ToxCard: Chloramphenicol Toxicity

Authors: Nabihah Kumte, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC); Anna Dulaney, PharmD (Clinical Toxicologist, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC) // Reviewed by Tony Spadaro, MD, MPH (Assistant Professor of Emergency Medicine, Medical Toxicology, and Addiction Medicine at University of Pennsylvania); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 3-week-old male infant is brought to the ED by his parents due to poor feeding and lethargy over the past 12 hours. He was born at 33 weeks gestation via spontaneous vaginal delivery. The infant was born overseas after his mother went into labor while traveling abroad. The infant had been admitted briefly to the hospital nursery after birth for suspected neonatal sepsis and was started on intravenous chloramphenicol because of a reported shortage of other antibiotics. He was discharged home on the same medication. On the day following discharge, the infant traveled back to the U.S. with his parents and had been doing well until two days ago when he started vomiting and appeared lethargic.

On arrival to the ED, the infant is ill-appearing and minimally responsive. His skin is ashen gray with mottling, and his abdomen appears distended. He is hypotensive, tachypneic, hypoxic, hypotonic, and has a poor suck reflex.

Questions:

1. What is the syndrome associated with chloramphenicol that can affect infants?
2. What routine labs do you obtain in the ED?
3. What is the treatment?

Background:

Chloramphenicol is an antibiotic used for the treatment of infections such as meningitis, cholera, typhoid fever, and rickettsial diseases. It was initially used for empiric treatment in pediatric patients presenting with a fever and petechial rash due to its coverage for meningococcal and rickettsial diseases.¹ In high doses, chloramphenicol can cause a rare but serious side effect in neonates called Gray Baby Syndrome which is characterized by circulatory collapse and an ashen gray skin color. The exact incidence of Gray Baby Syndrome is not well-defined however it is considered to be uncommon.² Chloramphenicol is not routinely used in the United States however its clinical use can be found in Asian and African countries where third-generation cephalosporins are unaffordable or unavailable.³

Clinical Presentation: 

Gray Baby Syndrome typically affects preterm infants who are directly receiving intravenous chloramphenicol; however, it can affect children up to 2 years of age. It can also affect neonates who are breastfed if the mother is taking chloramphenicol as it passes into breastmilk.⁴ Chloramphenicol is metabolized by glucuronidation in the liver; neonates are unable to produce sufficient UDP-glucanosyltransferase due to immature livers.^5,6 This results in an accumulation of chloramphenicol and causes Gray Baby Syndrome. Signs and symptoms include:^5-8

• Irritability and lethargy
• Hypothermia
• Poor feeding and vomiting
• Hypoglycemia
• Abdominal distention
• Hypotension
• Respiratory distress
• Skin discoloration

The cause of death in Gray Baby Syndrome is usually sudden cardiovascular and respiratory collapse. The severity of symptoms is correlated with the serum concentration of chloramphenicol; with a serum concentration greater than 50 mcg/mL consistent with gray baby syndrome.⁶ Given the rarity of this syndrome, a broad differential should still be considered including but not limited to sepsis, congenital cardiac abnormalities, toxicological ingestion/exposure, inborn errors of metabolism, pulmonary hypertension, and acute liver failure. A targeted history must be obtained in order to narrow the differential.

Diagnosis: 

Serum chloramphenicol is not a routine laboratory test ordered in the emergency department and may be a send-out lab in many hospital systems. Diagnosis of Gray Baby Syndrome relies heavily on a thorough history including pregnancy complications, recent or current medications including prophylactic treatments, and any medications that the mother may be taking if the infant is breastfed. Other causes of cyanosis in neonates must be evaluated and recommended; broad workup includes point of care glucose, blood gas, co-oximetry, methemoglobin, serum lactate, metabolic profile, chest/abdominal x-rays, cardiac biomarkers, electrocardiography, echocardiography, and a thorough physical exam.

Management: 

Treatment consists of immediate cessation of chloramphenicol and supportive management of symptoms.  Chloramphenicol can be directly removed from the serum via activated charcoal hemoperfusion or potentially, less preferably, through exchange transfusion.^6,7,9 However, there are very few places in the U.S. that perform charcoal hemoperfusion due to limited availability and expense. There has been some discussion regarding phenobarbital for treatment of Gray Baby Syndrome as it can induce the UDP-glucanosyltransferase enzyme required for the metabolism and excretion of chloramphenicol however this is not a formal recommendation based on phenobarbital’s FDA drug label.^7,10,11 For a hemodynamically unstable neonate with refractory cardiovascular collapse, prompt discussion with the pediatric intensivist and consideration for extracorporeal membrane oxygenation should occur. Otherwise, prognosis is generally good if the diagnosis of Gray Baby Syndrome is made early with adequate symptomatic management.⁶

Case Follow-up:

An astute emergency physician reviews the medication list and recognizes that the infant had been receiving high doses of chloramphenicol. Given the patient’s age, symptoms, and exposure history, the team suspects Gray Baby Syndrome.

Chloramphenicol is immediately discontinued. The infant is started on oxygen, intravenous fluids, vasopressors for hypotension, and broad-spectrum alternative antibiotics. The critical care team is consulted, and charcoal hemoperfusion is considered to reduce circulating drug levels.

The infant is admitted to the pediatric intensive care unit for further management and close monitoring.

Clinical Pearls:  

• Gray Baby Syndrome is caused by an accumulation of chloramphenicol in infants due to immature hepatic metabolism.
• Typically affects preterm neonates.
• This is rare in the United States due to limited use of chloramphenicol in clinical scenarios.
• The gray color is due to cardiovascular and respiratory collapse, not due to a pigment deposition.
• The primary treatment for Gray Baby Syndrome is the immediate cessation of chloramphenicol use. In more severe cases, charcoal hemoperfusion can be considered.

References:

1. Oong GC, Tadi P. Chloramphenicol. StatPearls. Treasure Island (FL): StatPearls Publishing. 2021. PMID 32310426.
2. Knight M. Adverse drug reactions in neonates. J Clin Pharmacol. 1994 Feb;34(2):128-35. doi: 10.1002/j.1552-4604.1994.tb03976.x. PMID: 8163712.
3. Weber MW, Gatchalian SR, Ogunlesi O, Smith A, McCracken GH Jr, Qazi S, Weber AF, Olsen K, Mulholland EK. Chloramphenicol pharmacokinetics in infants less than three months of age in the Philippines and The Gambia. Pediatr Infect Dis J. 1999 Oct;18(10):896-901. doi: 10.1097/00006454-199910000-00012. PMID: 10530587.
4. Chloramphenicol. Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US). 2006. PMID 30000554.
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6. Cummings ED, Kong EL, Edens MA. Gray Baby Syndrome. StatPearls. Treasure Island (FL): StatPearls Publishing. 2021. PMID 28846297.
7. Gude H. A Note on Gray baby syndrome. Endocrinology & Metabolic Syndrome. 2021;10:326.
8. Brousseau T, Sharieff GQ. Newborn emergencies: the first 30 days of life. Pediatr Clin North Am. 2006;53(1):69-vi. doi:10.1016/j.pcl.2005.09.011
9. Mauer SM, Chavers BM, Kjellstrand CM. Treatment of an infant with severe chloramphenicol intoxication using charcoal-column hemoperfusion. J Pediatr. 1980 Jan;96(1):136-9. doi: 10.1016/s0022-3476(80)80350-7. PMID: 7350295.
10. Windorfer A Jr, Pringsheim W. Studies on the concentrations of chloramphenicol in the serum and cerebrospinal fluid of neonates, infants, and small children. Reciprocal reactions between chloramphenicol, penicillin and phenobarbitone. Eur J Pediatr. 1977 Jan 26;124(2):129-38. doi: 10.1007/BF00477548. PMID: 832646.
11. SEZABY (phenobarbital sodium) [package insert]. Charlestown, MA: Eton Pharmaceuticals, Inc.; 2025.