A young man presented at the ophthalmology outpatient department of a hospital in rural South Africa with symptoms suggestive of conjunctivitis. He complained of progressive redness and swelling of both eyes, ocular discharge, and mild pain for 11 days. Eight days before presentation at the hospital, he had consulted with a local private practitioner for penile discharge and dysuria. He was treated for male urethritis syndrome with azithromycin (1 g stat dose), cefixime (400 mg stat dose), and metronidazole (2 g stat dose) as verified with his private practitioner. His genital symptoms had resolved after this antibiotic treatment, but ocular symptoms progressed over time. Reliable details of sexual history could not be obtained from this patient, except for currently having a female sexual partner. Written informed consent including for ocular photography was obtained from the patient.
On ocular inspection, bilateral diffuse conjunctival injection with oedema of upper and lower eye lids was observed with profuse mucopurulent discharge (Fig. 1). Slit-lamp examination did not reveal corneal abnormalities; fundoscopy was normal. Genital examination did not show any abnormalities; in particular, no genital discharge was observed. The HIV rapid test was reactive and subsequent CD4 count was 205 cells/mm3. A swab of conjunctival pus was taken for general bacterial culture and culture specific for Neisseria gonorrhoeae at the Lancet Laboratories in Tzaneen, South Africa. A second swab was obtained for polymerase chain reaction testing for Chlamydia trachomatis and N. gonorrhoeae. Regular rinsing of the eye was advised and, based on clinical presentation of hyperpurulent conjunctivitis, treatment of suspected uncomplicated gonococcal conjunctivitis was initiated: 1 g of ceftriaxone intramuscular injection combined with topical ciprofloxacin (3 mg/mL) ophthalmic drops and chloramphenicol ophthalmic ointment during the night. Ciprofloxacin drops were given as gentamicin and chloramphenicol ophthalmic drops, as indicated per South African national guidelines, were unavailable at the hospital at that time. At telephonic follow-up, the patient reported complete resolution of ocular symptoms including restoration of vision.
Microbial culture of conjunctival pus on Thayer-Martin agar revealed growth of N. gonorrhoeae; no other bacteria were cultivated. The antimicrobial resistance profile was as follows: penicillin susceptible (minimum inhibitory concentration of 0.016 μg/mL) and, based on disk diffusion, susceptibility to cefixime and ceftriaxone. Disk diffusion tests further revealed antimicrobial resistance to ciprofloxacin and tetracycline. Unfortunately, the strain was not available for further molecular characterisation due to operational logistics. Polymerase chain reaction testing of conjunctival pus by the Abbott RealTime CT/NG Assay (Abbott Molecular, Des Plaines, IL) was positive for N. gonorrhoeae, whereas C. trachomatis coinfection was not detected.
To our knowledge, we report the first case of possible progression of ocular, cephalosporin-susceptible, N. gonorrhoeae infection after successful syndromic treatment (including cefixime and azithromycin) for male urethritis syndrome. In contrast to several recently reported cases of progressive ocular infection due to N. gonorrhoeae strains with reduced cephalosporin susceptibility or resistance, the strain isolated from the conjunctiva of our patient was fully susceptible to cephalosporins.1,2
Ocular gonorrhea, as is the case in this patient, generally presents with eyelid swelling, conjunctival chemosis, and hyperacute purulent discharge. If left untreated, the infection will progress from the conjunctiva into the cornea resulting in peripheral corneal ulceration that may rapidly progress to corneal perforation.3,4 As such, delayed initiation of antimicrobial treatment may result in significant visual impairment and, ultimately, blindness due to cornea destruction.4 In our patient, infection was limited to the conjunctiva and reported visual outcome was good after treatment.
The case presented here shows that ocular N. gonorrhoeae infection may persist and could progress after successful treatment of urethral discharge syndrome, including 2 drugs active against gonorrhea. A limitation of this case is that we were not able to determine the cause of genital symptoms in this patient (these had resolved upon treatment and before presentation to the ophthalmology outpatient department), but the combination of drugs empirically given for urethritis syndrome would likely have cured genital N. gonorrhoeae infection, if present. The incubation period for ocular gonorrhea is from 3 to 19 days.5,6 It is certainly not unusual for genital symptoms to precede ocular manifestations for a period of up to 2 weeks; in this case, the ocular condition followed onset of genital symptoms by 3 days. Ocular symptoms were already present before treatment of urethritis syndrome was administered and showed a progressive course of disease. This makes (re)infection of the eye after exposure to treatment less likely.
Antimicrobial resistance determination showed susceptibility of the ocular N. gonorrhoeae strain to cephalosporins; unfortunately, susceptibility to azithromycin could not be determined. In addition, there was resolution of genital symptoms after syndromic treatment including drugs active against N. gonorrhoeae. As such, we hypothesize that progression of ocular N. gonorrhoeae infection is not due to reduced antimicrobial susceptibility, but rather the result of insufficient penetration of these drugs in the conjunctiva to achieve cure. Tissue penetration of cefixime and subsequent drug level are relatively good in the urogenital tracts achieving cure rates of more than 97%.7 However, penetration of cefixime in extragenital body sites is considerably lower as reflected by the cure rate of 92% and lower reported for oropharyngeal N. gonorrhoeae infections.7,8 To our knowledge, there are no data on cefixime and azithromycin drug levels in the conjunctiva, but ocular tissue levels of 2 cephalosporins, cefotaxim and cefepime, have been shown insufficient to achieve therapeutic effect for non–sexually transmitted infection (STI) ocular infections.9,10 As such, it seems plausible that low penetration of cefixime and azithromycin in the conjunctiva resulted in lack of cure in this patient. We do not know whether the patient's HIV infection and low CD4 cell count contributed to the course of disease.
South Africa has implemented a syndromic approach to STI management; that is, individuals are treated empirically based on presenting symptoms and without diagnostic testing.11,12 This patient was initially treated by a private practitioner with azithromycin, cefixime, and metronidazole. This combination of antibiotics would generally be adequate for urethritis syndrome, but is not in line with the recent (2015) South African STI management guidelines that indicate ceftriaxone 250 mg intramuscular injection instead of oral cefixime.11 Moreover, cefixime is not indicated for treatment of gonococcal ophthalmia in South Africa. We do not know the reason why the conjunctivitis was treated inappropriately by the private practitioner at the initial presentation. In our experience, however, cefixime use is still common in South Africa as this was the drug of choice (combined with doxycycline instead of azithromycin) in the previous version of national STI management guidelines.12 Also, prescription of oral drugs is preferred over administration of an injection by some health care workers, and drug availability regularly plays a role in choice of antibiotics given in our setting. As such, it may be expected that cefixime will continue to be used in our setting and possibly in other resource-constrained settings.
There are limited data available to support best practice in management of ocular gonorrhea. Based on a study by Haimovici and colleagues,13 who showed clinical response of ocular N. gonorrhoeae infection to 1 g of ceftriaxone in 12 patients, the Centers for Disease Control and Prevention recommends to administer 1 g of ceftriaxone for ocular gonococcal infection, combined with 1 g of azithromycin.14 There is currently no consensus about the effect of supplementing ceftriaxone injection with topical antimicrobial treatment on ocular N. gonorrhoeae infection. Another limitation is that the minimum inhibitory concentration for azithromycin to determine susceptibility of the N. gonorrhoeae strain to this drug could not be determined in our setting.
Gonococcal conjunctivitis is a condition with serious visual impact when left untreated and corneal ulceration occurs. Oral dual therapy of cefixime and azithromycin issued for male urethritis syndrome, or genital gonorrhea specifically, may fail to cure simultaneous ocular N. gonorrhoeae infection in the absence of drug resistance. This is possibly due to poor penetration of these drugs in the conjunctiva similar to other extragenital tissues. As such, awareness of N. gonorrhoeae as cause of progressive conjunctivitis, as well as progression of other extragenital infections, after syndromic treatment with cefixime and azithromycin is still warranted.
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