Potential dual role of cephalosporins in management of alcohol use disorders.

Abstract

Dear Sir, Apropos the paper by Alhaddad et al., titled “Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats,” we would like to share our views on the other aspects of the potential role of cephalosporins in the treatment of alcohol use disorders. Traditionally, cephalosporins, a β-lactam antibiotic group, have been considered successful drugs to treat infection caused by Gram-positive bacteria (Page 2004). Overall, cephalosporins generally cause few side effects and mainly consist of hypersensitivity reactions like fever, arthralgia, and exanthema; hematological reactions like increase risk of bleeding, eosinophilia, and thrombocytosis; and renal reaction like decreased renal function (Norrby 1987). However, the adverse reaction that caught the attention of addiction specialists is disulfiram-like reaction in patients consuming alcohol following a cephalosporin dose. Cefamandole, cefoperazone, andmoxalactam have been repeatedly reported to produce this reaction (Uri and Parks 1983; Norrby 1987). Other cephalosporins, which can cause disulfiram-like reactions, are cefonicid, ceftriaxone, cefmenoxime, and cefuroxime (Kannangara et al. 1984; Marcon et al. 1990; Billstein and Sudol 1992; Dong et al. 2013). The reaction is commonly ascribed to the methyl-thiotetrazole (MTT) group, resembling part of the disulfiram molecule. Additionally, recent preclinical studies have successfully demonstrated a role of certain cephalosporins like ceftriaxone in reducing alcohol consumption. The possible mechanism for this effect is through regulation of glutamate transporter 1 (GLT1) and immunomodulation (Sari et al. 2011; Qrunfleh et al. 2013; Alhaddad et al. 2014). The unique properties of cephalosporins to cause both disulfiram-like reactions (deterrent) and reduction in alcohol consumption (anticraving agent) are the two most important strategies, which are used, in pharmacological management of alcohol use disorders. While the currently available anticraving agents like naltrexone and acamprosate reduce the amount of alcohol intake, disulfiram act as a deterrent agent causing unpleasant reaction when it is consumed along with alcohol. The US Food and Drug Administration (FDA) has approved these three drugs for treatment of alcohol dependence. Most importantly, combined pharmacotherapies (deterrent and anticraving agent combination) have superior efficacy compared to monotherapy in the management of alcohol use disorders (Besson et al. 1998; Jung and Namkoong 2006; Suh et al. 2006; Lee and Leggio 2014). Hence, a molecule with the benefit of both these properties will prove to be a boon to management of alcohol use disorders. To the best of our knowledge, cephalosporins are the only group of drugs that can potentially have dual action of deterrent and anticraving agents for alcohol use disorders. Further research on the exact molecular groups responsible for the deterrent and anticraving action can provide an impetus for development of newer drugs as well. A single drug for longterm treatment will improve compliance and minimize side effects with much benefit to patients and clinicians alike.