Chloramphenicol: Action as a Reserve Antibiotic

Chloramphenicol is a broad spectrum antibiotic first used clinically in 1947. It acts against a wide spectrum of gram positive and gram negative pathogens including anaerobes and intracellular organisms such as Rickettsiae. Due to its severe hematological side effects, particularly dose independent aplastic anemia, chloramphenicol is today a reserve antibiotic in Germany. Systemic administration is limited to rare and severe infections where no other options are available.

Today topical application is more important than systemic therapy. Chloramphenicol containing eye drops and eye ointments remain standard therapy for bacterial conjunctivitis in many countries. Chloramphenicol also continues to play a role in veterinary medicine and in regions with limited availability of modern antibiotics. In clinical practice in Germany, the substance is seen mainly in ophthalmology and in travel or tropical medicine.

Mechanism of Action

Chloramphenicol reversibly binds to the 50S subunit of the bacterial 70S ribosome and thereby inhibits peptidyl transferase. The result is blockade of protein synthesis and a bacteriostatic effect. In some pathogens such as Haemophilus influenzae, Neisseria meningitidis, or Streptococcus pneumoniae, the effect can be bactericidal at higher concentrations.

The spectrum of activity is very broad: gram positive cocci, many Enterobacteriaceae, anaerobes, Rickettsiae, Chlamydiae, and some mycobacteria. However, many strains are now resistant, especially in hospitals. The substance penetrates tissues very well, including cerebrospinal fluid and the eye. This excellent distribution was historically an important reason for its use in meningitis, ophthalmology, and brain abscesses.

Chloramphenicol is metabolized hepatically through glucuronidation and excreted via the liver and kidney. The half life is approximately two to four hours. In newborns, hepatic glucuronidation is not yet fully developed, which can lead to accumulation and the feared Grey Baby Syndrome.

Areas of Application

• Bacterial conjunctivitis (topical), common indication in ophthalmology, well tolerated
• Otitis externa (topical), in some ear drop combinations
• Severe infections with multidrug resistant pathogens, when no alternatives are available, especially in tropical medicine and travel medicine
• Bacterial meningitis in severe penicillin allergy and lack of alternative
• Rickettsial infections, typhus, brucellosis, plague, and other rare infections in endemic areas
• Veterinary still relevant in certain areas

In Germany, systemic use of chloramphenicol is only indicated in exceptional cases. Standard infections are treated with beta lactams, cephalosporins, macrolides, or other modern antibiotics.

Dosage and Administration

Topical (eye): 0.5 percent eye drops every two hours in the acute phase, later three to four times daily, or 1 percent eye ointment once to twice daily, especially at night. Duration of therapy 5 to 7 days.

Systemic Adults: 50 to 100 mg per kg per day divided into four single doses, intravenously. Maximum dose 4 g per day. Administration typically only in hospital setting.

Pediatric: 50 to 100 mg per kg per day, adjusted for body weight. In infants under 28 days, very restrictive use due to risk of Grey Baby Syndrome.

Plasma levels: with systemic therapy advisable, target range 10 to 25 µg per ml. Above 25 µg per ml the risk of bone marrow toxicity and Grey Baby Syndrome increases. In children, level measurement is mandatory.

Renal impairment: moderate restriction requires no dose adjustment because hepatic glucuronidation is dominant. Hepatic impairment: significant increase in levels possible, caution and level measurement advised.

Side Effects

Common (topical): burning, irritation, local allergic reaction, transient blurred vision from ointment residue.

Common (systemic): nausea, vomiting, diarrhea, glossitis, stomatitis, skin rash.

Rare, but relevant: dose dependent reversible bone marrow suppression with anemia, leukopenia, and thrombocytopenia. This occurs at levels above 25 µg per ml and at higher daily doses, and is reversible after discontinuation.

Very rare, but feared: aplastic anemia, a dose independent idiosyncratic reaction that can affect any patient and carries a mortality risk of approximately 50 percent. It occurs in approximately one in 25,000 to 40,000 patients, sometimes weeks to months after therapy ends.

Grey Baby Syndrome: in newborns under 28 days, especially premature infants, chloramphenicol accumulates due to immature glucuronidation. Symptoms are grey skin color, circulatory failure, respiratory distress, hypothermia. Mortality is high. Avoid or institute strict level monitoring.

Very rare: optic and peripheral neuropathies with prolonged therapy, secondary mycoses, or Clostridioides difficile associated diarrhea.

Drug Interactions

• Vitamin K antagonists (warfarin, phenprocoumon): chloramphenicol inhibits CYP2C9, INR rises, bleeding risk, close monitoring.
• Phenytoin: level increase with neurotoxic symptoms.
• Sulfonylureas: enhanced hypoglycemic effect.
• Cyclophosphamide and some cytostatics: reduced effect with activation dependent substances.
• Iron, vitamin B12, folic acid: theoretically absorption or effect reduction, clinically rarely relevant.
• Penicillins and cephalosporins: theoretical antagonism with bactericidal effect, clinical significance low, avoid combination in practice.
• Other bone marrow toxic substances: additive toxicity, examine carefully.

Special Precautions

Pregnancy: systemic use is not recommended in pregnancy, especially not in the third trimester and perinatally due to risk of Grey Baby Syndrome in the child. Topical eye application is considered acceptable under observation, individual counseling required. Breastfeeding: transfer into breast milk in small amounts, systemic use during breastfeeding not recommended, topical eye application generally acceptable.

Newborns and infants: systemic use very restrictive, level measurement mandatory.

Elderly patients: with systemic therapy, close hematological monitoring, consider comorbidities.

Before starting therapy: complete blood count and differential, liver values, kidney values. Inform patient about the small but real risk of aplastic anemia. Patients and caregivers should be informed about warning signs such as fatigue, persistent infections, tendency to bruising, petechiae.

Monitoring: weekly blood count checks during therapy, if necessary more frequently. After therapy ends, continue checks for at least four weeks because delayed reactions are possible.

Topical eye application: patients should not place the dropper directly on the cornea. Wash hands after application. With prolonged use, ophthalmologist consultation may be advisable.

Fitness to drive: with topical application, blurred vision often briefly after dropping, wait a moment.

You Might Also Be Interested In

• Erythromycin, macrolide in penicillin allergy
• Clindamycin, lincosamide in gram positive and anaerobic infections
• Doxycycline, tetracycline in rickettsial and atypical pathogens
• Tetracycline, classic tetracycline antibiotic
• Vancomycin, glycopeptide in MRSA and severe gram positive infections

Frequently Asked Questions

Sources

• Gelbe Liste, Chloramphenicol Wirkstoffprofil
• BfArM, Bundesinstitut für Arzneimittel und Medizinprodukte
• AWMF, Leitlinien zu Konjunktivitis und Tropeninfektionen
• Robert Koch Institut, antibacterial resistance surveillance