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

Cefprozil has sometimes been described as a third-generation cephalosporin but its spectrum of activity is only slightly wider than that of cefaclor (Chin and Neu, 1987; Eliopoulos et al., 1987).

The chemical structure of cefprozil is shown in Figure 21.2

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro activity of cefaclor and cefprozil is summarized in Table 21.1.

Gram-positive aerobic bacteria

Cefprozil is active against S. aureus, including beta-lactamaseproducing strains. S. epidermidis is typically susceptible to cefprozil, but S. haemolyticus and S. hominis are often resistant. Streptococcus pyogenes and groups B, C, F, and G streptococci are susceptible. S. pneumoniae is quite susceptible to cefprozil and penicillin-resistant strains tend to have a lower MIC of cefprozil than penicillin. S. viridans is typically susceptible, but strains with high-level penicillin resistance are also cefprozil resistant (MIC 32 mg/ml).

Gram-negative aerobic bacteria All of these cephalosporins lack activity against Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, extendedspectrum beta-lactamase-producing Enterobacteriaceae, and AmpC hyper-producing Enterobacteriaceae (Neu and Fu, 1978; Preston, 1979).

Neisseria meningitidis, N. gonorrhoeae, Haemophilus influenzae, and M. catarrhalis are usually cefprozil susceptible, irrespective of beta-lactamase production. Among the Enterobacteriaceae, E. coli, P. mirabilis, Citrobacter diversus, and most Salmonella, Shigella, and Klebsiella spp. are susceptible to cefprozil. Citrobacter freundii, Morganella morganii, Serratia marcescens, Providencia, and Enterobacter spp. are cefprozil resistant because of AmpC beta-lactamase production.

Anaerobic bacteria

The Bacteroides fragilis group are usually resistant to these cephalosporins (Bach et al., 1978). Anaerobic Gram-positive cocci and some Gram-negative anaerobes (other than those of B. fragilis group) may be cefaclor susceptible.
Among Gram-positive anaerobes, the peptostreptococci and Clostridium spp. are susceptible to cefrozil. Clostridium difficile, with an MIC of 4–8 mg/ml, is also moderately cefprozil susceptible, but the clinical significance of this is not known (Chin and Neu, 1987; Eliopoulos et al., 1987; Kayser, 1987; Leitner et al., 1987; Mazzulli et al., 1990; Thornsberry, 1992; Barry et al., 1994). Among Gram-negative anaerobes, the Prevotella spp. such as P. melaninogenica and Fusobacterium spp. may be sensitive, but other Bacteroides spp., and in particular B. fragilis, are resistant (Chin and Neu, 1987; Eliopoulos et al., 1987; Leitner et al., 1987; Scribner et al., 1987; Arguedas et al., 1991; Thornsberry, 1992; Goldstein et al., 1995).

b. Emerging resistance and cross-resistance

Broader spectrum beta-lactamases such as extended-spectrum betalactamases, AmpC beta-lactamases, and metallo-beta-lactamases will lead to resistance to these cephalosporins.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Cefprozil is administered orally either once or twice daily. For milder infections, such as uncomplicated urinary tract infections or acute group A beta-hemolytic streptococcal pharyngitis, a dosage of 0.5 g once daily is sufficient (Christenson et al., 1991a; Christenson et al., 1991b; McCarty and Renteria, 1992). In more severe infections, such as lower respiratory tract infections, a dosage of 0.5 g 12-hourly is recommended (Pelletier, 1992).

b. Newborn infants and children

Depending on the nature and severity of infection, cefprozil has been given to children in dosages of 15, 20, or 30 mg/kg/day. The larger dosages have usually been administered orally in two divided doses (Saez-Llorens et al., 1990; Stutman and Arguedas, 1992; Milatovic et al., 1993).

There is a lack of data for both cefaclor and cefrozil regarding dosing in premature neonates.

Altered dosages

Impaired renal function

In patients with creatinine clearance of o30 ml/min, the dosage of cefprozil should be reduced by 50%. The drug is effectively removed by hemodialysis, and so a supplemental dose of 50% of the maintenance dose should be given after the dialysis procedure (Barriere, 1992).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Approximately 94% of the orally administered dose is absorbed (Barriere, 1992). Cefprozil is about 42% serum protein bound (Fassbender et al., 1993).

b. Drug distribution

After oral administration, cefprozil is rapidly absorbed, reaching the maximum serum level 1–2 hours after administration. After a 0.5 mg oral dose to adults, this peak is about 9.3 mg/ml. Doubling the dose nearly doubles the peak serum concentration. After the peak, the serum level falls with a terminal half-life of 1.2 hours and by 8 hours the serum level is less than 1 mg/ml (Barbhaiya et al., 1990a; Nye et al., 1990). There is no accumulation of the drug in serum if multiple 0.5-g doses are administered 8- or 12-hourly (Barbhaiya et al., 1990b; Lode et al., 1992). The presence of food in the stomach (Barbhaiya et al., 1990c) and the co-administration of antacids (Shyu et al., 1992) do not interfere with the absorption of cefprozil.

In children, after the administration of 15 and 30 mg/kg single doses, peak concentrations of 11.6 and 15.93 mg/ml, respectively, occurred 1 hour after the dose. The respective mean half-lives of cefprozil were 1.77 and 2.14 hours (Saez-Llorens et al., 1990). This shows that cefprozil is excreted somewhat more slowly in children than in adults. Cefprozil has been found to penetrate well into skin blister fluid, the mean concentration reached there after an oral dose of 0.5 g was 5.8 mg/ml. The skin blister fluid concentration has been found to decline more slowly than that in plasma (Barbhaiya et al., 1990d). Less than 0.3% of a cefprozil dose has been recovered from breast milk in the 24-hour period after administration (Barriere, 1992). Cefprozil penetrates well into tonsillar and adenoidal tissue. In patients undergoing tonsillectomy and/or adenoidectomy, the median ratios of cefprozil concentration in tonsillar tissue to that of plasma were 0.37 and 0.47 for patients receiving 7.5 or 20 mg/kg single doses of cefprozil, respectively. The corresponding median ratios for adenoidal tissue were 0.46 and 0.82, respectively (Shyu et al., 1993).

c. Excretion

Most of the absorbed cefprozil is eliminated via the kidney. Overall, about 61% of the administered dose is excreted in the urine as the active unchanged drug. The renal clearance is about 200 ml/min. This suggests that cefprozil is excreted by both glomerular filtration and tubular secretion. Mean concentrations of the drug in urine are highest during the first 4 hours after the dose and range from 175 to 658 mg/ml following doses of 250 mg and 1 g, respectively (Barbhaiya et al., 1990a; Barbhaiya et al., 1990b; Barriere, 1992; Lode et al., 1992). More cefprozil is absorbed (94% of dose) than is excreted in the urine (61% of dose), but it is not known what happens in the body to the fraction not excreted in urine. In patients who have hepatic disease, the kinetic disposition of cefprozil was only minimally altered. The kidney has the primary role in elimination of this drug (Barriere, 1992). No metabolites have been detected in urine (Lode et al., 1992).

e. Drug interactions

There are few clinically important drug interactions with these agents, except that concomitant administration of probenecid prolongs the serum levels of cefaclor.

TOXICITY

Adverse effects have been uncommon and similar to those observed with other oral cephalosporins. Rash and urticaria have been occasionally seen. Vomiting and diarrhea have been reported, but diarrhea with cefprozil has been less common than with cefixime, which is less completely absorbed. Cefprozil also only causes a minimal disturbance of the normal fecal flora, such as slight decrease in enterobacteria and a slight increase in enterococci and Bacteroides spp. A few patients have shown slight and reversible increase in liver enzymes (Lode et al., 1992; Wilber et al., 1992). Leukopenia also has been reported (Christenson et al., 1991a).

CLINICAL USES OF THE DRUG

In general, the use of these oral cephalosporins is limited to treatment of relatively mild infections.

b. Cefprozil

Good results have been obtained in pharyngitis due to S. pyogenes using cefprozil 0.5 g daily for adults for 10 days (Christenson et al., 1991a). In a study in children, cefprozil, in a dose of 7.5 mg/kg body weight twice daily, was given for 10 days, and a control group received oral penicillin V. The clinical responses in patients treated with cefprozil were significantly better than those in patients who received penicillin V (95.3% vs 88.1%). Eradication of the original serotype of S. pyogenes was achieved in 91.3% of patients treated with cefprozil, and 87.4% of patients treated with penicillin V; the difference here was not statistically significant. Beta-lactamase-producing S. aureus was more frequently isolated from the throat flora during penicillin V therapy (Milatovic et al., 1993). Cefprozil has also been superior to cefaclor in the treatment of this disease (McCarty and Renteria, 1992).

In randomized trials of patients with otitis media, cefprozil has been compared with co-amoxiclav, cefaclor, and cefixime for the treatment of this disease. The rate of clinical cure or improvement was similar with all these drugs. However, diarrhea with cefprozil was less common than with cefixime or co-amoxiclav (Stutman and Arguedas, 1992; Gehanno et al., 1994).

In the treatment of bronchitis and acute exacerbation of chronic bronchitis, cefprozil 0.5 g 12-hourly has been compared with standard regimens of cefaclor, cefuroxime axetil, and co-amoxiclav. The clinical efficacy of cefprozil was superior to that of cefuroxime axetil, but equal to that of cefaclor and co-amoxiclav. There was less diarrhea in cefprozil-treated patients than in those treated with co-amoxiclav. The value of cefprozil in the treatment of pneumonia has yet to be established (Pelletier, 1992).

For uncomplicated urinary tract infections, cefprozil in a dose of 0.5 g daily, given for 10 days, has efficacy similar to cefaclor 250 mg, given three times daily, for the same period (Christenson et al., 1991b; Iravani, 1991).

For skin and skin structure infections, caused mainly by streptococci and S. aureus, cefprozil in a dose of 0.5 g once daily has about the same efficacy as 250 mg of cefaclor administered three times daily or 400 mg of erythromycin administered four times daily (Nolen, 1992).

References

Greenberg RN, Sanders CV, Lewis AC, Marier RL (1981). Single-dose cefaclor therapy of urinary tract infection. Evaluation of antibody-coated bacteria test and C-reactive protein assay as predictors of cure. Am J Med 71: 841.
Hamilton-Miller JMT (1974). Comparative activity of ampicillin and seven cephalosporins against Group D streptococci. J Clin Path 27: 828.
Horner DB, McCracken GH, Ginsburg Jr CM, Zweighaft TC (1980). A comparison of three antibiotic regimens for eradication of Haemophilus influenzae type B from the pharynx of infants and children. Pediatrics 66: 136. Iravani A (1991). Comparison of cefprozil and cefaclor for treatment of acute urinary tract infections in women. Antimicrob Agents Chemother 35: 1940.
Kammer RB, Short LJ (1979). Cefaclor-summary of clinical experience. Postgrad Med J 55 (Suppl 4): 93.
Kayser FH (1987). Comparative antibacterial activity of the new oral cephalosporin BMY-28100. Eur J Clin Microbiol 6: 309.
Lindan R (1979). Comparison of cefaclor and amoxycillin in the treatment of urinary infections in a chronic disease hospital. Postgrad Med J 55 (Suppl 4): 67.
Lode H, Mu¨ller C, Borner K et al. (1992). Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers. Antimicrob Agents Chemother 36: 144.
McCarty JM, Renteria A (1992). Treatment of pharyngitis and tonsillitis with cefprozil: Review of three multicenter trials. Clin Infect Dis 14 (Suppl 2): 224.
McCracken Jr GH, Ginsburg CM, Clahsen JC, Thomas ML (1978). Pharmacokinetics of cefaclor in infants and children. J Antimicrob Chemother 4: 515.
Nye K, O’Neill P, Andrews JM, Wise R (1990). Pharmacokinetics and tissue penetration of cefprozil. J Antimicrob Chemother 25: 831.
Oberlin JA, Hyslop DL (1990). Cefaclor treatment of upper and lower respiratory tract infections caused by Moraxella catarrhalis. Pediatr Infect Dis J 9: 41.
Oguma T, Yamada H, Sawaki H, Narita N (1991). Pharmacokinetic analysis of the effects of different foods on absorption of cefaclor. Antimicrob Agents Chemother 35: 1729.
Pelletier Jr LL (1992). Review of the experience with cefprozil for the treatment of lower respiratory tract infections. Clin Infect Dis 14 (Suppl 2): 238. Peter G (1992). Streptococcal pharyngitis: Current therapy and criteria for evaluation of new agents. Clin Infect Dis 14 (Suppl 2): 218.

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