Cefotiam: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Cefotiam is widely used as perioperative prophylaxis in Japan. It is predominantly used intravenously (in the form of cefotiam hydrochloride – C18H23N9O4S3  2HC1), although an oral formulation is available (cefotiam hexetil hydrochloride – C27H37N9O7S3  2HCl). The molecular weight of cefotiam hydrochloride is 598.55 and that of cefotiam hexitil hydrochloride is 768.76. Their formulae are given in Figures 23.1 and 23.2.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro activity of cefotiam against common Gram-positive and Gram-negative pathogens is summarized in Tables 23.1 and 23.2, respectively.

Gram-positive aerobic bacteria

Cefotiam is active against methicillin-susceptible Staphylococcus aureus (MRSA) and streptococci other than pneumococci (Yamaguchi et al., 2006; Yamaguchi et al., 2007; Fujimura et al., 2008; Goto et al., 2008).Penicillin-susceptible Streptococcus pneumoniae is also sensitive to cefotiam, although penicillin-intermediate strains have increased cefotiam MICs; the drug is less active against penicillin-resistant strains (Fujimura et al., 2008). MRSA and enterococci are resistant (Yamaguchi et al., 2006).

Gram-negative aerobic bacteria

Cefotiam is quite active against Escherichia coli and Klebsiella. Proteus mirabilis is less sensitive to cefotiam, and other Proteus spp., Serratia marcescens, Enterobacter aerogenes, Citrobacter freundii, and Morganella morganii are resistant (Yamaguchi et al., 2006; Yamaguchi et al., 2007; Yoshida et al., 2008). Cefotiam lacks antipseudomonal activity.
b. Emerging resistance and cross-resistance These antibiotics are destroyed by extended-spectrum beta-lactamases (ESBLs), AmpC type beta-lactamases, and carbapenemases.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Cefotiam dihydrochloride is usually given in a regimen of 1 g intravenously every 6–12 hours. Given its extremely short half-life (see below under 4b. Newborn infants and children), some clinicians suggest that it be given every 6 hours.
The usual dose of cefotiam hexetil hydrochloride is 100–200 mg (up to 400 mg) three times daily by mouth.

b. Newborn infants and children

For children, a daily dose of cefotiam of 40–80 mg/kg is usually given in three or four divided doses. A maximum dose of 160 mg/kg/day can be given. In the neonatal period (immature, newborn or o3 weeks), it has been shown that the half-life of cefotiam is about 2.65 hours and falls to 1 hour after this period (Brogard et al., 1989). However, there are no published data about the manner to adjust dosing during the neonatal period.

c. Altered dosages Impaired renal function

The elimination half-life of cefotiam rises from approximately 1 hour in people with normal renal function to up to 12–13 hours in patients with significant renal impairment (Rouan et al., 1984). The Japanese product information is silent as to how to dose-adjust in renal failure.

A number of different dosing regimens have been suggested for patients with renal failure. Brogard et al. (1989) have suggested the dose of 1 g 12-hourly given i.v. for patients with creatinine clearances of W30 ml/min. For patients with creatinine clearances of between 5 and 30 ml/min and o5 ml/min, the dose should be reduced to 75% and 50%, respectively (Brogard et al., 1989).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

After oral administration of 400 mg of cefotiam hexetil, the bioavailability is about 45% (Korting et al., 1990). The protein binding of cefotiam at concentrations ranging from 12.5 to 50 mg/l reaches 40% (Brogard et al., 1989).

b. Drug distribution

Daschner et al. (1982) administered doses of 0.5, 1.0, and 2.0 g of cefotiam to healthy volunteers. Peak serum concentrations of 30– 170 mg/ml were achieved. The terminal half-life of the drug in plasma is only 0.6 to 1.1 hours. Therefore, serum concentrations were less than 1 mg/ml within 6 hours after all regimens (Daschner et al., 1982). Others have confirmed the half-life of only about 1 hour (Brisson et al., 1984; Rouan et al., 1985; Brogard et al., 1989).
With oral administration of 400 mg cefotiam hexetil, maximum plasma concentrations of 2.6 mg/ml occur at 2.1 hours after administration (Korting et al., 1990).

The ratio of concentrations of cefotiam in bronchial secretions to serum concentrations ranged from 26% (at 1 hour) to 200–300% (at 3–4 hours) in patients with acute respiratory infections (BergogneBerezin et al., 1982).

c. Clinically important pharmacokinetic and pharmacodynamic features

Like other cephalosporins, these drugs are time-dependent killers. Few, if any, pharmacodynamic analyses have been performed.

d. Excretion

Cefotiam is excreted mainly via the kidneys. After intravenous administration of cefotiam 0.5, 1 and 2 g, over 50% of the drug was excreted during the first 2 hours and the 8-hour urinary excretion represented 60–80% of the administered dose (Daschner et al., 1982). The urinary concentration of cefotiam was 900–7400 mg/ml during the first hour after intravenous administration of 1 g (Brogard et al., 1989).

CLINICAL USES OF THE DRUG

a. Respiratory tract infections

Beumer et al. (1985) conducted an open comparative study that compared cefotiam (1 g twice-daily) with cefamandole (1 g three times daily) in the treatment of respiratory tract infections (Beumer et al., 1985). They reported that the clinical and bacteriologic efficacy of both drugs was equivalent and the radiologic examinations showed a better improvement in patients treated with cefotiam.

Polis and Tuazon (1985) evaluated cefotiam in 29 patients with lower respiratory tract infection. In this study, satisfactory response was observed in 90% of the patients. However, there were three treatment failures, two superinfections, and four colonizations with Gramnegative organisms resistant to the drug.

b. Urinary tract infections

A study was carried out in 35 patients with urinary tract infections to compare the efficacy and tolerance of cefotiam (1 g twice-daily) and cephalothin (1 g four times daily) (Tselentis et al., 1983). In this study, only one patient of those receiving cefotiam failed to respond and suffered a delayed relapse, but five patients failed to respond to cephalothin: in three of them bacteriuria persisted throughout treatment and there was relapse in the other two patients. The time until disappearance of bacteriuria was significantly shorter in the cefotiam group.

c. Skin and skin-structure infection

Cefotiam was evaluated by a comparative open-label randomized trial with cephalothin in the therapy of skin and soft-tissue infections in 39 patients (Lentino et al., 1984). Cefotiam was found to be as effective as cephalothin in the therapy of skin and soft-tissue infections in this underpowered study.

d. Perioperative prophylaxis

Gaillard and Gilsbach (1991) reported a prospective, randomized, and controlled study on the efficacy of cefotiam for the prevention of wound infections following neurosurgery. Only clean or clean contaminated cases were included in this study, and contaminated cases, operations with a transnasal–transsphenoidal approach, shuntoperations, and patients with any other preoperative infection or antibiotic therapy were excluded. Cefotiam was administered intravenously in a single dose of 2 g with induction of anesthesia.

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