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

These cephalosporins are referred to as extended-spectrum or third-generation cephalosporins because they were developed after the first- and second-generation drugs. Owing to their prominence, Ceftriaxone, cefotaxime and ceftazidime are discussed in detail in their own chapters. However, other third-generation cephalosporins include ceftizoxime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefsulodin, and cefpiramide, which have availability limited to only certain countries or are seldom, if ever, used in contemporary practice. Description of these antibiotics is therefore limited, with the exception of ceftizoxime (as a representative of a parenterally administered third-generation cephalosporin) and cefpodoxime (as a representative of an orally administered third-generation cephalosporin).
Ceftizoxime is a 7-aminothiazolyl alpha-methoxymino cephalosporin, which is structurally related to cefotaxime and its desacetyl metabolite. Unlike cefotaxime, this drug is not deacetylated in vivo. It has similar activity to cefotaxime or ceftriaxone. It has poor activity against Pseudomonas aeruginosa (Barry et al., 1982). The chemical structure of ceftizoxime is shown in Figure 28.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

All of these cephalosporins have no activity against methicillinresistant Staphylococcus aureus, enterococci, and Listeria monocytogenes.

Gram-positive aerobic bacteria

S. aureus and coagulase-negative staphylococci are ceftizoxime susceptible, except for methicillin-resistant strains. Streptococcus pyogenes, S. pneumoniae, Group B streptococci, and viridans streptococci are also susceptible. The in vitro activity of ceftizoxime against common human pathogens is summarized in Table 28.1.

Gram-negative aerobic bacteria

Against Neisseria meningitidis and N. gonorrhoeae, ceftizoxime is equally potent as cefotaxime. Beta-lactamase-producing gonococcal strains are fully ceftizoxime-susceptible (Barry et al., 1982). Non-beta-lactamase producing gonococci (both relatively and completely penicillin G resistant) are also ceftizoxime-susceptible – but MICs (0.008–0.03 mg/ ml) for completely resistant strains are slightly higher than those for penicillin G-susceptible strains (Rodrı`guez et al., 1983).

Ceftizoxime shows a high degree of stability to the narrower spectrum TEM-1 and SHV-1 beta-lactamases, but is potentially hydrolyzed by extended-spectrum beta-lactamases, AmpC type beta-lactamases and most carbapenemases (Simpson et al., 1982; Sykes and Bush, 1983).

The activity of ceftizoxime against Enterobacteriaceae is virtually identical to cefotaxime; there being only minor variations with some bacterial species. Ceftizoxime is slightly more active than cefotaxime against Klebsiella, Enterobacter, Providencia, and Serratia spp., whereas Morganella morganii is more susceptible to cefotaxime (Fu and Neu, 1980; Greenwood et al., 1980; Barry et al., 1982; Muytjens and Van der Ros-van de Repe, 1982). Ceftizoxime, like cefotaxime, is quite active against Yersinia enterocolitica (Hornstein et al., 1985).

Haemophilus influenzae, including beta-lactamase-producing strains, is highly ceftizoxime susceptible (Barry et al., 1982). Pasteurella multocida is susceptible and Moraxella spp. are moderately susceptible, but Flavobacterium spp. are usually resistant (Yabuuchi et al., 1981; Appelbaum et al., 1982; Barry et al., 1982).

Ceftizoxime lacks clinically useful activity against P. aeruginosa, being about 2-fold less active even than cefotaxime (Kamimura et al., 1979; Bodey et al., 1981; Barry et al., 1982; see Table 28.1). Burkholderia cepacia, Acinetobacter spp., and P. putida are relatively resistant and P. fluorescens and Stenotrophomonas maltophilia are resistant (Yabuuchi et al.,1981; Appelbaum et al., 1982).

Anaerobic bacteria

Clostridium perfringens is sensitive, but C. difficile is usually resistant (Fu and Neu, 1980; Greenwood et al., 1980; Barry et al., 1982). Some anaerobic Gram-negative bacilli, such as Prevotella melaninogenica and P. disiens, are susceptible to low ceftizoxime concentrations. Beta-lactamases produced by Bacteroides fragilis can hydrolyze ceftizoxime (Eley and Greenwood, 1981; Rolfe and Finegold, 1981; Chow and Finegold, 1982; Neu, 1982). Nevertheless, it has been shown that using broth microdilution testing, the in vitro activity of ceftizoxime is sometimes as good as, or better than, that of cefoxitin or cefotetan against anaerobes, including the B. fragilis group (Aldridge, 1990; Aldridge and Stratton, 1991).

Other bacteria

Ceftizoxime is highly active against leptospirae in vitro (Oie et al., 1983). b. Emerging resistance and crossresistance Ceftizoxime is susceptible to hydrolysis by extended-spectrum beta-lactamases, AmpC beta-lactamases, and most carbapenemases. Cefpodoxime and the other orally administered third-generation cephalosporin antibiotics are also destroyed by these beta-lactamases. Some P. aeruginosa strains can become cefsulodin-resistant because they have a significant reduction in affinity for PBP3, which is the principal target for cefsulodin in P. aeruginosa (Gotoh et al., 1990).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

A commonly used dosage for ceftizoxime in adults is 2–4 g daily, given in two, three, or four divided doses. For serious infections, a daily dose of 6–12 g has been used (Johnson and Smith, 1982; Parks et al., 1982).

b. Newborn infants and children

For children, the ceftizoxime dosage is 50–150 mg/kg body weight per day, given in two, three, or four divided doses (Parks et al., 1982; Shikuma et al., 1982). In clinical trials, ceftizoxime was used to treat serious neonatal infections in dosages ranging from 100 to 400 mg/kg/ day without encountering toxicity (Parks et al., 1982; Yamauchi et al., 1982).

c. Altered dosages Impaired renal function

Ceftizoxime is not metabolized in the body, and its normal serum half-life of 1.4 hours is prolonged to some 30 hours in anephric patients (Ohkawa et al., 1982). Therefore, in patients with renal failure, ceftizoxime dosage should be reduced. Assuming that the usual dosage for normal adults is 1 g 8-hourly, the following dosages have been recommended for patients with renal failure. Patients with mild renal failure (creatinine clearance 70 ml/min) can be given the usual individual 1 g dose 12-hourly. Those with moderately severe renal failure (creatinine clearance 20–30 ml/min) should receive such a dose every 36–48 hours, whereas those with severe renal failure (creatinine clearance o1 ml/min) should be given the normal dose at a time interval greater than 48 hours, depending on frequency of hemodialysis (Kowalsky et al., 1983). Ceftizoxime is removed by hemodialysis but supplemental dosage is not always necessary after this procedure (Cutler et al., 1982). Some ceftizoxime is also removed by peritoneal dialysis. In patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis, a 3 g i.v. dose of ceftizoxime given once every 48 hours is recommended (Burgess and Blair, 1983).

b. Newborn infants and children

For children, the ceftizoxime dosage is 50–150 mg/kg body weight per day, given in two, three, or four divided doses (Parks et al., 1982; Shikuma et al., 1982). In clinical trials, ceftizoxime was used to treat serious neonatal infections in dosages ranging from 100 to 400 mg/kg/ day without encountering toxicity (Parks et al., 1982; Yamauchi et al., 1982).

c. Altered dosages

Impaired renal function

Ceftizoxime is not metabolized in the body, and its normal serum halflife of 1.4 hours is prolonged to some 30 hours in anephric patients (Ohkawa et al., 1982). Therefore, in patients with renal failure, ceftizoxime dosage should be reduced. Assuming that the usual dosage for normal adults is 1 g 8-hourly, the following dosages have been recommended for patients with renal failure. Patients with mild renal failure (creatinine clearance 70 ml/min) can be given the usual individual 1 g dose 12-hourly. Those with moderately severe renal failure (creatinine clearance 20–30 ml/min) should receive such a dose every 36–48 hours, whereas those with severe renal failure (creatinine clearance o1 ml/min) should be given the normal dose at a time interval greater than 48 hours, depending on frequency of hemodialysis (Kowalsky et al., 1983). Ceftizoxime is removed by hemodialysis but supplemental dosage is not always necessary after this procedure (Cutler et al., 1982). Some ceftizoxime is also removed by peritoneal dialysis. In patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis, a 3 g i.v. dose of ceftizoxime given once every 48 hours is recommended (Burgess and Blair, 1983).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Serum protein binding of ceftizoxime in humans is 31% (Cutler et al., 1982).

b. Drug distribution

If 2 g of ceftizoxime is infused i.v. over a 30 minutes period in adults, the mean peak serum level after the infusion is about 150 mg/ml. The level then falls to 30, 10, 4, and 0.3 mg/ml, at 2, 4, 6, and 8 hours after infusion, respectively (Peterson et al., 1982; Quintiliani and Nightingale, 1982). Distribution of this drug in the body is probably similar to that of cefotaxime. It does not penetrate well into normal CSF, but therapeutic levels are found in most patients with bacterial meningitis. Cable et al. (1982) gave single doses of 30 mg/kg by i.v. infusion to 12 patients with bacterial meningitis. Concentrations of CSF 2 hours later were 0–17 (mean 4.9) mg/ml. In animals, ceftizoxime reaches therapeutic levels in the kidney, liver, lungs, heart, and tissue fluid (Murakawa et al., 1980; Gerding et al., 1982; Van Etta et al., 1983).

c. Excretion

Ceftizoxime is not metabolized in the body; most of an administered dose is excreted via the kidneys by both glomerular filtration and tubular secretion. Probenecid partially blocks renal tubular secretion, thereby delaying excretion and enhancing serum levels by about 50%. High urinary levels of the active drug are attained, which are 700–3200 mg/ml during the first 4 hours after an i.m. dose of 0.5 g (Neu and Srinivasan, 1981; Cutler et al., 1982; Le Bel et al., 1983). Urinary recovery of ceftizoxime after parenteral administration has been reported to be between 70% and 100% (Neu and Srinivasan, 1981; Peterson et al., 1982; Le Bel et al., 1983). Very little ceftizoxime is excreted by non-renal routes in humans. In animals, small amounts are excreted in bile, including an antimicrobially active metabolite, but no such metabolite has been detected in human bile (Murakawa et al., 1980).

TOXICITY

In clinical trials, side-effects have been mild and infrequent and are similar to those of most other cephalosporins. These include hypersensitivity rashes, eosinophilia, drug fever, and transient elevations of hepatic transaminases and serum alkaline phosphatase.

Elevated platelet counts (thrombocytosis) occur not infrequently during ceftizoxime therapy. These are not associated with symptoms, and counts revert to normal after the drug is stopped. Reversible thrombocytopenia and neutropenia are less frequent. Some patients develop a positive Coombs’ test. Diarrhea, nausea, and vomiting are infrequent. C. difficile-associated diarrhea has been reported. Transient elevations of blood urea and serum creatinine levels occur in some patients, but serious nephrotoxicity has not been encountered (Counts et al., 1982; Parks et al., 1982).

CLINICAL USES OF THE DRUG

Clinical experience with this drug is more limited than that with cefotaxime or ceftriaxone, but ceftizoxime is very similar, and so the potential clinical uses of them may be much the same. Ceftizoxime has been used with success in severe hospital-acquired infections caused by the Enterobacteriaceae, such as pyelonephritis, pneumonia, and septicemia (Bechard, 1982; Cohen and Mogabgab, 1982; Scully and Neu, 1982).

Ceftizoxime has not been adequately evaluated for bacterial meningitis caused by Enterobacteriaceae. Adequate CSF concentrations of the drug are reached in patients with meningitis. A small number of patients with meningitis caused by pneumococci, meningococci, and H. influenzae type B have been cured by i.v. ceftizoxime in a dosage of 200 mg/kg body weight per day (Cable et al., 1982; Overturf et al., 1984). Ceftizoxime has been quite effective in the treatment of other severe H. influenzae infections in both adults and children (Parks et al., 1982).

Lou et al. (1982) found ceftizoxime satisfactory for the treatment of 119 patients with peritonitis. In one randomized study, ceftizoxime in large dosages (3 g i.v. 8-hourly) was equally effective to a clindamycin– tobramycin combination for the treatment of intra-abdominal and female genital tract infections (Harding et al., 1984).

Uncomplicated genital gonorrhoea responds well to a single 0.5– 1.0 g i.m. dose of ceftizoxime without probenecid. It is effective for infections caused by beta-lactamase-producing strains (Lutz et al., 1982; Spencer et al., 1984).

References

Aldridge KE (1990). An update on the in vitro activity of ceftizoxime and other cephalosporin/cephamycin antimicrobial agents against clinically significant anaerobic bacteria. Clin Ther 12 (Suppl C): 3.
Aldridge KE, Stratton CW (1991). Bactericidal activity of ceftizoxime, cefotetan and clindamycin against cefoxitin-resistant strains of Bacteroides fragilis group. J Antimicrob Chemother 28: 701.
Borin MT, Hughes GS, Spillers CR, Patel RK (1990). Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob Agents Chemother 34: 1094.
Burgess ED, Blair AD (1983). Pharmacokinetics of ceftizoxime in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother 24: 237.
Cable D, Edralin G, Overturf GD (1982). Human cerebrospinal fluid pharmacokinetics and treatment of bacterial meningitis with ceftizoxime. J Antimicrob Chemother 10 (Suppl C): 121.
Chachaty E, Depitre C, Mario N et al. (1992). Presence of Clostridium difficile and antibiotic and beta-lactamase activities in feces of volunteers treated with oral cefixime, and cefpodoxime proxetil, or placebo. Antimicrob Agents Chemother 36: 2009.
Dumont R, Guetat F, Andrews JM et al. (1990). Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil. J Antimicrob Chemother 26 (Suppl E): 41.
Edlund C, Stark C, Nord CE (1994). The relationship between an increase in beta-lactamase activity after oral administration of three new cephalosporins and protection against intestinal ecological disturbances. J Antimicrob Chemother 34: 127.
Eley A, Greenwood D (1981). in vitro activity of ceftizoxime against Bacteroides fragilis: comparison with benzylpenicillin, cephalothin, and cefoxitin. Antimicrob Agents Chemother 20: 332.
Fu KP, Neu HC (1980). Antibacterial activity of ceftizoxime, a beta-lactamasestable cephalosporin. Antimicrob Agents Chemother 17: 583.
Gibson TP, Granneman GR, Kallal JE, Sennello LT (1982). Cefsulodin kinetics in renal impairment. Clin Pharmacol Ther 31: 602.
Gibson TP, Granneman GR, Kallal JE, Sennello LT (1984). Kinetics of cefsulodin in patients with renal impairment. Rev Infect Dis 6 (Suppl 3): 689.

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