What are alternatives to erythromycin ophthalmic ointment for prophylaxis of gonococcal ophthalmia neonatorum?

Introduction

Ophthalmia neonatorum is the most common infection during the first month of life.1 Among chemical, viral, chlamydial, and bacterial etiologies, bacterial conjunctivitis caused by Neisseria gonorrhoeae carries significant concerns. Although the incidence of gonococcal ophthalmia neonatorum in the US is low (≤0.4 cases per 100,000 live births per year between 2013 and 2017), the condition can cause corneal scarring, ocular perforation, and blindness as early as 24 hours after birth.1-3

Prophylaxis with topical ophthalmic medication strongly reduces the risk of transmission of gonococcal infection, which otherwise ranges from 30% to 50%.3 The most common prophylactic regimen for gonococcal ophthalmia neonatorum is erythromycin ophthalmic ointment, which is considered standard neonatal care. However, as of July 2019, the product is currently on shortage in the US.4 Confusion may arise when determining appropriate alternatives to this first-line agent for preventing gonococcal ophthalmia neonatorum, which is the focus of this review.

Pathophysiology & epidemiology

Gonococcal ophthalmia neonatorum occurs with exposure of the neonate to infected cervical secretions during delivery, including during cesarean delivery.2,5 Clinical findings of ophthalmia neonatorum include purulent conjunctivitis with exudate and eyelid swelling, which typically manifest between 2 to 5 days after birth.2 If untreated, disseminated infection can occur, including sepsis or meningitis.6,7

The incidence of gonococcal ophthalmia neonatorum is related to the prevalence of gonococcal infection in women of reproductive age.3 Therefore, screening and treatment of pregnant women is recommended as the best strategy to prevent vertical transmission to the newborn.8 These preventive measures, as well as legislative mandates for topical prophylaxis in most states, have dramatically lowered incidence of gonococcal newborn infection, which is approximately 1% worldwide.5,6

The US Preventive Services Task Force (USPSTF) recommends screening for gonorrhea in all sexually active women 24 years and younger, in older women at increased risk for infection, and in pregnant women.3 Although rates of gonorrhea in pregnant women in the US primary care setting are not available, rates peak in adolescents and young adult women at age 19 years (872.2 cases per 100,000 women).

Guideline recommendations

Recommendations for prophylaxis of gonococcal ophthalmia neonatorum are provided by the American Academy of Pediatrics, the Centers for Disease Control and Prevention (CDC), and the USPSTF.3,5,8,9 All recommend erythromycin 0.5% ophthalmic ointment be administered to all neonates as soon as possible after delivery, regardless of whether delivery is vaginal or cesarean. However, delaying administration as late as 1 hour after delivery in order to facilitate parent-infant bonding is unlikely to affect efficacy.9 Erythromycin is the only antibiotic ointment recommended by guidelines and approved by the US Food and Drug Administration (FDA) for this use.3 The CDC guideline notes that ideally, erythromycin ointment would be administered from single-use rather than multiple-use tubes.5

Alternatives to erythromycin

The preference for prophylaxis with erythromycin is rooted in the unavailability of silver nitrate and tetracycline ophthalmic ointments in the US, lack of efficacy of bacitracin, adverse effects of gentamicin ophthalmic ointment, and inadequate study of povidone-iodine.5 If erythromycin ointment is unavailable, the CDC guideline recommends that neonates at risk for exposure to N. gonorrhoeae during delivery (especially those born to a mother at risk for gonococcal infection or with no prenatal care) be administered ceftriaxone 25 to 50 mg/kg intravenously or intramuscularly, up to a maximum single dose of 125 mg. This recommendation was reaffirmed in March 2019 in response to the current erythromycin shortage.8

Other prophylactic agents that have been described include off-label use of azithromycin and ciprofloxacin.9 However, challenges with azithromycin 1% ophthalmic solution are its cost and the difficulty in instilling the solution, which may require one person to hold open the neonate’s eyelids while another performs instillation. Ciprofloxacin 0.3% ophthalmic ointment was also considered a less suitable, but acceptable alternative.

During previous shortages of erythromycin and tetracycline ophthalmic ointments, gentamicin ophthalmic ointment was explored and its clinical effects have been described. These publications reported adverse effects of gentamicin, such as edema, exudate, and ulcerative dermatitis.10-12 The estimated incidence of dermatitis with gentamicin ophthalmic ointment in one study was 5.6 events per 100 newborns.11 These reports of use of alternatives to erythromycin during shortages helped inform subsequent recommendations from CDC.5

Given the limited alternatives to erythromycin ointment, questions may arise regarding compounding agents that are on shortage or not available in the US. A compounding recipe for erythromycin 0.5% ophthalmic ointment was published during a 2009 erythromycin shortage.13  The publication described a recipe that first requires preparation of erythromycin 2% sterile concentrate from erythromycin base powder, as well as an ophthalmic base sterile ointment. In addition, a recipe for tetracycline 1% ophthalmic ointment describes preparation using tetracycline hydrochloride, mineral oil, and white petrolatum.14 However, no compounded formulations are endorsed by guidelines for prevention of gonococcal ophthalmia neonatorum.5,8

Future directions

In their 2019 update, the USPSTF recognized the proposal for risk-based rather than universal topical ophthalmic prophylaxis for gonococcal ophthalmia neonatorum.3 Some countries, including Canada, Denmark, Norway, Sweden, and the United Kingdom, no longer mandate universal prophylaxis and instead advocate for better screening and prevention in pregnant women. Currently, the American Academy of Pediatrics believes the US practice of legislatively mandated ophthalmic prophylaxis should be reevaluated.9 However, there are currently no tools to quantify risk based on maternal risk factors, and the use of risk-based vs universal prophylaxis has not been evaluated. Therefore, risk-based prophylaxis remains an area of further research.3

Conclusion

Shortages of erythromycin ophthalmic ointment present challenges in providing optimal prophylaxis against gonococcal ophthalmia neonatorum because erythromycin is the only ophthalmic antibiotic ointment recommended and FDA-approved for this use. Although alternative ophthalmic medications have been proposed, they either have demonstrated adverse effects or lack sufficient study. Thus, during the current erythromycin ointment shortage, parenteral ceftriaxone, as recommended by CDC, will remain the recommended alternative for prophylaxis of gonococcal ophthalmia neonatorum.

References

  1. Orge FH. Examination and common problems in the neonatal eye. In: Martin R, Fanaroff AA, Walsh MC, eds. Fanaroff and Martin's Neonatal-Perinatal Medicine. 11th ed. Philadelphia, PA: Elsevier; 2020: 1934-1969.
  2. Ram S, Rice PA. Gonococcal infections. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018. accesspharmacy.mhmedical.com/content.aspx?aid=1155966776. Accessed July 18, 2019.
  3. Curry SJ, Krist AH, Owens DK, et al. Ocular prophylaxis for gonococcal ophthalmia neonatorum: US Preventive Services Task Force reaffirmation recommendation statement. JAMA. 2019;321(4):394-398.
  4. American Society of Health-System Pharmacists. Drug shortages. American Society of Health-System Pharmacists website. https://www.ashp.org/Drug-Shortages. Accessed July 18, 2019.
  5. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(Rr-03):1-137.
  6. Costumbrado J, Ghassemzadeh S. Gonococcal conjunctivitis. In: Bolla SR, Abai B, Abu-Ghosh A, et al., eds. StatPearls. Treasure Island (FL): StatPearls Publishing; 2019. https://www.ncbi.nlm.nih.gov/books/NBK459289/. Accessed July 17, 2019.
  7. Matejcek A, Goldman RD. Treatment and prevention of ophthalmia neonatorum. Can Fam Physician. 2013;59(11):1187-1190.
  8. Centers for Disease Control and Prevention. Erythromycin (0.5%) ophthalmic ointment shortage. Centers for Disease Control and Prevention website. https://www.cdc.gov/std/treatment/drugnotices/erythromycin-ophthalmic.htm. Updated March 12, 2019. Accessed July 17, 2019.
  9. Kimberlin DW, Long SS, Jackson MA. Prevention of neonatal ophthalmia. In: Kimberlin DW, Long SS, Jackson MA, eds. Red Book 2018 : Report of the Committee on Infectious Diseases. 31st ed. Elk Grove Village, IL: American Academy of Pediatrics; 2018: 1049-1050.
  10. Nathawad R, Mendez H, Ahmad A, et al. Severe ocular reactions after neonatal ocular prophylaxis with gentamicin ophthalmic ointment. Pediatr Infect Dis J. 2011;30(2):175-176.
  11. Binenbaum G, Bruno CJ, Forbes BJ, et al. Periocular ulcerative dermatitis associated with gentamicin ointment prophylaxis in newborns. J Pediatr. 2010;156(2):320-321.
  12. Merlob P, Metzker A. Neonatal orbital irritant contact dermatitis caused by gentamicin ointment. Cutis. 1996;57(6):429-430.
  13. McElhiney LF. Developing an erythromycin ophthalmic ointment: putting the puzzle pieces together. Int J Pharm Compd. 2010;14(4):270-274.
  14. Nahata MC, Pai VB. Pediatric Drug Formulations. 6th ed. Cincinnati: Harvey Whitney Books Company; 2011.

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2019

The information presented is current as of July 16, 2019.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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