High-dose ceftriaxone, as recommended by French guidelines, was well tolerated with limited toxicity in adults with central nervous system (CNS) infections, according to a study published in the Journal of Antimicrobial Chemotherapy.

Guidelines by the European Society of Clinical Microbiology and Infectious Diseases and Infectious Diseases Society of America recommend a ceftriaxone dosage limited to 4 g daily as a single or double injection with no body weight adjustment. French guidelines for meningitis, however, recommend 75 to 100 mg/kg/day ceftriaxone (in 1 or 2 injections per day) adjusted to body weight without an upper limit. While the higher dosage is purported to provide sufficient coverage of all strains of Streptococcus pneumoniae encountered in bacterial meningitis, no study has specifically assessed ceftriaxone-related adverse drug reactions when administered at a higher dosage.

Therefore, this open-label, multicenter, prospective cohort study (ClinicalTrials.gov identifier: NCT01745679) evaluated the toxicity of a high-dose ceftriaxone regimen (daily dose ≥4 g or ≥75 mg/kg/day) by screening for ceftriaxone-related adverse drug reactions in adults with CNS infections. An expert committee who reviewed the medical charts for all included patients assessed drug causality systematically.

Over a 31-month period between December 2012 and July 2015, 196 patients were enrolled. Median age was 59 years (interquartile range [IQR] 40-68 years). Community-acquired bacterial meningitis was the most common diagnosis (n=109) with S pneumoniae being the most frequent causative bacteria (n=32).

The median ceftriaxone initial dosage was 96.4mg/kg/day (IQR 81.6-103.9), corresponding to a median of 7 g/day (IQR 6-8 days). The median duration of treatment was 8 days (IQR 5-12 days).

The expert committee analysis showed that a total of 17 patients experienced ceftriaxone-related adverse drug reactions (8.7%; 95% CI, 5.1%-13.4%) with only 1 case of treatment discontinuation because of biliary pseudolithiasis. Neurotoxicity (n=7) was the most frequently reported adverse drug reaction.

The univariate analysis showed that older age (odds ratio [OR] 1.06; 95% CI, 1.02-1.10; P =.004), male gender (OR 5.05; 95% CI, 1.12-22.74, P =.035), and having a total ceftriaxone trough plasma concentration above 100 mg/L (OR 4.06; 95% CI, 1.31-12.60; P =.02) were associated with the occurrence of ceftriaxone-related adverse drug reactions. Higher renal clearance was a protective factor (OR 0.98, 95% CI, 0.97-1.00; P =.010).

The multivariate analysis was limited by the small number of patients with ceftriaxone-related adverse drug reactions and showed only age and male gender as risk factors.

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The results of this study supported the use of high-dose ceftriaxone regimen in CNS infections as recommended by the French guidelines. “In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring may be useful,” concluded the investigators.

Reference

Le Turnier P, Navas D, Garot D, et al. Tolerability of high-dose ceftriaxone in CNS infections: a prospective multicentre cohort study [published online January 29, 2019]. J Antimicrob Chemother. doi: 10.1093/jac/dky553