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

Cefpodoxime is another oral third-generation cephalosporin, which has good stability to many beta-lactamases and activity against Gramnegative and some Gram-positive bacteria. It is not absorbed from the gastrointestinal tract as such; therefore, the carboxy group on the cephem nucleus of cefpodoxime has been esterified to produce the oral prodrug cefpodoxime proxetil, which itself is antibacterially inactive. This ester is about 50% absorbed; thereafter, it is de-esterified in the intestinal mucosa and the active drug cefpodoxime is released into the blood (Borin et al., 1990; Sader et al., 1993). The chemical structure of cefpodoxime is shown in Figure 28.2.

These cephalosporins are referred to as extended-spectrum or thirdgeneration 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 thirdgeneration 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).

ANTIMICROBIAL ACTIVITY

Gram-positive aerobic bacteria

The hemolytic streptococci of Groups A, B, C, G, and F are cefpodoxime susceptible. Penicillin-sensitive strains of S. pneumoniae are also susceptible, but strains of pneumococci with any degree of penicillin G resistance have higher MICs for cefpodoxime than those for penicillin G-sensitive strains. S. aureus, and coagulase-negative staphylococci, irrespective of beta-lactamase production, are susceptible, but methicillin-resistant strains are not. Enterococcus faecalis and other enterococci are cefpodoxime-resistant (Fass and Helsel, 1988; Jones and Barry, 1988; Dabernat et al., 1990; Sader et al., 1993; Spangler et al., 1993). The in vitro activity of cefpodoxime against common human pathogens is summarized in Table 28.2.

Gram-negative aerobic bacteria

Neisseria meningitidis, N. gonorrhoeae, and H. influenzae are cefpodoxime sensitive, irrespective of beta-lactamase production (Jones and Barry, 1988; LiPuma et al., 1990; Fekete et al., 1991; Valentini et al., 1994). The same is true for Moraxella catarrhalis (Sarubbi et al., 1989), but the MICs for ampicillin-resistant non-beta-lactamase producing H. influenzae strains are somewhat elevated. Bordetella pertussis and B. parapertussis are moderately resistant (Hoppe and Mu¨ller, 1990). The Enterobacteriaceae such as Escherichia coli, the Klebsiella, Salmonella, and Shigella spp., Citrobacter diversus, Proteus mirabilis, P. vulgaris, Providencia rettgeri, and P. stuartii are usually cefpodoxime susceptible. However, AmpC hyperproducers such as Enterobacter spp., C. freundii, S. marcescens, and M. morganii are usually resistant (Fass and Helsel, 1988; Jones and Barry, 1988; Wise et al., 1990; Sader et al., 1993; Valentini et al., 1994; see Table 28.2).

Among other aerobic Gram-negative bacteria, the Aeromonas spp., Yersinia spp., and Acinetobacter spp. are usually resistant, as is Campylobacter jejuni. P. aeruginosa, other Pseudomonas spp., and S. maltophilia are always resistant (Fass and Helsel, 1988; Sader et al., 1993; Valentini et al., 1994).

MODE OF DRUG ADMINISTRATION AND DOSAGE

The dosage varies with indication and ranges between 100, 200, and 400 mg orally twice-daily. The dosage of cefpodoxime proxetil is expressed in milligrams of active cefpodoxime. A dosage of 100 mg 12- hourly is sufficient for relatively mild infections caused by highly susceptible organisms, such as streptococcal pharyngitis and acute bronchitis. A dosage of 200 mg 12-hourly is recommended for the treatment of more severe infections, such as bacterial pneumonia or acute exacerbations of chronic bronchitis (Periti et al., 1990; Safran, 1990; Portier et al., 1994). For skin infections, 400 mg 12-hourly is recommended.

b. Newborn infants and children

The recommended dose is 5 mg/kg every 12 hours.

c. Altered dosages Impaired renal function

For patients with a creatinine clearance of less than 30 ml/min, the dosing interval is increased to every 24 hours.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Approximately 50% of the administered dose of cefpodoxime proxetil is absorbed after oral administration and released into the circulation as active cefpodoxime (Borin et al., 1990; O’Neill et al., 1990; Tremblay et al., 1990). Cefpodoxime proxetil is slightly better absorbed if it is given together with food (Wise, 1990; Borin and Forbes, 1995). Optimal absorption of cefpodoxime requires low gastric pH. Therefore the co-administration of antacids and H2 receptor antagonists significantly reduce the absorption of this drug (Saathoff et al., 1992). Cefpodoxime is approximately 40% serum protein bound (Fassbender et al., 1993).

b. Drug distribution

After a single 200 mg dose of oral cefpodoxime proxetil, a mean peak serum level of 2.18 mg/ml of cefpodoxime is reached in about 3 hours. The serum level thereafter falls and it is less than 0.5 mg/ml in 12 hours. The elimination half-life is 2.7 hours. If 400 mg cefpodoxime proxetil is administered, the serum levels are approximately doubled. Cefpodoxime does not accumulate in serum if 200- or 400-mg doses are given every 12 hours.

Cefpodoxime has penetrated into blister fluid reaching concentrations there which were 67–103% of the serum levels at the time (Borin et al., 1990; O’Neill et al., 1990). The mean penetration of cefpodoxime in bronchial mucosal fluid was recorded as 54% (Baldwin et al., 1992). The mean concentrations of this drug in lung tissue were recorded as 0.63, 0.52, and 0.19 mg/g at 3, 6, and 12 hours after administration of a 200 mg cefpodoxime proxetil dose, respectively (Couraud et al., 1990). In another study, the ratios between concentrations in lung parenchyma and simultaneous concentrations in plasma were 84.7% and 51.2% at 3 and 6 hours, respectively, after administration of 200 mg oral cefpodoxime proxetil (Muller-Serieys et al., 1992). In pleural effusions in patients who received a single 200-mg dose, the concentrations were 0.62, 1.84, and 0.78 mg/ml at 3, 6, or 12 hours after the dose, respectively (Dumont et al., 1990). In tonsillar tissue after a dose of 100 mg of cefpodoxime proxetil, the concentrations after 4 and 7 hours were 0.24 and 0.09mg/g, respectively, this being approximately 23% of plasma concentrations (Gehanno et al., 1990).

c. Excretion

Cefpodoxime excretion is predominantly renal, with approximately 80% of the absorbed dose excreted in urine as the active drug (Tremblay et al., 1990). The mean 8- to 12-hour urine concentration after 200 mg of cefpodoxime was 19.8 mg/ml and, from 12–24 hours, was 3.9 mg/ml (Wise, 1990). The drug is excreted by both glomerular filtration and tubular secretion. Probenecid delays tubular secretion resulting in higher serum levels (St Peter et al., 1992). A small amount of absorbed cefpodoxime undergoes biotransformation in humans (Johnson et al., 1993).

TOXICITY

Similar to other cephalosporins, cefpodoxime proxetil is a drug with low toxicity. Skin eruptions and pruritus have occurred in a few patients. Neutropenia, eosinophilia, and mildly abnormal liver function tests have also been noted infrequently. Nausea, vomiting, soft stools, and diarrhea have been slightly more frequent. In one trial, six healthy adult volunteers were given 400 mg of oral cefpodoxime proxetil daily for 10 days. Before treatment, no volunteers had C. difficile in stools, but during treatment C. difficile was detected in the stools of all volunteers. These strains were cefpodoxime-resistant. Intestinal side-effects were limited to modification of stool consistency (Chachaty et al., 1992). In another study with healthy volunteers, overgrowth of enterococci and yeasts were noted during administration of cefpodoxime proxetil (Edlund et al., 1994).

CLINICAL USES OF THE DRUG

Cefpodoxime was found to be superior to amoxicillin–clavulanic acid for the treatment of otitis media in children in a single study (Gehanno et al., 1994). A total of 220 adults and children over ten years of age with streptococcal pharyngitis or tonsillitis were randomized to receive either cefpodoxime proxetil 100 mg 12-hourly for 5 days or penicillin V 600 mg 8-hourly orally for 10 days. Clinical and bacteriologic cure was high (over 90%) in both groups, but the advantage of cefpodoxime appeared to be the shorter course of treatment (Portier et al., 1994). The oral third-generation cephalosporins do appear to have a role in the treatment of streptococcal pharyngitis.

For the treatment of bacterial sinusitis, cefpodoxime (84% clinical cure) was found to be superior to cefaclor (68% clinical cure) (Gehanno et al., 1990). In patients with bronchopneumonia, cefpodoxime proxetil 200 mg 12-hourly orally was equally as effective as i.m. ceftriaxone 1 g daily, both given for a 10-day period (Zuck et al., 1990). In patients with exacerbations of chronic bronchitis, cefpodoxime proxetil was effective, and the results of treatment were similar to those obtained with coamoxiclav (Periti et al., 1990).

In uncomplicated gonorrhoea in males, a single oral dose of cefpodoxime proxetil 100 mg or even 50 mg was curative (Novak et al., 1992). However, clinical experience is quite limited.

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