Ceftriaxone

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Abstract
Since ceftriaxone was first reviewed in the Journal, further studies have confirmed its broad antibacterial spectrum in vitro and extended its clinical documentation in comparative studies with other widely used drugs in infections of the urinary and lower respiratory tract, meningitis in infants and children, uncomplicated gonorrhoea, perioperative prophylaxis in patients undergoing surgery, and in several other types of infection. As in earlier studies, which primarily used a twice-daily dosage regimen, few significant differences were found between therapeutic groups in comparative studies and results have demonstrated the efficacy of once-daily ceftriaxone in all but the most serious infections, such as sole antibiotic therapy in pseudomonal infections. Wider clinical experience has established that ceftriaxone is generally well tolerated. Thus, ceftriaxone now has a well-defined place as an appropriate alternative for the parenteral treatment of a variety of infections due to susceptible organisms, as well as for perioperative prophylaxis of surgery, and may offer advantages of greater convenience over other parenteral antibiotics which are administered more frequently. Ceftriaxone has a broad spectrum of activity in vitro which includes Gram-positive and Gram-negative aerobic and some anaerobic bacteria. Both penicillin-sensitive and-resistant strains of Staphylococcus aureus are sensitive to ceftriaxone (MIC90 2 to 8 mg/ L), but the drug is poorly active against methicillin- or oxacillin-resistant strains. Ceftriaxone is similar in activity to several penicillins and other cephalosporins against Streptococcus pneumoniae and Streptococcus pyogenes, and is also active in low concentrations against other Streptococcus species (S. agalactiae and viridans streptococci). However, Staphylococcus epidermidis is only moderately sensitive and Streptococcus faecalis is usually resistant to ceftriaxone. Ceftriaxone is generally more active than cefoperazone (except against Pseudomonas aeruginosa), and is similar in activity to cefotaxime and latamoxef (moxalactam) against Gram-negative bacilli. 90% of tested strains of most Enterobacteriaceae were inhibited by a ceftriaxone concentration of ≤ 1 mg/L, but Enterobacter cloacae is less sensitive. The reported activity of ceftriaxone against Pseudomonas aeruginosa varies widely, but generally at least 32 mg/L is required to inhibit most strains, and is thus usually less active than the aminoglycosides, aztreonam, imipenem, cefoperazone, ceftazidime, carumonam and piperacillin. The combination of ceftriaxone and an aminoglycoside is usually synergistic against P. aeruginosa in vitro (20 to 80% of tested strains). However, synergy is less common against aminoglycoside-resistant and/or multidrug-resistant strains. Ceftriaxone is active at very low concentrations against β-lactamase-positive and -negative strains of Haemophilus influenzae and Neisseria gonorrhoeae and N. meningitidis (all with MIC90 ≤ 0.025 mg/L). Clostridium difficile and several species of Bacteroides, including B. fragilis, are only moderately sensitive or insensitive to ceftriaxone, but some other anaerobic bacteria are inhibited by the drug. Ceftriaxone is stable to inactivation by β-lactamases produced by many bacteria, but not to those produced by B. fragilis or by some strains of Klebsiella species, Proteus vulgaris and Pseudomonas cepacia. In general, the β-lactamase stability of ceftriaxone is similar to that of cefotaxime and cefuroxime, which are inactivated by fewer β-lactamases than cefamandole, cephalothin and cephaloridine, but by more β-lactamases than latamoxef and cefoxitin. Mean peak plasma concentrations of ceftriaxone were 151 and 286 mg/L following bolus intravenous administration of 0.5 and 1.5g, respectively, and 82, 151 and 257 mg/ L after 30-minute infusions of 0.5, 1 and 2g, respectively. Due to saturable plasma protein binding the plasma concentration and the area under the plasma concentration-time curve (AUC) of total ceftriaxone increased less than dose-proportionally after intravenous doses greater than 1g. However, the peak free (unbound) plasma concentration increased disproportionally, thus supporting once daily administration of ceftriaxone in large doses rather than the same daily dose as divided smaller doses. Mean peak plasma ceftriaxone concentrations after intramuscular injection were around one-half those after intravenous administration of the same dose, and bioavailability was similar to that after intravenous injection. Accumulation of ceftriaxone in plasma was around 40% after 12-hourly intravenous injection, but only 8% when administered at 24-hour intervals. The volume of distribution of total (bound plus unbound) ceftriaxone during the terminal elimination phase increased with increasing dose, but the volume of distribution of the free fraction remained relatively constant. Recent studies have confirmed that mean ceftriaxone concentrations inhibitory for most Gram-negative bacteria were present in many body fluids and tissues, and particularly in cerebrospinal fluid of patients with meningitis, 24 hours after 1 to 2g administered intravenously. Ceftriaxone is excreted in breast milk (around 3 to 4% of that in...