gonococcal infections. Sex Tranrm Dis 6:181-184, 1979 104. Thornsberry C, Jaffee H, Brown ST, et al: Spectinomycinresistant Neisseria gonorrhoeae. JAMA 237:240%2406, 1977
1987
ULLMAN ET AL 105. Thygeson P: Marginal cornea1 infiltrates and ulcers. TranrAm Acad Ophthalmol Otolaryngol 51: 198-209, 1947 106. Ullman S, Roussel TJ, Culbertson WW, et al: Ntisereia gonorrhoeac keratoconjunctivitis. Ophthalmology 94:525-531, 1987 107. Valenton MJ, Abendanio R: Gonorrhea1 conjunctivitis. Complication after ocular contamination with urine. Can J Ophthalmol8:421-427, 1973 108. Wan WL, Farkas GC, May WN, Robin JB: The clinical characteristics and course of adult gonococcal conjunctivitis. Am J O~hthalmol102:575-583, 1986 109. Wand M, Olive GM, Mangiaracine AB: Cornea1 perforation and iris prolapse due to Mima ,bolymor,bha. Arch Ophthalmol 93:239-241, 1975 1 IO. Weiss JL, Williams P, Lindstrom RL, Doughman DJ: The use of tissue adhesive in cornea1 perforations. Ophthalmology 90: 610-615, 1983 11 I. Wiesner PJ, Thompson SE: Gonococcal Infections, in Evan AE, Feldman HA (eds): Bacterial Inzctiom of Humunr. New York, Plenum Medical, 1980, pp 235-257 112. Wilhelmus KR, Peacock J, Coster DJ: Branhamella keratitis. Br J Ophthalmol64:892-895, 1980 113. Willcox RR: A survey of problems in the antibiotic treatment of gonorrhoea. With special reference to South-East Asia. Br J Vener Dis 46:217-242, 1970 114. Wong PC, Ho WY, Ng WW: In-vitro stability of beta-lactam antibiotics to hydrolysis by beta-lactamases of N&eria gotwrrhoeac from Southeast Asia. Sex Trams Dis 12:128-133, 1985 115. Yoshida S, Urade S, Mizuguchi Y: Antibiotic sensitivity patand penicillinase-negative terns of penicillinase-positive strains of Ncisseria gonorrhoeae isolated in Fikuoka, Japan. Br J Vener Die 58:305-307, 1982 116. Zajdowicz TR, Kerbs SB, Berg W, Harrison WO: Laboratoryacquired gonococcal conjunctivitis: Successful treatment with single-dose ceftriaxone. Sex Trunsm Dir 11:28-29, 1983 117. Zenilman JM, Shepard M, Biddle JW, et al: Spectinomycinresistant gonococcal infections in the United States; 19851986. J Infect Die (in press)
Supported in part by Research to Prevent Blindness, Inc., New York and in part by the Florida Lions Eye Bank. Reprint requests should be addressed to Thomas J. Roussel, M.D., Bascom Palmer Eye Institute, P.O. Box 016880, 900 N.W. 17th Street, Miami, FL 33101.
VOLUME 32 * NUMBER 3 * NOVEMBER-DECEMBER
THERAPEUTIC
REVIEW,
1987
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 Neiskeratitis resulting in visual loss. The therapeutic decision making process is complicated by the necessity for prompt, effective parenteral therapy, frequent coinfection with other sexually transmitted diseases, and emergence of antibiotic 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 conjunctivitis. Spectinomycin may be a useful alternative in the penicillin-allergic adult patient. (Surv Ophthalmol 32:199-208, 1987) keratoconjunctivitis
seria gonort-hoeae can cause a rapid, severe, ulcerative
Key words. penicillin l
ceftriaxone spectinomycin
l
gonococcal
keratoconjunctivitis
Despite effective antimicrobial agents, public health intervention, and improved health education efforts, gonorrhea incidence remains high.‘* In 1986 over 900,000 cases of gonorrhea in the United States were reported to the Centers for Disease Control.23 It is estimated that less than half of all cases are reported; therefore, a more accurate estimate of the annual incidence is approximately two million cases. The incidence of gonococcal conjunctivitis in adults is estimated at one per 700-800 cases of gonorrhea. 42Therefore, the incidence of gonococcal conjunctivitis may be as high as 2000 cases annually. Gonococcal keratoconjunctivitis is a potentially devastating infection because of the ability of N. gonorrhoeae to cause a rapid, severe, ulcerative keratitis which may result in a cornea1 perforation.30@ Studies have shown that with prompt, effective parenteral antibiotics this infection can be eradicated and complications avoided.4’~ggJ08 A presumptive diagnosis of gonococcal conjunctivitis is made when a hyperpurulent conjunctivitis is associated with in-
l
Neisseria gonorrhoeae
l
tracellular gram-negative diplococci on gram stain (Figs. 1 and 2). However, since N. meningitidies, Branhamella catarrhalis, and Acinetobacter calcoaceticus can present with similar clinical and gram stain findings, definitive cultures and sensitivities are mandatory in all cases.‘0~43~60J0gJ’2The laboratory characteristics and diagnostic techniques of gonococcal infections have been reviewed elsewhere.36J’i Bacterial keratoconjunctivitis is usually treated with regional antibiotics (both topical and subconjunctival) modified by culture results. Gonococcal keratoconjunctivitis, however, is unique in several respects. Gonococcal keratoconjunctivitis requires parenteral antimicrobial agents and its course can progress rapidly. g5,‘ooFrequently, coinfection with other sexually transmitted diseases is present.35,50*57 These factors, coupled with emerging antibiotic resistance, have complicated the therapeutic decisionmaking process. The rapidity and potential severity of this infection necessitates treatment before culture and sensitivity results are known. Unfortunately, this initial empiric treatment must be based on 199
Surv Ophthalmol
32( 3) November-December
1987
ULLMAN
Fig. 2. Numerous Fig. 1. Typical clinical appearance of a purulent tivitis secondary to N. gonorrhoeae.
conjunc-
inadequate clinical and experimental information. This article will review the historical aspects and current literature on the medical treatment of gonococcal keratoconjunctivitis. Only empirically derived guides for therapy can be recommended because of the paucity of clinical data. Prophylaxis for ophthalmia neonatorum and the surgical management of infectious keratitis have been reviewed elsewhere and will not be addressed in this article 2,27Z%37~85~~10
I. Historical
Background
Allusions to gonorrhea may have been made in the Book of Leviticus. Galen ( 130 AD), referring to the urethral discharge of men with urethritis, first used the term gonorrhea, meaning “a flow of seed.” In 1879, Neisser identified the gonococcus, and Bumm cultivated the bacteria in vitro by 1885. Karl Crede’ (early 1880s) experimented with topical silver nitrate to prevent gonococcal ophthalmia neonatorum. In 1939 sulfonamides were introduced to the physicians’ armamentarium. During World War II, sulfonamide resistant strains of gonococcus were encountered. Fortunately, penicillin was developed at this time and quickly became the drug of choice for gonorrhea. Still, the diagnosis of gonorrhea was difficult because of the problems in obtaining a pure culture. In 1964, Thayer and Martin developed an antibiotic selective medium that allowed the pathogenic species N. gonorrhoeae and N. meningitidis to grow.‘O’ In 1972, in response to a precipitous increase in incidence and relative resistance of the gonococcus to penicillin, the federal government financed state efforts to control gonorrhea. Beta-lactamase-producing N. gonorrhoeae (PPNG) were first discovered
intracellular
and extracellular
ET AL
gram-
negative diplococci in association with acute inflammatory cells. (Hematoxylin and Eosin)
in 1976, and have become important pathogens in many parts of the world. 6,76Chromosomally-mediated resistance (CMRNG) to penicillin and tetracycline was first reported in the United States in 1983.‘6J7 CMRNG is relatively difficult to diagnosis because it requires performing formal susceptibility testing on gonococcal isolates. In 1985, plasmidmediated tetracycline resistance (TRNG) was first described.21@’ The implications of this strain on tetracycline prophylaxis of the newborn are unknown.
II. General
Considerations
In addition to the general criteria ofsafety, ease of administration, compliance, and cost, three other important factors are important in the selection of a treatment regimen for gonococcal keratoconjunctivitis: the prevalence of PPNG and other antibioticresistant strains in their community, the possibility of concomitant nongonococcal infection, and the rapidity in which gonococcal keratoconjunctivitis can progress. Because man is the only natural reservoir of N. gonorrhoeae, no reproducible experimental animal model exists for gonococcal conjunctivitis.“,58 Infection with the gonococcus results in little, if any, immunity to reinfection. Reinfection, therefore, is a common cause of apparent treatment failure. Persistence of a concomitant nongonococcal infection (i.e., Chlamydia trachomatis conjunctivitis) is another cause of apparent treatment failure.ag Treatment failure may be due to antibiotic resistance (PPNG or CMRNG), poor compliance, or the inability of the antibiotic to reach inhibitory concentrations at the site of infection.40,4g,82,g6 The paramount concern in the treatment of gonococcal keratoconjunctivitis is the evolution and
GONOCOCCAL
201
KERATOCONJUNCTIVITIS TABLE
Current Recommendations -
1
Centers for Disease Control*
Gonococcal Ophthalmia in Adults Aqueous penicillin G 10 million units intravenously daily for 5 days For PPNG Infections: Cefotaxime 500 mg intravenously 4 times daily for 5 days OR Ceftriaxone 1.O gram intramuscularly or intravenously daily for 5 days Gonococcal Ophthalmia in Neonates Aqueous penicillin G 100,000 units/kg/day intravenously in 4 divided doses for 7 days For PPNG infections: Cefotaxime or gentamicin intravenously in appropriate neonatal doses. *From the Centers for Disease Control: ment Guidelines: MMWR 34:75S, 1985.
1985 STD Treat-
spread of strains of N. gonorrhoeae with diminished susceptibility to antimicrobial agents.‘*~83~“3~“4~“5~“7 The gonococcus has demonstrated the capacity to develop relative or absolute resistance to the penicillins, tetracyclines, sulfonamides, aminoglycosides, and other antimicrobial drugs.‘2,g3 Resistance occurs through a chromosomally mediated mechanism (CRMNG) or the acquisition of plasmids bearing genes coding for beta-lactamase.25,64@ In CMRNG strains, the organism’s outer membrane is less permeable to the antimicrobial agents. This change often simultaneously confers relative resistance to several antimicrobial agents (penicillins, tetracyclines, and erythromycin). Plasmid-mediated (PPNG) resistance to the penicillins and some cephalosporins are noted in the organisms that produce beta-lactamase which breaks down penicillin extracellularly. 32,33 Plasmid-mediated tetracycline resistance affects ribosomal binding of tetracycline? The recommendations of the Centers for Disease Control (CDC) for treatment of gonococcal ocular infections as of April, 1987, are shown in Table 1 .22 These recommendations are not based on controlled clinical studies and are similar to the treatment regimen for disseminated gonococcal infections.‘03 These treatment recommendations are independent of the severity of the ocular infection (whether there is cornea1 involvement or not). Most cases of gonococcal conjunctivitis are believed to be due to inoculation of the conjunctiva with infected genital secretions, either directly or via contaminated lingers. ‘g.74.‘oo We feel this mechanism differs from “classic” hematogenously disseminated gonococcal disease (arthritis-dermatitis syndrome, endocarditis, meningitis). Reports of laboratory-acquired
gonococcal conjunctivitis and conjunctivitis after ocular contamination with urine support this hypothesis.‘~‘3~‘07~“6 I n patients with a gonococcal ocular infection without cornea1 involvement, we believe hospitalization and intravenous therapy may be unnecessary. Case reports and our own experience indicate that gonococcal conjunctivitis responds promptly to intramuscular antibiotics, similar to other localized mucosal gonococcal infection (i.e., urethritis, cervicitis) .3g.57,74~‘06.“6 If out-patient therapy is contemplated for gonococcal conjunctivitis, a single dose regimen that ensures patient compliance is necessary. In addition, daily ocular examinations until the infection is eradicated is mandatory. If there is doubt about compliance with follow-up examinations, or if disease progression is noted (cornea1 involvement), the patient should be hospitalized. We recommend hospitalization for patients with either preexisting ocular disease, cornea1 involvement, or immunocompromised states.
III. Topical Therapy After the introduction of penicillin, there were enthusiastic reports of gonococcal ocular infections treated solely with topical penicillin.g4 These initial studies were inadequate because clinical and not microbiologic cure were shown, and extraocular infected sites were not examined. Subsequent studies have found that topical treatment may transiently alleviate the signs of the conjunctivitis without eradicating the infection.7g,86 Moreover, topical therapy will not affect any extraocular sites of infection. Topical antimicrobial agents may be used in addition to parenteral therapy. They have no role in the primary treatment of gonococcal infections and some experts feel they are superfluous when appropriate parenteral therapy is given.’ Many clinical studies have shown that topical antimicrobial agents are not necessary when parenteral therapy is used. However, Fransen and coworkers, in assessing the efficacy of single-dose kanamycin therapy for gonococcal ophthalmia neonatorum, reported an increased cure rate with the addition of topical gentamicin ointment when compared with the kanamycinlsaline eye wash regimen.34 We recommend adjunctive irrigation with approximately 50 cc of saline every hour as needed to remove the possibly toxic purulent conjunctival discharge. Since topical therapy delivers a large concentration of antibiotic locally without great risk of systemic side effects, and some studies suggest that it may be of benefit, we recommend the use of an antibiotic ointment four times daily. Antibiotic selection should be based upon the culture results, cost, toxicity, and availability. Topical gentamicin,
202
Surv Ophthalmol
32(3) November-December
erythromycin, or bacitracin are reasonable choices. Because of the frequent bulbar conjunctival chemosis, and subsequent cornea1 dellen formation with irritation, we feel an antibiotic ointment may provide more patient comfort than antibiotic drops. Patients with unilateral disease should be cautioned not to inoculate the uninvolved eye when applying the topical antimicrobial ointment. In patients with severe cornea1 thinning or an actual perforation, the eye should be manipulated as little as possible. We therefore do not recommend topical antibiotics or saline lavage when the integrity of the globe is in question.
A. PENICILLIN
1987
ULLMAN
ET AL
They found that from 1982 thru 1986, seven of the 43 (16%) cases of gonococcal conjunctivitis were penicillin resistant. The need for hospitalization and live days of intravenous penicillin to eradicate gonococcal ocular infections has never been proven. This infection generally results from inoculation of the conjunctiva with infected genital secretions, not from hematogenously disseminated disease.1g,74J00 Since gonococcal conjunctivitis most likely represents a localized mucosal infection, similar to goncococcal urethritis, a single-dose treatment with an effective antibiotic should be effective. Recent studies in the treatment of gonococcal ophthalmia neonatorum and case reports of adult gonococcal ophthalmia suggest that single-dose therapy is effective.3ga57,74,“6
Until recently, aqueous procaine penicillin G (APPG), a bactericidal beta-lactam antibiotic, has B. SPECTINOMYCIN been the basis of treatment of gonococcal infections. 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 antibiof 20 years, N. gonorrhoeae isolates with increasing otics. It is poorly absorbed from the gastrointestinal resistance to penicillin have been found, necessitattract but is well absorbed when given intramuscuing 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 inhibadult results in blood levels of about 100 microits the active secretion of penicillin by the renal grams/ml one hour after injection.63 Spectinomycin tubules and therefore results in higher and proinhibits 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 gonoThe 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 oroThis regimen is independent of the severity of the pharyngeal infection may relate to failure of the ocular disease and has not been subjected to conantibiotic to be secreted into saliva in inhibitory trolled clinical studies. Multiple reports, which uticoncentrations. 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 spectinopenicillin-sensitive gonococcal keratoconjunctiviisolates that are penicillin-remycin. 45 Gonococcal tis.7J3~g8J00J08 In addition, this regimen will also cure sistant are no more likely to be resistant to spectinoincubating syphylis, is not teratogenic, assures commycin than isolates that are penicillin-sensitive.70 pliance, and is effective against gonococcal infecSpectinomycin-resistant N. gonorrhoeae was first nottions of all sites.38,87 ed in Denmark in 1973.84 Additional cases have subThe paramount concern with the use of intravesequently been reported in the United States, but nous penicillin for the treatment of gonococcal kerathe incidence remains rare.4,20,53,78 In 1985-l 986, toconjunctivitis is the proliferation of antibiotic rethere were nine confirmed cases of spectinomycinsistant 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 toldata). Numerous case reports have documented the erate spectinomycin well. Spectinomycin appears to occurrence of ocular infections secondary to N. gonbe 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 suggest that spectinomycin poses a threat to the fetus.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 Chlamydia trachomatis.50 The use of spectinomycin for gonococcal urethritis has increased in areas where antibiotic-resistant gonorrhea is prevalent. No studies have been performed 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 reported a case of PPNG conjunctivitis treated unsuccessfully with two grams of intramuscular spectinomycin daily for two days; on the fourth day a clinical relapse was noted, suggesting this therapy was inadequate.8’ The high failure rate of spectinomycin in oropharyngeal gonorrhea illustrates the problem of extrapolating the results of urethritis treatment to other 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” semisynthetic 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 cephalosporins differ in their susceptibility to beta-lactamases, antibacterial spectrum, and pharmacokinetic properties. There is no present evidence that the cephalosporins produce fetal toxicity or teratogenicity, but clinical experience has been limited.38@ In general, first-generation cephalosporins (cephaloridine, cephalothin, cefazolin, and cephalexin) are less active by weight than second-generation cephalosporins (cefamandole, cefuroxime, cefonicid, and cefaclor) against N. gonorrhoeae.67 The third-generation cephalosporins (ceftriaxone, cefotaxime, ceftizoxime, and cefoperazone) are the most active betalactam antibiotics against N. gonorrhoeae.”
203 There is a good correlation between in vitro activity of the cephalosporins against N. gonorrhoeae and clinical efficacy. 67 Single-dose therapy with lirstgeneration 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 infections. Cefoxitin, a semisynthetic cephamycin, has been studied most extensively and has been shown to be effective as a single-dose therapy against penicillinase-producing gonococcal urethritis.g,48,75 Cefoxiten 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 reported. 74,81Cefoxiten, and the second-generation cephalosporins, are relatively ineffective for gonococcal pharyngitis and incubating syphilis.40 In addition, they are ineffective against chlamydial disease.‘j’ Ceftriaxone (Rocephin@), a third-generation cephalosporin, has properties which suggest it may be the best available antimicrobial agent for gonococcal keratoconjunctivitis. 5’.66,goIts long plasma halflife (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-positive 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 humor concentration of 0.93 micrograms/ml was noted 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 administered intravenously to children with severe infections.3 Multiple clinical studies have shown the impressive success of ceftriaxone in eradicating N. gonorrhoeae from all mucosal sites.24 As little as 125 mg of ceftriaxone cured 100% of 52 anorectal gonococcal infections and 94% of 32 pharyngeal infections5* Single-dose ceftriaxone therapy is not effective 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 antimicrobial agent for single-dose therapy of gonococcal
204
Surv Ophthalmol
3!2(3) November-December
ophthalmia secondary to both penicillinase producing and non-penicillinase producing N. gonorrhoeae.3g Laga and coworkers conducted a randomized clinical trial utilizing a single intramuscular dose of 125 mg of ceftriaxone for gonococcal ophthalmia neonatorum. They demonstrated a 100% cure rate in the 61 infants who received the ceftriaxone. Thirty-one (51%) of the isolates were PPNG. In addition, it was extremely effective in eradicating extraocular gonococcal infections (nasopharyngeal infections). Zajdowicz and coworkers reported a case of laboratory acquired adult gonococcal conjunctivitis that responded dramatically to 1.0 gram of ceftriaxone.l16 The efficacy of ceftriaxone in the treatment of incubating syphilis is unknown. Johnson and coworkers have shown that ceftriaxone may be effective against experimentally induced syphilis in rabbits.47 The high level of in vitro activity against penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae, along with its prolonged half-life, and safety, make ceftriaxone the preferred drug for the treatment of gonococcal keratoconjunctivitis. D. OTHER
ANTIMICROBIAL
AGENTS
Other antimicrobial agents, including tetracythiamphenicol, ampicillin, cline, doxycycline, trimethoprim/sulfaamoxicillin, erythromycin, methoxazole, amikacin, and tobramycin have been used successfully in the treatment of genital gonococcal infections.56,62~6g~g7~104 Anecdotal case reports have noted success with some of these agents in gonococcal keratoconjunctivitis.g5 However, none of these agents have been subjected to controlled clinical studies for the treatment of gonococcal keratoconjunctivitis. In addition, the need for patient compliance with an oral regimen and/or the limited efficacy of these antimicrobial agents preclude their use as the initial drug of choice in gonococcal keratoconjunctivitis. Kanamycin, an aminoglycoside, has been shown in clinical studies to be efficacious in ophthalmia neonatorum due to penicillin-sensitive and penicillin-resistant N. gonorrhoeae.34,57J02 Fransen and coworkers successfully used single-dose kanamycin in combination with topical gentamicin in gonococcal ophthalmia neonatorum. 34Interestingly, they noted an unacceptable failure rate when topical gentamitin was excluded. Laga and coworkers recently showed that single dose parenteral kanamycin (75 mg) plus topical tetracycline or gentamicin was effective in the treatment of gonococcal ophthalmia neonatorum.57 They noted this regimen was less than optimal for nonocular sites of gonococcal infection and inferred it was not as effective as parenteral ceftriaxone.
1987
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ET AL
The potential serious toxicity of kanamycin limits its widespread use. Most notable is ototoxicity (both the auditory and vestibular functions of the eighth cranial nerve) and nephrotoxicity. Both of these untoward effects are dose and duration dependent and would therefore be unlikely in a single-dose regimen. In addition, the apparent need for topical treatment with parenteral kanamycin and its relative ineffectiveness for extraocular gonococcal infections (nasopharyngeal) make it less than an ideal regimen. Because of the lack of information available and potential serious toxicity, kanamycin cannot be recommended for the routine treatment of gonococcal keratoconjunctivitis.
IV. Treatment
Recommendations
Specific therapeutic recommendations for gonococcal keratoconjunctivitis must be based on incomplete information and are therefore empiric and intuitive. Initial treatment should be modified by the clinical response and culture results. These recommendations should not be construed as rules but rather as general guidelines from which the treating ophthalmologist should individualize care. In all cases, cultures prior to antimicrobial therapy and follow-up cultures after treatment to document cure should beperformed. Patients should be examined daily until the infection has resolved. No patient should be considered adequately treated until he has been counseled regarding his disease and his sexual partners have been properly dispositioned. Pregnancy testing should be routinely performed on all sexually active females. Since other sexually transmitted diseases may frequently coexist, all patients should have serology for syphilis performed. If serology for syphilis is positive, the patient should be treated in the customary fashion (intramuscular benzathine penicillin G). In addition, because gonococcal and chlamydial infections commonly coexist (up to 32% of men with urethral gonorrhea and 63% of women with endocervical gonorrhea) and isolation techniques for chlamydia are not readily available, we recommend empiric treatment with an oral antimicrobial agent effective for Chlamydia trachomatis.35~44~50~72~g2~g7 This oral regimen is in addition to the parenteral therapy for the gonococcal infection. Fransen and coworkers, in a series of 117 infants with gonococcal ophthalmia neonatorum, noted postgonococcal chlamydial conjunctivitis in 14 (12%) infants.34 Scott and coworkers, reported a case in which C. trachomatis was the etiologic agent of postgonococcal conjunctivitis in an adolescent female.8g These reports suggest an association between gonococcal and chlamydial ocular infections.
GONOCOCCAL
205
RERATOCONJUNCTIVITIS TABLE
2
TABLE
3
Authors’ Recommendation: Treatment af Comcoccat Ophthalmia in Adults
Authors’ Recommendation -
Conjunctivitis: Ceftriaxone 1.O gram intramuscularly (one dose) In penicillin allergic patients: Spectinomycin 2.0 grams intramuscularly (one dose) Keratoconjunctivitis: Ceftriaxone 1.0 gram intravenously every 12 hours for 3 days In penicillin allergic patients: Spectinomycin 2.0 grams intramuscularly every 12 hours for 2 days. Concurrent treatment with: Topical Saline Lavage AND Topical Erythromycin Ointment OR Gentamicin Ointment OR Bacitracin Ointment 4 times daily. AND Treatment for Chlamydia trachomatis infection with: Tetracycline hydrochloride 500 mg by mouth 4 times daily for 14 days OR Doxycycline 100 mg by mouth twice daily for 14 days
Conjunctivitis: Ceftriaxone 50 mg/kg intramuscularly (one dose) In penicillin allergic neonates: Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours for 3 days Keratoconjunctivitis: Ceftriaxone 25-40 mg/kg intravenously every 12 hours doses for 3 days In penicillin allergic neonates: Gentamicin 2 to 2.5 mg/kg intravenously every 8 hours for 3 davs Concurrent tre6tment with: Topical Saline Lavage AND Topical Erythromycin Ointment OR Gentamicin Ointment OR Bacitracin Ointment 4 times daily AND Treatment for Chhmydia trachomatis infection with: Oral erythromycin syrup 50 mg/kg/day in 4 divided doses for 14 davs
(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 gonococcal 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 progression, 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 treatment of conjunctivitis with these antimicrobial agents. In patients with isolated conjunctival disease, without preexisting ocular disease or immunosuppression, we feel that out-patient treatment with ceftriaxone and daily examinations is sufftcient. The 1.O gram dose of ceftriaxone may seem high considering the efficacy of 125 mg in gonococcal genital infections. However, we feel this dose is appropriate considering the potential complications of gonococthe belief that using “supracal conjunctivitis, 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-
Treatment of Gonocwcal ophthalmia in Neonates
crobial regimens may not be as effective, the treating ophthalmologist must be as certain as possible that a penicillin allergy exists before abandoning ceftriaxone. In penicillin allergic patients, intramuscular spectinomycin (2.0 grams) should be used. Until more experience with spectinomycin in gonococcal conjunctivitis is obtained, we recommend hospitalization initially until clinical improvement is noted and culture and sensitivity results are known. Cornea1 involvement is a poor prognostic sign and requires hospitalization and emergent therapy. “,‘08 Isolated punctate epithelial cornea1 staining 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 hypersensitivity phenomenon, have also been described in association with gonococcal conjunctivitis.105,‘06 Patients with an epithelial defect, stromal infiltrate, or stromal thinning should be considered to have an infectious keratitis and treated emergently with parenteral antibiotics. Intravenous ceftriaxone, which provides rapid, high peak serum levels is recommended 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 intravenous ceftriaxone, the optimal duration of therapy
206
Surv Ophthalmol
32(3) November-December
1987
is not known and must be individualized. Our treatment recommendations of neonatal gonococcal conjunctivitis is shown in Table 3. These recommendations are based largely on several studies on the single-dose therapy of gonococcal ophthalmia neonatorum with ceftriaxone.3g,57 Outpatient single-dose intramuscular ceftriaxone therapy in conjunction with daily examinations is suflicient in the neonate with uncomplicated gonococcal conjunctivitis. All neonates with cornea1 involvement should be hospitalized and treated emergently with intravenous ceftriaxone (50-80 mg/kg/day in two divided doses). The optimal duration of therapy has not been established; however, we empirically suggest a minimum of three days of therapy (6 doses). Therapy can then be adjusted based on the clinical course and culture results. In the extremely rare case of gonococcal ophthalmia neonatorum in which ceftriaxone is contraindicated, we recommend consultation with an infectious disease expert. Empirically, we recommend three days of intravenous gentamicin in appropriate pediatric dosages in these cases. Additional studies are needed to confirm and reline these recommendations for the treatment of gonococcal keratoconjunctivitis. Considering the proliferation of N. gonorrhoeae isolates resistant to various antimicrobial agents, the need for cost containment, and pharmacologic advances, the treatment regimen of choice has become less clearcut. The necessity for periodic review of drug efficacy and toxicity in the treatment of ocular infections secondary to N. gonorrhoeae cannot be overemphasized. Undoubtedly, new recommendations will become necessary in the future as antibiotic resistance problems evolve and new antimicrobial agents become available. Acknowledgment The authors are indebted to Dr. Jonathan M. Zenilman for his editorial assistance and critical review of the manuscript.
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ET AL
6. Axelrod JL, Newton JC, Sarakhum C, et al: Ceftriaxone. A new cephalosporin with aqueous humor levels effective against Enterobacteriaceae. Arch Ophthalmol103:71-72, 1985 7. Baker FJ, Wood DR: Adult gonococcal ophthalmia. South Med J 77:800-801, 1984 8. Berg SW: Spectinomycin as primary treatment ofgonorrhea in areas of high prevalence of penicillinase-producing Neissereia gonorrhoeae.Sex Transm Dis 8338-39, 1981 9. Berg SW, Kilpatrick ME, Harrison WO, McCutchan JA: Cefoxitin as a single-dose treatment for urethritis caused by penicillinase-producing Neisseria gonowhoeae. N Engl J Med 301: 509-511, 1979 10. Brook I, Bateman B, Pettit TH: Meningococcal conjunctivitis. Arch Ophthalmol.97:890-891, 1979 11. Brown J, Lucas CT, Kuhn USG: Gonorrhoeae in the chimpanzee infection with laboratory-passed gonococci and by natural transmission. Br J Vmcr Dis 48: 177-l 78, 1972 12. Brown S, Biddle J, Warnnissorn T, et al: Antimicrobial resistance of Netiseria gonorrhoeaein Bangkok: Is single-drug treatment passe? Lancet 1:1366-1368, 1982 13. Bruins SC, Tight RR: Laboratory-acquired gonococcal conjunctivitis. JAMA 241:274, 1979 14. Centers for Disease Control: Table 1. Summary - Cases of specified notiticable diseases, United States. MMWR 34:782, 1986 15. Centers for Disease Control: Penicillinase-producing Neisseria gonowhoeae- United States, Florida. MMWR 3512-14, 1986 16. Centers for Disease Control: Penicillin-resistant gonorrhea North Carolina. MMWR 32:273-275, 1983 17. Centers for Disease Control: Chromosomally mediated resistant Neisscriagonorrhoeae- United States. MMWR33:408-410, 1984 18. Centers for Disease Control: Infections due to penicillinaseproducing Neisseriagonowhoeaein the United States: 1976-1980. JZnfect Dis 144:191-196, 1981 19. Centers for Disease Control: Gonococcal eye infections in adults - California, Texas, Germany. MMWR 30:341-343, 1981 Neisseria 20. Centers for Disease Control: Spectinomycin-resistant gonorrhoeae- worldwide. MMWR 31:637-638, 1982 Neisseria 21. Centers for Disease Control: Tetracycline-resistant gonorrhoeae Georgia, Pennsylvania, New Hampshire. MMWR 34:563-570, 1985 22. Centers for Disease Control: 1985 STD treatment guidelines. MMWR 34~8 1S-9OS, 1985 Cases speci23. Centers for Disease Control: Table 1 Summarylied notifiable diseases, United States. MMWR 3.5~810, 1987 study 24. Collier AC, Judson FN, Murphy VL, et al: Comparative of ceftriaxone and spectinomycin in the treatment of uncomplicated gonorrhea in women. Am J Med 77 (Suppl 4C):6%72, 1984 25. Coovadia VM, Krarsany A, Ramsaroop U: Antimicrobial susceptibility of N&&a gonorrhoeae isolated in Durban, South Africa. Br J Vener Di.s 60:30&308, 1984 26. Curtis FR, Wilkinson AE: A comparison of the in vitro sensitivity ofgonococci to penicillin with the results of treatment. Br 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 B, Hammerschlag MR, Pringle GF, Bouchet L: Ophthalmia neonatorum caused by beta-lactamase-producing Neisseria gonowhoeae.JAMA 250:790-79 1, 1983 29. Du NJ, Chen JW, Gong XM, et al: Therapeutic keratoplasty in the management of purulent cornea1 ulceration - Report of 100 cases. Jpn J Ophthalmol23:412-420, 1979 30. Duke-Elder S: Diseases of the Outer Eye, System of Ophthalmology, Vol8, Part 2. St. Louis, CV Mosby, 1965, pp 167-174 31. Dunlop EM, Rodin P, Seth AD, Kolator B: Ophthalmia neonatorum due to beta-lactamase producing gonococci. Br Med J 1:281-483, 1980 32. Eisenstein BI, Sox T, Biswas G, et al: Conjugal transfer of the gonococcal penicillinase plasmid. Scicace 195:99&999, 1977 33. Elwell LP, Roberts M, Mayer LW, Falkow S: Plasmid-mediated beta-lactamase production in Neisseria gonowhoeac. Antimicrob Agents Chemother11:52%533, 1977
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Supported in part by Research to Prevent Blindness, Inc., New York and in part by the Florida Lions Eye Bank. Reprint requests should be addressed to Thomas J. Roussel, M.D., Bascom Palmer Eye Institute, P.O. Box 016880, 900 N.W. 17th Street, Miami, FL 33101.