Chapter XVII.1. Neonatal Conjunctivitis and Eye Prophylaxis
Jaxon J. Huang
Sheree Kuo, MD
January 2023

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This is a four week old male infant born to a 26 year old G2P2 O+, rubella immune, group B strep negative, HBsAg negative, VDRL negative, gonorrhea and chlamydia negative, married female at 40 weeks gestation via spontaneous vaginal delivery with Apgar scores of 8 and 9 at 1 and 5 minutes. Pregnancy, delivery and postpartum hospital course were uncomplicated. He presents with his mother to your office with a two day history of bilateral eye drainage. He had been in good health until two days ago when he developed yellow drainage and mild periorbital swelling. He has a recent mild cough that he probably caught from his older brother.

Exam: VS T 37.5, P 120, RR 60, BP 60/40, oxygen saturation 94% on room air, weight 4.0 kg (50th percentile). He is a well developed, well nourished, non-toxic male infant with mild tachypnea and staccato cough, but in no acute distress. His upper and lower eyelids are edematous. There is mild conjunctival injection with moderate amounts of mucopurulent drainage bilaterally. Pseudomembranes are seen with eversion of the upper eyelids. Coarse breath sounds are appreciated bilaterally with occasional rales and fine expiratory wheezes. The remainder of his exam is unremarkable.

You swab the conjunctiva for gram stain, culture and chlamydia direct fluorescent antibody (DFA) staining. Complete blood count is remarkable for eosinophilia. Chest radiograph reveals bilateral patchy infiltrates with hyperinflation. After receiving positive chlamydia DFA results, you inform the mother of the diagnosis. Initially shocked, she admits that six months ago she and her husband had separated briefly, but are now back together.


Neonatal conjunctivitis, also known as ophthalmia neonatorum, is a form of conjunctivitis that typically occurs in infants less than four weeks of age. The condition is commonly transmitted during delivery as the neonate passes through a colonized or infected birth canal. Major causative agents of neonatal conjunctivitis include chemical and both sexually transmitted and non-sexually transmitted bacterial causes. Viral ocular infection, usually caused by adenovirus or herpes simplex virus, occurs infrequently in the neonatal period. Severe complications include corneal ulceration and perforation, which in some cases can result in permanent blindness (1).

Nearly every bacterial species has been implicated as a cause of neonatal conjunctivitis. However, the single most common infectious agent in the United States is Chlamydia trachomatis, which accounts for 2% to 40% of cases (estimated 0.8% of all newborns). Neisseria gonorrhoeae is significantly less common, accounting for less than 1% of cases (estimated 0.03% of all newborns). Non-sexually transmitted bacteria, including Staphylococcus aureus, group A or B streptococcus, Haemophilus influenzae, and Pseudomonas aeruginosa, cause about 30% to 50% of cases (1,2).

Although Neisseria gonorrhoeae is currently an uncommon cause of neonatal conjunctivitis, it is felt to be one of the most serious due to its potential to cause blindness and progress into meningitis and septicemia (3). These complications prompted the widespread use of silver nitrate for gonococcal ophthalmia prophylaxis in the neonate since the 1880's, consequently decreasing the incidence. Despite being effective at preventing gonococcal ophthalmia, the irritant effects of silver nitrate were found to result in the development of chemical conjunctivitis in about 50% of infants (4). Silver nitrate has largely been replaced by less chemically irritating alternatives in preventing neonatal gonococcal conjunctivitis such as 0.5% erythromycin ointment, 1% tetracycline ointment, and 2% povidone-iodine solution (1). However, these prophylactic measures have not been shown to prevent chlamydial conjunctivitis or nasopharyngeal colonization (5).

Shortly after birth, prophylaxis for gonococcal ophthalmia should be administered to all infants, including those delivered by caesarean section since ascending infection can occur. Erythromycin ointment is the most commonly used, since tetracycline ophthalmic ointment is no longer manufactured in the United States and there are limited studies on povidone-iodine solution. A 1 cm ribbon of 0.5% erythromycin ointment is applied to each lower conjunctival sac and the ointment is spread by gently massaging the eyelids. The eyes should not be flushed or irrigated. If 0.5% erythromycin ointment is not available, one to two drops of 1% azithromycin ophthalmic solution is recommended, or 0.3% ciprofloxacin ointment can be used as a last resort (2,6). Infants born to mothers with untreated gonococcal infection should receive a one-time dose of 25 to 50 mg/kg ceftriaxone (2). In infants with hyperbilirubinemia, particularly those born preterm, ceftriaxone should be used with caution due to potential bilirubin displacement that may increase the risk of kernicterus (6,7). Therefore, close monitoring of serum bilirubin following ceftriaxone administration is recommended. Ceftriaxone is contraindicated in infants receiving intravenous calcium (such as in parenteral nutrition), due to ceftriaxone-calcium complex formation in the biliary system, pulmonary, and renal vasculature (7,8). In cases where intravenous calcium cannot be discontinued, a single dose of gentamicin (2.5 mg/kg IM or IV) can be administered in lieu of ceftriaxone. Currently, there is no antibiotic agent effective for use as prophylaxis for neonatal chlamydial conjunctivitis (8).

The presentation of neonatal conjunctivitis varies with the causative agent, but is typically characterized by erythema and chemosis (swelling) of the conjunctiva, eyelid edema, and non-purulent or purulent discharge. Inflammation due to chemical irritation (such as from silver nitrate drops) is first appreciated 6 to 12 hours after birth, with spontaneous resolution by 24 to 48 hours. In contrast, the incubation period for N. gonorrhoeae is usually 2 to 5 days, with the onset of symptoms ranging from birth to beyond 5 days of age. Initial signs of gonococcal conjunctivitis include bilateral mild inflammation and serosanguinous drainage that later progresses to thick, profuse, purulent discharge and tense eyelid edema with marked chemosis (1,8). In contrast, the incubation period for C. trachomatis is 5 to 14 days, with the onset of symptoms most commonly occurring during the 2nd week of life. Chlamydial conjunctivitis can begin unilaterally, but usually progresses to affect both eyes. Infants present with conjunctival inflammation, eyelid edema, and pseudomembranes in the palpebral conjunctiva. The discharge can initially be watery, evolving into purulent and bloody discharge that may be profuse (1,5).

In infants exposed to C. trachomatis during birth, the risk of a distinct pneumonia is 5% to 30% with concomitant conjunctivitis occurring in 25% to 50% of cases. Patients typically present at 2 to 19 weeks after birth with a history of afebrile illness of insidious onset. The infant usually appears well with tachypnea, a prominent "staccato" cough, and rales on auscultation of the chest. Chest radiograph reveals bilateral, diffuse, patchy infiltrates and hyperinflation. Complete blood count commonly reveals moderate eosinophilia (5,9).

Diagnosis of ocular infection with N. gonorrhoeae can be made following identification of gram negative, oxidase positive diplococci on gram stain or culture on Thayer-Martin media and/or chocolate agar of conjunctival swabs or eye drainage. Cultures of blood, cerebrospinal fluid, or other sites of infection should be obtained in infants with gonococcal ocular infection to rule out disseminated infection. Tests for concomitant C. trachomatis, T. pallidum, and HIV infection should also be performed (8).

For the diagnosis of C. trachomatis in conjunctival swabs, DFA is the only FDA approved culture-independent method. Nucleic acid amplification tests (NAATs), such as polymerase chain reaction (PCR) assays, though not FDA approved, may be offered by clinical laboratories once validated according to regulations of the Clinical Laboratory Improvement Amendments (CLIA). Ligase chain reaction (LCR), DNA probe, enzyme immunoassays (EIAs), or Giemsa-stained epithelial cells scraped from the conjunctivae are other tests that may be used for diagnosis. Specimen collection is conducted by swabbing an everted eyelid and must contain conjunctival cells, not discharge alone. Infants with suspected chlamydial conjunctivitis should have samples taken from both the conjunctivae and the oropharynx (5). Diagnosis of gonococcal or chlamydial infection should prompt testing for other sexually transmitted infections (STIs) in the infant as well as examination of the mother and her sexual partners (2).

For nondisseminated gonococcal ophthalmia, infants should receive one dose of 25 to 50 mg/kg (IV or IM) ceftriaxone. Alternatively, one dose of 100 mg/kg cefotaxime (IV or IM) can be given. Antibiotic therapy is extended to 7 days for septicemia and 10 to 14 days for meningitis (8). Saline irrigation of the eyes should also be performed every 10 to 30 minutes with a gradual increase to 2 hour intervals until the discharge is eliminated (1).

Infants who develop chlamydial conjunctivitis with or without pneumonia should be treated with 50 mg/kg/day oral erythromycin in 4 divided doses for 14 days. In infants less than 6 weeks of age, parents should be counseled regarding a reported association between oral erythromycin and infantile hypertrophic pyloric stenosis (1). Treatment with topical antibiotics is generally not effective due to the risk of conjunctivitis recurrence and the inability to eliminate nasopharyngeal colonization (2). Chemical conjunctivitis is self-limiting and requires no treatment (1).

Without prompt treatment, N. gonorrhoeae ocular infection may spread to the deeper layers of the conjunctivae and cornea. Corneal ulceration, ocular globe perforation, iridocyclitis, anterior synechiae, and panophthalmitis from untreated gonococcal ophthalmitis may result in permanent vision loss and blindness (1). Disseminated gonococcal disease can result in scalp abscess, bacteremia, arthritis, meningitis, endocarditis or death (8). Chlamydial conjunctivitis is often self-limiting and will subside within 2 to 3 weeks without treatment (1). Chlamydial pneumonia, rather than conjunctivitis, is the most serious consequence of neonatal C. trachomatis infection (3). Although the pneumonia is usually mild, severe disease has occurred and can lead to chronic cough and long term pulmonary impairment (5).


Questions
1. Which details of this patient's presentation (in the case) distinguish his illness from neonatal N. gonorrhoeae infection?
2. Besides the infant presented in the case vignette, which other family members should be treated for this condition?
3. What etiologies should be considered when a neonate presents with eye drainage?
4. Of 1% silver nitrate solution, 0.5% erythromycin ointment, 1% tetracycline ointment, and 2.5% povidone-iodine solution, which is/are considered effective for prophylaxis of ocular chlamydial infection?
5. What is the treatment for chlamydial ophthalmia? For gonococcal ophthalmia?
6. What are the long-term complications of gonococcal ophthalmia? Of neonatal C. trachomatis infection?
7. Infants under 6 weeks of age are at increased risk for the development of what disease following treatment with erythromycin?


References
1. Olitsky SE, Marsh JD. Chapter 644. Disorders of the Conjunctiva. In: Kliegman RM, St. Geme J, et al. Nelson Textbook of Pediatrics, 21st edition. 2020. Elsevier, Philadelphia. pp: 3364-3368.
2. Neonatal Ophthalmia. In: Kimberlin DW, Barnett E, Lynfield R, Sawyer MH (ed). Red Book 2021: Report of the Committee on Infectious Diseases, 32nd edition. 2021. American Academy of Pediatrics, Itasca, IL. pp. 1023-1026.
3. Filippakis D, Gkentzi D, Dimitriou G, Karatza A. Neonatal meningococcal disease: an update. J Matern Fetal Neonatal Med. 2020:1-6. doi: 10.1080/14767058.2020.1849092.
4. Moore DL, MacDonald NE, Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Preventing ophthalmia neonatorum. Paediatr Child Health. 2015;20(2):93-6.
5. Chlamydial Infections. In: Kimberlin DW, Barnett E, Lynfield R, Sawyer MH (ed). Red Book 2021: Report of the Committee on Infectious Diseases, 32nd edition. 2021. American Academy of Pediatrics, Itasca, IL. pp. 260-266.
6. Hile GB, Musick KL, Dugan AJ, et al. Occurrence of Hyperbilirubinemia in Neonates Given a Short-term Course of Ceftriaxone versus Cefotaxime for Sepsis. J Pediatr Pharmacol Ther. 2021;26(1):99-103. doi:10.5863/1551-6776-26.1.99.
7. Donnelly PC, Sutich RM, Easton R, et al. Ceftriaxone-Associated Biliary and Cardiopulmonary Adverse Events in Neonates: A Systematic Review of the Literature. Paediatr drugs. 2017;19(1):21-34. doi:10.1007/s40272-016-0197-x.
8. Gonococcal Infections. In: Kimberlin DW, Barnett E, Lynfield R, Sawyer MH (ed). Red Book 2021: Report of the Committee on Infectious Diseases, 32nd edition. 2021. American Academy of Pediatrics, Itasca, IL. pp. 338-344.
9. Hammerschlag MR. Chapter 253. Chlamydia trachomatis. In: Kliegman RM, St. Geme J, et al. Nelson Textbook of Pediatrics, 21st edition. 2020. Elsevier, Philadelphia. pp: 1616-1618.


Answers to questions
1. Late presentation at 4 weeks of life, presence of pseudomembranes, and accompanying respiratory symptoms that are cause by chlamydia pneumonia.
2. The patient's mother and her sexual contacts should seek medical attention and treatment for urogenital chlamydia and other sexually transmitted diseases.
3. Chemical irritants, Neisseria gonorrhoeae, and Chlamydia trachomatis are the most common causes. However, Staphylococcus aureus, group A or B streptococcus, Streptococcus pneumonia, Haemophilus influenzae, Pseudomonas aeruginosa and Herpes simplex virus could also be a potential pathogens.
4. None. Currently, there is no antibiotic agent effective for use as prophylaxis for neonatal chlamydial conjunctivitis. This is interesting because one would think that since chlamydia is generally sensitive to erythromycin and tetracycline, these drops would be able to effectively prophylax against chlamydia conjunctivitis, but they donít. It might be that chlamydia organisms enter the respiratory system as well where eye drops donít have access to.
5. Infants who develop chlamydial conjunctivitis with or without pneumonia should be treated with oral erythromycin (50 mg/kg/day in 4 divided doses) for 14 days. Keep in mind that this might change in the future since azithromycin has replaced erythromycin for nearly all previous indications for erythromycin. For nondisseminated gonococcal ophthalmia, infants should receive 25 to 50 mg/kg ceftriaxone (IV or IM) once. Alternatively, 100 mg/kg cefotaxime (IV or IM) can be given. Cefotaxime has not been recently available. It might return or there might be other cephalosporin alternative recommendations.
6. Without prompt treatment, N. gonorrhoeae ocular infection may result in corneal ulceration and perforation, iridocyclitis, anterior synechiae, and panophthalmitis leading to permanent vision loss and blindness. Left untreated, chlamydia conjunctivitis will subside within 2 to 3 weeks, but chronic infection is common. Chlamydia pneumonia is the most serious consequence of neonatal C. trachomatis infection.
7. Infantile hypertrophic pyloric stenosis.


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