Abstract

Chloramphenicol, C₁₁H₁₂Cl₂N₂O₅, is a commercially significant antibacterial agent. Although widespread use of this antibiotic declined in the United States in the 1960s because of reports of serious toxic effects, this situation changed a decade later when ampicillin-resistant Hemophilus influenzae emerged on the clinical scene. The appearance of Bacteroides species and of Streptococcus pneumoniae resistant to -lactam antibiotics contributed further to the resurgence. In the 1970s, chloramphenicol also became important in the treatment of serious Salmonella invasive gastroenteritis in infants less than three months of age. Because chloramphenicol crosses the blood brain barrier, it is indicated in infections of the central nervous system caused by susceptible organisms. The emergence of quinolones and other antibiotics is expected to curtail the use of chloramphenicol in the future, but this drug is relatively inexpensive, orally active, and the toxicity, except for the rare idiosyncratic aplastic anemia, can be managed through monitoring of blood levels by sensitive modern analytical procedures. However, clinical use is being further curtailed by the emergence of chloramphenicol-resistant organisms. Both chloramphenicol and thiamphenicol cause reversible bone marrow suppression. The irreversible, often fatal, aplastic anemia, however, is only seen for chloramphenicol. Thiamphenicol lacks potency and has never found much usage in the United States. An analogue of thiamphenicol having antimicrobial potencies equivalent to chloramphenicol was sought. Florfenicol was selected for further development. Of the many mechanisms of bacterial resistance to chloramphenicol and thiamphenicol, the plasmid-mediated transmissible resistance conferred by the presence in resistant bacteria of chloramphenicol-acetyltransferases (CAT) is the most important. Structure–activity and mechanism of action studies indicate that the requirements for chloramphenicol activity are the D-threo-configuration, the 1,3-propanediol moiety, and a strong electron-withdrawing group on the aromatic ring. Because the lack of biological activity of 3-substituted chloramphenicols, biological activity of 3-fluorochloramphenicol against chloramphenicol-sensitive and -resistant organisms was determined. The synthesis and biological evaluation of a number of amphenicols containing a fluorine atom at the 3-position resulted. The most promising florfenicol, 3-fluorothiamphenicol, is not only active against the chloramphenicol-thiamphenicol-resistant strains, but its potency against sensitive organisms is also superior to any of the other amphenicols. The absolute ban on the use of chloramphenicol in food-producing animals in the United States and Canada has accentuated the need for an effective broad-spectrum antibiotic in animal food medicine. Florfenicol and other antibiotics commonly used in veterinary medicine have been evaluated in vitro against a variety of important veterinary and aquaculture pathogens. Florfenicol was broadly active. Florfenicol was also superior to chloramphenicol, thiamphenicol, oxytetracycline, ampicillin, and oxolinic acid against the most commonly isolated bacterial pathogen of fish in Japan. The inhibitory activities of chloramphenicol, thiamphenicol, and florfenicol against a sensitive E. coli strain have been studied. In two different liquid media, both chloramphenicol and florfenicol allowed only 20–30% residual growth at a drug concentration of 2 mg/L. Florfenicol was also found to be a selective inhibitor of prokaryotic cells. Florfenicol is similar to thiamphenicol in acute toxicity by oral and subcutaneous (sc) administration, but is comparable to chloramphenicol by intraperitoneal (ip) and intravenous (iv) routes. A dramatic effect was seen for florfenicol against Shigella (3 mg/kg sc, 2 mg/kg oral) as compared to chloramphenicol and thiamphenicol (100 mg/kg by both routes). Against resistant strains of Enterobacter, Klebsiella, Providencia, Serratia, Salmonella, and Staphylococcus, the PD₅₀ values for florfenicol ranged from 5 to 60 mg/kg whereas chloramphenicol and thiamphenicol were practically ineffective.