Cefpodoxime Proxetil

Abstract

Synopsis

Cefpodoxime proxetil is an orally administered prodrug which is absorbed and de-esterifled by the intestinal mucosa to release the third generation cephalosporin, cefpodoxime.

Cefpodoxime is stable towards the most commonly found plasmid-mediated β-lactamases and the drug has a broad spectrum of antibacterial activity encompassing both Gram-negative and Gram-positive bacteria, rendering it a possible option for empirical use in a wide range of community acquired infections in both adult and paediatric patinets. The extended plasma half-life of cefpodoxime (1.9 to 3.7h) permits twice daily administration.

In comparative trials, twice daily cefpodoxime proxetil (dose equivalent cefpodoxime 100 to 400mg) was as effective as a 3- to 4-times daily regimen of phenoxymethylpenicillin in pharyngotonsillitis, as well as thrice daily amoxicillin (with or without clavulanic acid) or cefaclor against infections of the ear, the upper and lower respiratory tract, the urinary tract and those of the skin and soft tissues. The latter reflects the enhanced antistaphylococcal activity of cefpodoxime, which distinguishes it from other orally active third generation cephalosporins such as cefixime. Most notably, an oral regimen of cefpodoxime proxetil was as efficacious as parenterally administered ceftriaxone for the treatment of bronchopneumonia in hospitalised patients at risk due to the presence of underlying diseases, addictions or advancing age. A single oral dose of cefpodoxime was also as efficacious as ceftriaxone in uncomplicated anogenital gonococcal infections.

Cefpodoxime proxetil is generally well tolerated, with mild to moderate gastrointestinal disturbances occurring in 4 to 15% of patients treated with therapeutic doses.

Thus, a convenient twice daily oral regimen of cefpodoxime proxetil can be prescribed as an effective alternative to established β-lactam therapies in the empirical outpatient treatment of infections of the respiratory and urinary tracts as well as those of the skin and soft tissues.

Antibacterial Activity

Cefpodoxime is highly active against both Haemophilus influenzae and Moraxella catarrhalis including β-lactamase producing strains, with a minimum inhibitory concentration for 90% of tested strains (MIC90) ⩽ 1 mg/L; cefpodoxime had a similar potency to that of cefixime but greater than that of cefuroxime, cefaclor and cephalexin against these microorganisms. Moreover, cefpodoxime was more active against H. influenzae including β-lactamase producing strains than amoxicillin/clavulanic acid, although these drugs shared a similar potency against M. catarrhalis.

Cefpodoxime is particularly active against Neisseria spp., including N. gonorrhoeae (MIC₉₀ ⩽ 0.06 mg/L), against which it was only slightly less potent than ceftriaxone.

Most tested strains of Enterobacteriaceae including Escherichia coli, Proteus mirabilis, Klebsiella (pneumoniae and oxytoca) and Providencia (rettgeri and stuartii) are susceptible to cefpodoxime (MIC₉₀ < 2 mg/L). In general, cefpodoxime shows a greater inhibitory activity against Enterobacteriaceae compared with cefaclor, cephalexin and cefuroxime, but it is less potent than cefixime. However, cefpodoxime shows a weak inhibitory activity against Citrobacter freundii, Serratia marcescens, Morganella morganii, and Enterobacter cloacae (MIC₅₀ and/or MIC₉₀ ⩾ 4 mg/L), reflecting the presence of inducible cephalosporinases within these species. Pseudomonas aeruginosa is resistant to cefpodoxime.

Cefpodoxime is very active against Streptococcus pyogenes and penicillin-susceptible strains of Streptococcus pneumoniae (MIC₉₀ ⩽ 0.06 mg/L). Moreover, penicillin-resistant strains of S. pneumoniae are moderately susceptible to cefpodoxime, though resistant to cefixime and cefaclor. The activity of cefpodoxime against these streptococci is similar to that reported for cefuroxime and amoxicillin with or without clavulanic acid, but greater than that of cefixime or cefaclor. In common with other orally active cephalosporins, cefpodoxime was inactive against Enterococcus faecalis.

Most penicillin and methicillin-susceptible strains of Staphylococcus epidermidis and Staphylococcus aureus are moderately susceptible to cefpodoxime (MIC₉₀ ⩽ 3 mg/L), although the drug is less active against Staphylococcus saprophyticus. Against these staphylococci, cefpodoxime is much more active than cefixime, but slightly less potent than cefuroxime. Cefpodoxime is inactive against methicillin-resistant strains of S. aureus.

Helicobacter pylori is moderately susceptible to cefpodoxime.

The inhibitory activity of cefpodoxime against a range of anaerobic respiratory tract pathogens including Prevotella, Peptostreptococcus and Fusobacterium spp. is similar to that of cefaclor, cefuroxime and amoxicillin, although less than that of amoxicillin with clavulanic acid.

The in vitro inhibitory activity of cefpodoxime is little affected by the addition of plasma serum or the type of testing medium used, although increasing the inocula size >10⁶ cfu/ml reduced the potency of the drug against β-lactamase producing strains of Enterobacteriaceae.

Cefpodoxime appears to be a low activator of β-lactamase activity and is stable towards the most commonly found plasmid-mediated β-lactamases (TEM-1,2; SHV-1; OXA-1); the drug shows a similar stability to that of cefixime, cefuroxime and cephalexin, but is generally superior to cefaclor.

The antibacterial effect of cefpodoxime is based on inhibition of cell wall synthesis and the drug is bactericidal against most tested strains at a concentration equal to or 4-fold greater than the respective MIC. The bactericidal activity against tested β-lactamase producing strains of Enterobacteriaceae is comparable to that of cefixime and cefuroxime, but superior to that of cefaclor. Cefpodoxime proxetil demonstrated a postantibiotic effect of up to 2 hours against Gram-positive species, although it was without effect against Gram-negative species.

Cefpodoxime proxetil demonstrates a potent protective effect against death in mice caused by septicaemia induced with a range of Gram-positive and Gram-negative bacteria; the drug demonstrates an effect which is equivalent to or greater than that of cefaclor and amoxicillin, although it is somewhat less active against S. aureus infections. Cefpodoxime proxetil is comparable or less active than cefixime against Gram-negative infections, but is superior against Gram-positive infections.

Pharmacokinetic Properties

The pharmacokinetics of cefpodoxime have been investigated in healthy young and elderly volunteers as well as in paediatric and adult patients, including those with renal failure. Cefpodoxime proxetil is absorbed and de-esterified in vivo to release its active metabolite, cefpodoxime, which has ≈ 50% systemic availability. Peak plasma concentrations (C_max) of cefpodoxime were achieved approximately 2 to 3 hours after oral administration of cefpodoxime proxetil to healthy volunteers; C_max appears to be slightly higher in patients with renal failure or elderly patients with respiratory disease. The pharmacokinetics of cefpodoxime are linear with single doses within the therapeutic range (100 to 400mg) and the drug does not accumulate following twice daily administration for 15 days. The bioavailability of cefpodoxime is significantly increased by food, whereas it is significantly reduced by agents which elevate gastric pH.

Cefpodoxime is extensively distributed throughout tissues and fluids of the respiratory tract; for 7 to 12 hours after a single oral dose of cefpodoxime 100 or 200mg, the concentrations of the drug achieved in upper (tonsils) or lower respiratory tract tissues (bronchial mucosa, lung parenchyma, pleural fluid), were greater than or equivalent to the MIC₉₀ for common respiratory tract pathogens. Similarly, a therapeutic concentration of cefpodoxime is achieved in the nasal mucosa and concha after administration of a single dose (200mg). Cefpodoxime 400mg penetrates well into the interstitial fluid and inflammatory exudate associated with skin damage to achieve a peak concentration greater than or equivalent to the mean MIC₉₀ for common skin pathogens including some Staphylococcus spp. (methicillin-sensitive S. aureus and S. epidermidis). Lower, but still clinically relevant, concentrations of cefpodoxime are found in the myometrium and prostate. Small amounts of cefpodoxime are excreted into breast milk.

Once cefpodoxime reaches the systemic circulation little further metabolism occurs (80% of an intravenous dose of cefpodoxime is recovered in the urine as cefpodoxime) and the drug is eliminated primarily by renal excretion. The extended plasma half-life of cefpodoxime (2.1 to 3.6h) combined with the potent antibacterial activity of the drug, enables once or twice daily administration.

The pharmacokinetic properties of cefpodoxime do not appear to be altered to a clinically significant extent by age. However, clearance of cefpodoxime is reduced in proportion to creatinine clearance (CL_Cr) and dosage restrictions may be necessary in patients with CL_Cr values below 3.0 L/h.

Clinical Efficacy

Dosages of cefpodoxime proxetil refer to the cefpodoxime equivalent.

In adult patients, cefpodoxime proxetil has demonstrated a comparable efficacy to that of standard β-lactams in upper and lower respiratory tract infections due predominantly to S. pyogenes, H. influenzae, H. parainfluenzae, S. pneumoniae, M. catarrhalis and S. aureus.

The clinical and bacteriological efficacy of a 5- to 10-day regimen of cefpodoxime proxetil 100mg twice daily was equivalent to that of a 3 or 4 times daily regimen of phenoxymethyl-penicillin 250 to 600mg, amoxicillin 500mg or cefaclor 250mg as well as twice daily cefuroxime axetil 250mg in acute pharyngitis/tonsillitis. Although cefpodoxime proxetil 200mg twice daily resulted in a sigificantly higher clinical cure rate than cefaclor 500mg thrice daily in acute sinusitis (84 vs 68%, p < 0.01), the overall clinical efficacy (cure + improvement) and bacterial eradication rates were similar for each drug.

Cefpodoxime proxetil 100 or 200mg twice daily for 7 to 14 days (mean 10 days) proved as efficacious as thrice daily amoxicillin 500mg, amoxicillin/clavulanic 625mg or cefuroxime axetil 250mg for the treatment of acute bronchitis and/or acute exacerbations of chronic bronchitis. Similarly, cefpodoxime proxetil 200mg twice daily was also as efficacious as thrice daily administration of amoxicillin 500mg or cefaclor 500mg in community-acquired pneumonia.

Most notably, however, in a single trial cefpodoxime proxetil 200mg twice daily was as effective as parenterally administered ceftriaxone 1g per day in the treatment of community-acquired bronchopneumonia in hospitalised patients with additional ‘risk’ factors such as advanced age (⩾65 years), respiratory failure, cardiovascular disease or smoking.

Cefpodoxime proxetil 200 to 400mg twice daily for 7 to ≈ 14 days resulted in a complete clinical cure or improvement in all patients treated for mild to severe skin and soft tissue infections (SSTI), caused primarily by S. aureus, S. epidermidis, S. pyogenes, P. mirabilis and E. coli; the pathogen eradication rate was 98%. In comparative trials involving American patients, cefpodoxime proxetil 400mg twice daily was as effective as cefaclor 500mg thrice daily and ciprofloxacin 500mg twice daily in SSTI.

Cefpodoxime proxetil 100 to 300mg twice daily for 7 to 14 days is also effective in the treatment of patients with uncomplicated and complicated urinary tract infections (UTIs) caused primarily by E. coli, Klebsiella, Proteus or Staphylococcus spp. In comparative trials, cefpodoxime proxetil 100mg twice daily was as effective as thrice daily regimens of cefaclor 250mg or amoxicillin 250mg in the treatment of UTIs, achieving a clinical cure and bacteriological eradication rate of 79 and 80%, respectively.

Cefpodoxime is particularly effective against uncomplicated anogenital gonococcal infections, with a single oral dose (200mg) proving as effective as a single intramuscular injection of ceftriaxone 250mg. The presence of Chlamydia trachomatis infection in addition to N. gonorrhoeae infection before treatment did not appear to affect the overall clinical efficacy of cefpodoxime proxetil.

In Japanese paediatric patients aged ⩽ 16 years of age, cefpodoxime proxetil (standard dose 10 mg/kg/day administered in 2 to 3 daily doses for 10 days) is effective in pharyngitis/tonsillitis, lower respiratory tract and urinary tract infections as well as those of the skin and soft tissues, including impetigo, achieving a good to excellent clinical response in ⩾ 92% of treated patients.

In two large scale comparative trials (n ⩾ 229) involving American paediatric patients aged >2 months to 18 years, the clinical efficacy of cefpodoxime proxetil given twice daily was equivalent to that of thrice daily amoxicillin/clavulanic acid 50 mg/kg/day in otitis media (92 vs 88%, respectively) and phenoxymethylpenicillin 40 mg/kg/day in streptococcal pharyngitis (92 vs 87%, respectively). Moreover, a significantly higher (p < 0.01) S. pyogenes elimination rate was reported for cefpodoxime proxetil (93%) than phenoxymethylpenicillin (81%) in the latter study.

Tolerability

A 7- to 14-day regimen of cefpodoxime proxetil 100 to 400mg twice daily appears to be generally well tolerated, with adverse events reported in ≈8 to 19% of patients. The majority of these adverse events were judged to be of ‘mild to moderate’ severity, and the number of adult patients withdrawing from treatment with cefpodoxime proxetil 100 to 200mg twice daily was small (≈ 2%), although this rate may increase to 5% with a higher dosage (400mg twice daily); diarrhoea, nausea and dermatologic rash were cited as the main reasons for discontinuation.

As for other broad spectrum cephalosporins, gastrointestinal-related complaints were the most frequently reported adverse events, with diarrhoea and/or soft/loose stools occurring in ≈ 3 to 5% of adult patients treated with cefpodoxime proxetil (100 or 200mg twice daily). Disturbances of the skin and mucosa (rash, pruritus, candidiasis and vaginitis) have also been reported with this regimen, occurring in ⩽ 2% of patients. Similarly, gastrointestinal disturbances were the most frequently reported adverse events in paediatric patients treated with cefpodoxime proxetil 10 mg/kg/day, followed by adverse dermatological events (rash, urticaria, pruritus).

In both adult and paediatric studies, the overall tolerability of cefpodoxime proxetil was similar to that of phenoxymethylpenicillin, amoxicillin with or without clavulanic acid and cefaclor, although the latter tended to be associated with a slightly lower incidence of adverse gastrointestinal-related events in adult patients.

Reports of pseudomembranous colitis have been recorded during phase IV studies, despite the fact that this condition was not observed in over 7300 patients treated with cefpodoxime proxetil during pre-marketing studies. Clostridium difficile has been identified in 3 patients during diarrhoeal episodes associated with cefpodoxime proxetil therapy, although diarrhoea was infrequently associated with C. difficile colonisation in healthy volunteers receiving the drug.

Cefpodoxime proxetil does not appear to have a clinically significant effect on standard laboratory blood assays, although post-treatment eosinophilia is typically reported in a small proportion (⩽ 4%) of both adult and paediatric patients receiving the recommended regimen.

Dosage and Administration

A 5- to 16-day regimen of cefpodoxime proxetil therapy has demonstrated efficacy in a wide variety of community-acquired bacterial infections. The stated cefpodoxime proxetil doses refer to the cefpodoxime equivalent.

Adults: Cefpodoxime proxetil 200mg twice daily is recommended for the treatment of sinusitis, otitis media and lower respiratory tract infections including pneumonia, acute bronchitis and bronchitis as well as complicated urinary tract infections. A treatment duration of 7 to 14 days (mean 10 days) is typical for sinusitis, lower respiratory tract and complicated urinary tract infections, but therapy of otitis media should be continued for at least 10 days. A lower dose of cefpodoxime proxetil 100mg twice daily is effective in the treatment of tonsillitis/pharyngitis (10 days) as well as uncomplicated urinary tract infections (7 days). A single dose of cefpodoxime proxetil 200mg is recommended for the treatment of uncomplicated gonorrheal infections.

Cefpodoxime proxetil 200 to 400mg twice daily for 7 to 14 days is effective against infections of skin and soft tissues, with the higher dosage recommended for more severe infections or infections caused by less susceptible organisms.

Dosage adjustment may be required in patients with renal impairment or age-related decline in renal function which results in a creatinine clearance below 3 L/h.

Postprandial administration is recommended, particularly in patients receiving concomitant H₂-antagonist or antacid therapy.

Children (aged 2 months to 18 years): Twice daily administration of cefpodoxime proxetil flavoured granules (suspension) 10 mg/kg/day for 10 days is recommended for the treatment of infections in paediatric subjects, including otitis media and infections of the respiratory and urinary tracts as well as those of the skin and soft tissues.