Strategies for handling the erythromycin ophthalmic ointment shortage

During the summer, many hospitals were faced with an erythromycin eye ointment shortage. When trying to find a replacement product, many were surprised to find that there are no other FDA-approved drug therapy options for ophthalmia neonatorum prophylaxis. This poses a challenge for clinicians who must choose a safe, efficacious alternative for a practice that has been around for decades.

Dr. Carl Siegmund Franz Credé, the German gynecologist and obstetrician, first introduced prophylaxis for ophthalmia neonatorum in 1881, by cleansing the infant’s eyes and instilling silver nitrate solution 2% in the conjunctival sac after birth. This therapy has since been proven effective in preventing opthalmia neonatorum, conjuncitivitis in the newborn, the most common gonococcal infection in neonates. Fewer data are available regarding efficacy of this approach for prophylaxis against Chlamydia trachomatis.

Silver nitrate has since fallen out of favor due to its adverse effects of chemical conjunctivitis and argyria, a bluish discoloration of the eyes and surrounding skin. Topical preparations can be used for ophthalmia neonatorum prophylaxis, but treatment requires systemic antibiotics. Clinical symptoms of gonococcal ophthalmia neonatorum are usually mild but can quickly progress to corneal scarring and, in severe cases, subsequent blindness.

Therefore, prophylaxis has been identified as the preferred method to address this infection. Although rare, the devastating consequences in the small number of infected children warrant a comprehensive prophylactic approach. In the United States today, the only available FDA-approved medication for ophthalmia neonatorum prophylaxis is erythromycin ophthalmic ointment 0.5%. The CDC’s 2006 Sexually Transmitted Disease (STD) Treatment Guidelines recommend instilling the ointment into both eyes of every neonate immediately after delivery. This guidance has subsequently been adopted as mandate in many states.

CDC addresses shortage

In late August, the CDC’s Division of STD Prevention issued a statement in conjunction with the FDA regarding the shortage of erythromycin ophthalmic ointment 0.5% due to a combination of events. Akorn Consolidated Midland and Wilson discontinued production of erythromycin ointment. Fougera sold the rights for erythromycin ophthalmic ointment to Fera Pharmaceuticals, which then experienced production delays. At the time, Fougera was the only producer of 1g tubes of the ointment, the preferred package for opthalmia neonatorum prophylaxis. All of these factors led to an increased demand on Bausch & Lomb.

There are two FDA-approved indications for erythromycin ophthalmic ointment 0.5%: prophylaxis of ophthalmia neonatorum caused by N. gonorrhoeae or C. trachomatis and superficial ocular infections involving the conjunctiva and/or cornea caused by susceptible organisms. Only the latter condition has FDA-approved commercially available alternatives in the United States. So which medication options are there for health care providers to prevent ophthalmia neonatorum if erythromycin ophthalmic ointment is not available?

One of the initial proposed solutions was to use bulk supplies of the erythromycin ointment that remained commercially available and draw up aliquots in sterile glass syringes. However, this was rejected because of concern of contamination and potential medication errors. Several alternative medications were considered by individual institutions; however, many of these were problematic.

FDA recommendations

As far as medications to avoid, the FDA specifically recommends against the use of betadine (povidone iodine) due to the risk of serious harm with medication errors that may possibly occur if there was confusion with the detergent formulation. Additionally, although silver nitrate solution 1% was recommended for ophthalmia neonatorum prophylaxis in the CDC’s 2002 STD Treatment Guidelines, the product is not available in the United States because of previously mentioned toxicities. Tetracycline ophthalmic ointment 1% is an effective treatment option but is also not commercially available. Health care providers are thus faced with the difficulty of choosing appropriate alternatives for this potentially eyesight-threatening condition that is caused by an increasingly resistant organism.

First, it should be noted that all of the following suggested alternatives to erythromycin ophthalmic ointment 0.5% are not FDA approved for ophthalmia neonatorum prophylaxis, nor is there efficacy data regarding their usage for this indication. The FDA, however, stated that the recommendations are based upon pharmacology and gonococcal microbiologic sensitivity data. All of the alternative prophylaxis options are recommended for infants delivered vaginally and by cesarean section.

Azithromycin ophthalmic solution 1% (AzaSite, Inspire Pharmaceuticals) is recommended as the preferred alternative therapy option when erythromycin ophthalmic ointment 0.5% is not available. The recommended dose is one to two drops in the conjunctival sac of each eye, without touching the applicator tip to the eye. Difficulty in instilling a solution as opposed to ointment should be handled by one person holding the infant’s eye lid open and a second person administering the medication.

In situations in which neither erythromycin ophthalmic ointment nor the alternative azithromycin ophthalmic solution is available, the FDA recommends the following therapy options: gentamicin ophthalmic ointment 0.3% (Gentak, Akorn) or tobramycin ophthalmic ointment 3% (Tobrex, Alcon Laboratories).

Of interest, case reports from 11 states have associated adverse events with gentamicin ophthalmic ointment. The reports have described lid swelling and dermatitis several days after administration. Most cases were not serious and did not require treatment, but a few severe cases involved skin blistering. No cases have been reported to affect the conjunctiva, orbital contents or cornea; all cases resolved without complications or treatment. Gentamicin ophthalmic ointment is still considered a potential alternative option when erythromycin ophthalmic ointment and azithromycin ophthalmic solutions are not available.

A last-line option would be a fluoroquinolone ophthalmic ointment such as ciprofloxacin ophthalmic ointment 0.3% (Ciloxan, Alcon Laboratories), but due to the high rates of N. gonorrhoeae resistance to fluoroquinolones, this is a less appropriate choice. Fluoroquinolone resistance to N. gonorrhoeae has been a growing problem over the past several years. There were 336,742 cases of gonorrhea reported in 2008 in the United States, making it the second most frequently reported infectious disease after chlamydia.

Emergence of resistance

Due to the emergence of resistance to fluoroquinolones in rates of more than 25% in certain United States cities, in 2007, the CDC issued an update to its 2006 STD Guidelines, recommending against the use of drugs from this class to treat N. gonorrhoeae infections. The 2007 Annual Report for the CDC’s Gonococcal Isolate Surveillance Project (GISP) reported a 16.1% rate of total isolate intermediate resistance or resistance to ciprofloxacin. Several regions and cities demonstrated alarming increases rates of resistance, such as Las Vegas’ rise from 8.7% resistant isolates in 2006 to 18.7% in 2007. Consequently, cephalosporin-based regimens are the first-line recommendation for treatment of gonococcal infections, with ceftriaxone as a treatment choice for all types of N. gonorrhoeae infection.

The rate of gonorrhea cases remained relatively stable for the last decade. Of concern, resistance rates continue to rise while there is a lack of new prospective therapy options for N. gonorrhoeae infections. This stresses the importance of preventing the spread of N. gonorrhoeae to neonates. To ensure that the most effective available prophylaxis option for ophthalmia neonatorum caused by N. gonorrhoeae is available for this indication, the FDA currently recommends reserving the use of erythromycin ophthalmic ointment for ophthalmia neonatorum prophylaxis and using alternative agents for superficial ocular infections involving the conjunctiva and/or cornea caused by susceptible organisms.

Although initial estimates were that supplies of erythromycin ophthalmic ointment would return to sustainable levels in early 2010, the supply remains very limited. Many centers that developed initial contingency plans in the summer are now being forced to select alternate agents. Additionally, it is important for infectious diseases practitioners to know that these practice changes have been occurring as we continue to track the epidemiology of these infections.

Elizabeth Rightmier, PharmD, is a pharmacy practice resident at the University of Rochester Medical Center in Rochester, N.Y.