Chloramphenicol

Objectives

After completing this article, readers should be able to:

1. Explain why chloramphenicol no longer is the drug of choice for any infection.

2. Name those conditions for which chloramphenicol may be an effective alternative therapy.

3. Discuss why serum concentrations of chloramphenicol are erratic, especially in those who have liver disease.

4. Recognize the major adverse effects of chloramphenicol.

5. Explain why serum concentrations of chloramphenicol are affected by the concomitant use of certain drugs such as phenytoin, rifampin, or phenobarbital.

Introduction

Chloramphenicol is an antimicrobial agent used rarely today in the United States because of its associated adverse effects (Table 1). At one time it was hailed as a highly effective, broad-spectrum agent against many gram-positive and gram-negative bacteria, spirochetes, chlamydiae, and rickettsia. Chloramphenicol had a major role in the treatment of meningitis caused by Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis because of its bactericidal activity against these organisms and the ability to achieve high concentrations in the cerebrospinal fluid. As is the case with more recent “miracle” antimicrobials, perhaps chloramphenicol was overused since its discovery in 1947. This may have led to the development of resistance and increased reports of adverse events. Today there are many alternative agents that have greater safety profiles, but chloramphenicol remains a useful antimicrobial agent. This review addresses the clinical indications for chloramphenicol usage, spectrum of antimicrobial activity, pharmacokinetic properties, bacterial resistance, and major adverse effects.

Chemistry and Mechanism of Action

Chloramphenicol is produced synthetically, but it was isolated originally from the organism Streptomyces venezuelae found in soil and compost. Production of the oral preparation, chloromycetin palmitate, was discontinued in the United States, but it is readily available in other parts of the world in capsule form. The parenteral formulation, chloromycetin sodium succinate, still is being produced in limited supply in the United States.

Chloramphenicol inhibits protein synthesis in susceptible organisms by competing with messenger RNA for binding sites on the ribosome required for the formation of peptide bonds. Chloramphenicol reversibly binds to the 50S subunit of the 70S ribosome, which prevents the attachment of the amino acid-containing end of the aminoacyl-tRNA to its binding region, thereby inhibiting peptidyl transferase. This mechanism of action is usually bacteriostatic, although chloramphenicol is bactericidal against the three most common causes of meningitis in children: H influenzae, S pneumoniae, and N meningitidis. The spectrum of activity for chloramphenicol includes gram-positive and gram-negative bacteria, anaerobes, spirochetes, rickettsia, chlamydiae, and mycoplasma.

Resistance

Chloramphenicol was at one time the universal treatment of choice for typhoid fever. However, because of the unrestricted, over-the-counter availability of chloramphenicol in many parts of the world, much of the Salmonella typhi in developing countries has developed resistance. Chloramphenicol resistance also has been reported in other previously susceptible organisms, including Shigella sp and H influenzae. Bacteria become resistant to chloramphenicol by becoming impermeable to the drug or by producing an inactivating enzyme, chloramphenicol acetyltransferase. The latter mechanism is plasmid-mediated, which is important, because cross-resistance to other antimicrobials, such as aminoglycosides and tetracyclines, is not uncommon.

Pharmacokinetics

Chloramphenicol is available for systemic use as capsules, a tasteless oral suspension, and a parenteral formulation. The oral formulations of chloramphenicol palmitate are well absorbed from the gastrointestinal tract, achieving higher peak serum levels than equal doses administered intravenously or intramuscularly. The earlier formulations of oral suspension often produced erratic serum levels, but current formulations are said to achieve levels comparable to capsules. Chloramphenicol palmitate is hydrolyzed in the intestine to produce active chloramphenicol.

The intravenous formulation of chloramphenicol sodium succinate is hydrolyzed to biologically active chloramphenicol. This preparation achieves serum concentrations that are approximately 70% of the levels obtained by oral administration due to incomplete hydrolysis. Although intramuscular preparations are well tolerated, there are conflicting data on their bioavailability. Generally they appear to achieve lower serum concentrations than achieved by intravenous administration. Intramuscular administration usually is discouraged because of the delayed therapeutic response and increased relapse rate associated with lower serum concentrations.

Chloramphenicol is metabolized primarily in the liver, where it is conjugated and excreted in its inactive form by the kidneys. The rate of metabolism varies greatly in children, especially among newborns and young children. Because of this wide variation, it is imperative to monitor serum levels weekly, especially in low-birthweight infants.

Patients who have hepatic insufficiency also conjugate chloramphenicol at a slower rate, which may produce serum levels of active chloramphenicol capable of causing bone marrow suppression. Dose adjustment is required in such cases, and serum levels must be monitored more frequently.

No adjustment is required in patients who have renal insufficiency because the half-life of biologically active chloramphenicol differs only slightly from that seen in healthy individuals. Serum levels are not affected by peritoneal or hemodialysis.

Concurrent use of rifampin or phenobarbital may result in decreased serum concentrations of chloramphenicol because both agents are inducers of hepatic microsomal enzymes. Concomitant administration of phenytoin may cause accumulation of chloramphenicol in serum that may reach toxic levels. Toxic levels of phenytoin also have been reported. Other drugs metabolized in the liver, such as acetaminophen, isoniazid, and theophylline, may have similar effects. Serum concentrations of chloramphenicol should be measured to monitor safe and effective levels of the drug. Peak serum concentrations of chloramphenicol generally are reached 30 minutes after completion of an intravenous infusion or 90 minutes after oral administration and should be maintained at 15 to 30 mcg/mL to ensure an adequate therapeutic level and to avoid toxicity. Serum levels should be obtained after two or three doses and monitored weekly or more frequently if clinically indicated.

Chloramphenicol diffuses well into many tissues and body fluids, achieving levels in the cerebrospinal fluid that are approximately 30% to 50% of serum concentrations. This is greater than levels achieved by other antibiotics and possibly is due to the drug’s small molecular size and its high degree of lipid solubility and low protein binding. Therapeutic levels also are achieved in pleural, ascitic, and synovial fluid.

Adverse Reactions

Bone marrow suppression is the most significant adverse effect of chloramphenicol and may occur by two very distinct mechanisms. The first and more common form is a dose-related bone marrow suppression associated with elevated peak (>25 mcg/mL) and trough (>10 mcg/mL) levels, which usually occurs after a minimum of 7 days of therapy. It is the result of inhibition of mitochondrial protein synthesis and is characterized by cytoplasmic vacuolization of early erythroid and myeloid precursors in the bone marrow. Laboratory findings include anemia, leukopenia, thrombocytopenia, decreased reticulocyte count, and increased concentration of serum iron. It is reversible when chloramphenicol is discontinued.

The second form is a rare, but often fatal, irreversible idiosyncratic aplastic anemia. Most cases occur weeks to months after the completion of therapy, although approximately 20% of the cases occur during treatment. Idiosyncratic aplastic anemia is believed to occur in approximately 1 in 40,000 to 100,000 courses of therapy. It is seen more frequently following oral administration, although cases have been reported following parenteral and ophthalmic administration of the drug. The more common occurrence of bone marrow aplasia after oral administration compared with parenteral administration possibly reflects the relative frequency of oral administration compared with parenteral administration. The mechanism is unknown, but theories include direct toxicity by degradation products of chloramphenicol. Monitoring of complete blood counts twice weekly for all patients receiving chloramphenicol is recommended. If the white blood cell count decreases below 2.5×10³/mcL (2.5×10⁹/L), chloramphenicol should be discontinued if the clinical condition allows.

The gray baby syndrome of neonates is characterized by abdominal distention, vomiting, flaccidity, cyanosis, circulatory collapse, and death. These symptoms of cardiovascular collapse are due to direct interference with myocardial tissue respiration and oxidative phosphorylation caused by increased serum concentrations of chloramphenicol. This results from the decreased ability of the immature liver in neonates to metabolize chloramphenicol and to excrete the inactive form in urine. Chloramphenicol use should be avoided in neonates. However, if chloramphenicol is used, the dose should be reduced to 25 mg/kg per day, and peak and trough levels should be monitored closely. This syndrome also has been recognized in older children and adults after accidental overdoses resulting in serum concentrations of chloramphenicol of greater than 50 mcg/mL.

Although the effect on breastfeeding infants is not known, women receiving chloramphenicol should not breastfeed because of the theoretical risk of idiosyncratic and dose-related bone marrow suppression or gray baby syndrome in the infant. Additionally, chloramphenicol should be avoided by women near term or in active labor.

Other less common adverse effects include hemolytic anemia in patients who have the Mediterranean form of glucose-6-phosphate dehydrogenase deficiency, hepatitis, pseudomembranous colitis, encephalopathy, optic neuritis, and hypersensitivity reaction.

Clinical Indications for Use

Chloramphenicol no longer is the drug of choice for any specific infection (Tables 2 and 3). Rocky Mountain spotted fever and other rickettsial infections in young children or pregnancy were exceptions in the past because of the concern about using tetracyclines in children younger than 8 years of age. However, doxycycline currently is considered the drug of choice against Rocky Mountain spotted fever and ehrlichiosis for children of any age because permanent dental discoloration is less likely with this agent, especially if the treatment is of short duration. Chloramphenicol may be considered an alternative therapy in severe infections such as meningitis among penicillin-allergic patients or if cephalosporin-resistant S pneumoniae is present. Other possible indications include use as an oral agent for bacterial meningitis or for typhoid fever in developing countries where parenteral therapy is not available.

As happened with vancomycin, chloramphenicol may become an important agent in the treatment of multiple drug-resistant organisms such as vancomycin-resistant Enterococcus (VRE) or methicillin-resistant Staphylococcus aureus (MRSA). New agents developed to treat resistant gram-positive infections, such as quinupristin, dalfopristin, and linezolid, already have been associated with clinical failures or resistance. Although there have been cases of clinical failure with chloramphenicol-treated cancer patients who had bacteremia caused by VRE, studies have shown an overall improved clinical outcome and reduced mortality when chloramphenicol was used as early empiric therapy. Chloramphenicol also is being used in patients who have acquired immunodeficiency syndrome and VRE or MRSA infections not responding to quinupristin, dalfopristin, or linezolid.

Summary

Chloramphenicol was the first truly broad-spectrum antibiotic that had excellent tissue penetration available for clinical use. It was the drug of choice for many serious infections, such as bacterial meningitis, epiglottitis, typhoid fever, and Rocky Mountain spotted fever, until better and safer alternatives became available. Almost immediately after becoming licensed, adverse effects were reported with its use, including bone marrow suppression, idiosyncratic aplastic anemia, and cardiovascular collapse (gray baby syndrome). Chloramphenicol is a valuable antimicrobial agent that presently has very limited indications for use in the United States due to potential adverse effects. Chloramphenicol is currently available only as a parenteral formulation and in limited supply in the United States. However, the drug continues to play a major role in the treatment of serious infections in developing countries and may be of great therapeutic benefit for the management of life-threatening drug-resistant infections or in persons who are allergic to penicillin. It is important, therefore, that we reacquaint ourselves with this potent antimicrobial.