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Drugs

, Volume 44, Issue 5, pp 800–834 | Cite as

Cefodizime

A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use
  • Lee B. Barradell
  • Rex N. Brogden
Drug Evaluation

Abstract

Synopsis

Cefodizime is a third generation cephalosporin with a broad spectrum of antibacterial activity. Administered intravenously or intramuscularly, cefodizime 1 to 4g daily for an average of 7 to 10 days produced clinical cure in 80 to 100% of patients (adults, elderly or children) with upper or lower respiratory tract infections or urinary tract infections, and in comparative trials cefodizime was as effective as other third generation cephalosporins. A single dose of cefodizime 1 or 2g is also useful in treating lower urinary tract infections, particularly uncomplicated infections, with a rate of clinical success of 72 to 88%. Urogenital gonorrhoea, whether caused by β-lactamase producing or non-β-lactamase producing Neisseria gonorrhoeae, is very effectively treated by single dose therapy with intramuscular cefodizime 0.25 to 1g (virtually 100% cured). Preliminary data from a small number of patients indicate that cefodizime may also be useful in the treatment of otitis media, sinusitis and gynaecological infections, and for the prophylaxis or treatment of surgical infections.

The clinical efficacy of cefodizime in comparison with other third generation cephalosporins is superior to that predicted from in vitro results. This superior activity of cefodizime may be related to the relatively long elimination half-life of the drug or its ability to modify some functions of the immune system — a potentially important finding awaiting further investigation.

Cefodizime is well tolerated and has a tolerability profile similar to other members of its class with systemic adverse events being primarily gastrointestinal or dermatological.

Thus, limited comparative studies indicate cefodizime has the potential to become a useful alternative to current antimicrobial therapy for the treatment of a variety of infections. Cefodizime may be more convenient to administer than some other agents of its class as it may be given once or twice daily. While there are no trials comparing cefodizime to other third generation cephalosporins in immunosuppressed populations, preliminary information indicates cefodizime may be useful in this group.

Antimicrobial Activity

Cefodizime has a broad spectrum of antibacterial activity against Gram-negative and Gram-positive aerobic organisms. For the purposes of this review, bacterial species are considered to be susceptible to cefodizime if 90% of tested strains of the bacteria are inhibited at cefodizime concentrations of 8 mg/L in vitro. Enterobacteriaceae including Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Shigella sonnei, Yersinia enterocolitica and Salmonella species were all consistently sensitive to cefodizime in vitro. Cefodizime had marginal but variable inhibitory activity against Citrobacter species including Citrobacter freundii, and Serratia marcescens and, in common with most other third generation cephalosporins, cefodizime was ineffective in vitro at inhibiting Enterobacter spp.

Cefodizime inhibited other Gram-negative bacteria including Haemophilus influenzae (ampicillin-sensitive or resistant), Moraxella catarrhalis, Neisseria gonorrhoeae (β-lactamase and non-β-lactamase producing) and Neisseria meningitidis, but was inactive against Pseudomonas aeruginosa and Xanthomonas maltophilia.

Methicillin-sensitive Staphylococcus aureus were susceptible, while Staphylococcus epidermidis and methicillin-resistant S. aureus were resistant to cefodizime. Streptococcus agalactiae, pneumoniae and pyogenes were all inhibited by cefodizime in vitro, which had activity comparable with that of the first and second generation cephalosporins.

Cefodizime is a bactericidal antibiotic having high affinity for penicillin-binding proteins 1A/B, 2 and 3 of E. coli. The in vitro concentrations of cefodizime resulting in bactericidal activity against susceptible strains of Gram-positive and Gram-negative bacteria are generally similar to the minimum inhibitory concentrations.

In experimental models of infection in vivo, cefodizime was at least as effective as other third generation cephalosporins in achieving bacterial clearance or decreasing bacterial counts. Cefodizime had inhibitory activity comparable with or better than that of cefotaxime against experimental infections caused by E. coli, K. pneumoniae, P. mirabilis, S. marcescens and S. pneumoniae.

Immunomodulatory properties may account for differences observed between the in vitro activity of cefodizime against specific bacteria and the greater efficacy apparent in in vivo models of infection. After administration of therapeutic doses of cefodizime to humans, in vitro and ex vivo experiments have demonstrated that cefodizime stimulates some functions of phagocytic and lymphocytic cells, restoring them when impaired.

Pharmacokinetic Properties

Administration of cefodizime 1 or 2g intravenously as a single dose to healthy volunteers resulted in peak serum cefodizime concentrations (Cmax) of 215 and 394 mg/L, respectively; Cmax was dose-proportional over this range. Intravenous infusions and intramuscular injections of cefodizime 1g resulted in peak serum concentrations of 124.1 mg/L and 59.6 to 75.2 mg/L, respectively. Bioavailability of cefodizime after intramuscular administration is 90 to 100%. Cefodizime is approximately 81% plasma protein bound (primarily to albumin), and distributes into many body tissues and fluids providing concentrations above the minimum inhibitory concentration (MIC) of susceptible organisms within 2 to 3 hours of administration and for several hours thereafter. Cefodizime is primarily eliminated by glomerular filtration and to a lesser extent by tubular secretion, with the majority of the drug excreted unchanged in the urine in the first 12 hours after drug administration. Concomitant administration of probenecid to healthy volunteers decreases cefodizime elimination by 30%. In patients with acute exacerbation of chronic bronchitis the terminal phase elimination half-life of cefodizime has been reported to be 4.8 to 5.0 hours, and the elimination half-life is prolonged 2-fold in patients with severe renal impairment Systemic absorption of cefodizime from the intraperitoneal fluid is variable and serum elimination is prolonged in patients undergoing continuous peritoneal dialysis. Cefodizime is removed from the systemic circulation by haemodialysis with a terminal phase elimination half-life of 3.5 hours, similar to that in patients with normal renal function.

Therapeutic Efficacy

Cefodizime has shown efficacy in the treatment of upper and lower respiratory tract infections, urinary tract infections and gonorrhoea in comparative and noncomparative trials. Cefodizime 2 to 4 g/day in 1 to 2 doses daily, administered intravenously or intramuscularly for an average of 7 to 10 days, eradicated H. influenzae, K. pneumoniae, non-β-lactamase-producing M. catarrhalis, and S. pneumoniae in patients with pneumonia and other lower respiratory tract infections. Cefodizime was clinically effective in 80 to 100% of these patients and bacterial eradication rates (89 to 98%) paralleled clinical efficacy. In the few comparative trials reported, clinical and bacteriological success rates of cefodizime were similar to those of ceftriaxone, cefuroxime and cefotaxime. In children and elderly patients with lower respiratory tract infections, cefodizime treatment achieved good clinical results in 86 to 100% and 87.5% of patients, respectively. Similar clinical cure rates were observed in the treatment of upper respiratory tract infection in noncomparative trials undertaken primarily in children.

Cefodizime 1 to 2 g/day in single or divided doses for 7 to 9 days (mean) resulted in clinical cure in 86 to 100% of paediatric, adult or elderly patients with urinary tract infections. In the treatment of complicated and uncomplicated urinary tract infections, single dose therapy with intramuscular cefodizime 1 or 2g resulted in clinical cure in 72 and 88% of patients, respectively. Preliminary evidence from trials comparing cefodizime with cefuroxime, ceftizoxime and nor-floxacin suggests that cefodizime is as effective as these standard therapies in the treatment of urinary tract infection.

A single intramuscular injection of cefodizime 0.25 to 1g demonstrated almost 100% efficacy in the treatment of urogenital gonorrhoea; cefodizime 0.5 or 1g was as effective as a single dose of cefotaxime 1g, producing clinical cure in 100, 100 and 99% of patients, respectively. Cefodizime was effective irrespective of the sex of the patient or the penicillinase-producing status of the N. gonorrhoeae.

Cefodizime has also been assessed in small noncomparative trials in patients with meningitis, otitis media, gynaecological infections and various surgical infections. Administration of cefodizime 100 mg/kg/day to adults or 200 mg/kg/day to children with bacterial meningitis resulted in clinical cure, without sequelae, in 80% of cases. Intravenous cefodizime was clinically effective in 88 to 100% of Japanese women with various gynaecological infections. Pathogen eradication rates of 40 to 75% were achieved; Enterococcus faecalis was the most common persisting organism. The post-operative infection rate in immunocompromised patients administered a single intramuscular injection of cefodizime 2g 30 minutes before abdominal surgery was 5%, compared with 25% in untreated patients. Noncomparative trials of intravenous infusions of cefodizime 0.5 to 2g daily in 2 divided doses have demonstrated clinical cure rates of 65 to 80% in patients with various surgical infections. Bacteriological efficacy was 75 to 85% and 68 to 71% in infections caused by Gram-negative and Gram-positive bacteria, respectively.

Tolerability

Cefodizime has generally been well tolerated by adults and children following intravenous and intramuscular injection in clinical trials conducted worldwide. Adverse reactions which were thought to be ‘definitely’, ‘probably’ or ‘possibly’ related to treatment occurred in 3.1% of patients on multiple-dose therapy and 1.2% of patients receiving a single dose of cefodizime. Adverse reactions which were classified as ‘doubtfully’ or ‘conditionally’ treatment-related were experienced by 2.0% of patients undergoing multiple-dose treatment with cefodizime. 2.8% of patients undergoing trials in Japan were reported to experience adverse events. Adverse events lead to treatment withdrawal in 0.9% of patients. No deaths were reported to be causally related to cefodizime therapy. Adverse events most frequently involved local irritation, and gastrointestinal and dermatological reactions. Gastrointestinal symptoms, including diarrhoea, nausea, vomiting and elevated transaminases, occurred in 2.4% of patients and resulted in treatment withdrawal in 0.5% of cases. Allergic reactions most commonly manifested as dermatological reactions including exanthema, urticaria, and pruritus, and developed in 1.1% of patients; treatment was withdrawn in 0.4% of patients as a result of dermatological reactions and in 0.2% of patients with other manifestations of allergy. Local reactions at the injection site consisted of pain accompanying intramuscular administration and phlebitis associated with intravenous delivery. In elderly patients the incidence of adverse events, excluding death, was 8%. Cefodizime did not affect the coagulation system and appeared to exert little influence on renal function.

Dosage and Administration

Cefodizime can be administered intramuscularly, or by intravenous bolus or infusion. The most frequently used adult dosage in clinical trials has been 2 or 4g daily in 1 or 2 divided doses, either intramuscularly or intravenously. For uncomplicated lower urinary tract infections single doses of 1 or 2g have been effective. In patients with gonorrhoea 0.25 to 1g as a single dose has resulted in clinical and bacteriological cure rates of virtually 100%. Dosage should be modified in patients with renal impairment, with a maximum of cefodizime 2g daily given to patients with a creatinine clearance of 0.6 to 1.8 L/h (10 to 30 ml/min), and half this dose to patients with a creatinine clearance of < 0.6 L/h (< 10 ml/min). In patients undergoing haemodialysis, cefodizime 1 to 2g should be administered after each dialysis cycle. A dosage of 60 mg/kg/day (typically in 3 to 4 divided doses) is frequently used for the treatment of infections in paediatric populations, except in bacterial meningitis where 200 mg/kg/day (in 4 divided doses) has been administered.

Keywords

Urinary Tract Infection Minimum Inhibitory Concentration Cefotaxime Cefuroxime Lower Respiratory Tract Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1992

Authors and Affiliations

  • Lee B. Barradell
    • 1
  • Rex N. Brogden
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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