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Cefprozil

Cefprozil is a semisynthetic, second generation cephalosporin antibiotic.

Uses

Cefprozil is used orally for the treatment of mild to moderate respiratory tract infections (i.e., acute sinusitis, secondary bacterial infections of acute bronchitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia) caused by susceptible bacteria. The drug also is used orally for the treatment of acute otitis media caused by susceptible bacteria, pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci), and mild to moderate uncomplicated skin and skin structure infections caused by susceptible bacteria.

Respiratory Tract Infections

Acute Sinusitis

Oral cefprozil is used in adults and children 6 months of age or older for the treatment of acute sinusitis. In an open-label, multicenter study in adults and children 13 years of age or older with acute maxillary sinusitis, the overall clinical response rate was 80-83% in those who received cefprozil and 78% in those who received amoxicillin and clavulanate potassium. Since sinus aspirate cultures are not routinely indicated in patients with acute sinusitis, these infections usually are treated empirically with an anti-infective regimen active against bacteria commonly involved in sinus infections (e.g., S. pneumoniae, H. influenzae, M. catarrhalis, S. pyogenes).

Various anti-infectives have been shown to be effective for the treatment acute community-acquired sinusitis (e.g., amoxicillin and clavulanate potassium, cefaclor, cefixime, cefpodoxime, cefprozil, cefuroxime axetil, co-trimoxazole, levofloxacin, loracarbef), and the most appropriate drug for the individual patient usually is selected based on considerations relating to cost, convenience, and tolerability.

Acute and Chronic Bronchitis

Oral cefprozil is used in adults and children 13 years of age or older for the treatment of secondary bacterial infections of acute bronchitis and acute bacterial exacerbations of chronic bronchitis caused by susceptible S. pneumoniae, H. influenzae (including b-lactamase-producing strains), or M. catarrhalis (including b-lactamase-producing strains). Safety and efficacy of the drug for the treatment of these infections in children 12 years of age or younger have not been established to date. Results of a multicenter, open-label randomized study in adults with bronchitis indicate that oral cefprozil (500 mg every 12 hours) may be slightly more effective than oral cefuroxime axetil (500 mg every 12 hours) for these infections. The overall clinical response rate was 96% in those who received cefprozil and 82.% in those who received cefuroxime; the bacteriologic eradication rate was 100% and 91.%, respectively.

Community-Acquired Pneumonia

Cefprozil is used in the treatment of mild to moderate community-acquired pneumonia (CAP). The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) suggest that certain oral cephalosporins can be used in outpatient regimens for the treatment of CAP. Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients.

The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant Streptococcus pneumoniae, enteric gram-negative bacilli, Pseudomonas aeruginosa).

Most experts recommend that an empiric regimen for the outpatient treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens; some other pathogens often involved in outpatient CAP are Mycoplasma pneumoniae, Chlamydia pneumoniae, respiratory viruses, and Haemophilus influenzae (especially in cigarette smokers).

For empiric outpatient treatment of acute CAP in immunocompetent adults, the IDSA recommends monotherapy with an oral macrolide (azithromycin, clarithromycin, erythromycin), oral doxycycline, or an oral fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin) and states that alternative empiric regimens include oral amoxicillin and clavulanate or certain oral cephalosporins (cefpodoxime, cefprozil, cefuroxime axetil).

For outpatient treatment of CAP in immunocompetent adults without cardiopulmonary disease or other modifying factors that would increase the risk of multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends an empiric regimen of monotherapy with azithromycin or clarithromycin or, alternatively, doxycycline.

However, for empiric outpatient treatment of immunocompetent adults with cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug empiric regimen consisting of a b-lactam anti-infective (e.g. oral cefpodoxime, oral cefuroxime axetil, high-dose oral amoxicillin, oral amoxicillin and clavulanate, parenteral ceftriaxone followed by oral cefpodoxime) and a macrolide or doxycycline or, alternatively, monotherapy with an oral fluoroquinolone active against S. pneumoniae (e.g., ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin [risk of hepatic toxicity should be considered]).

The US Centers for Disease Control (CDC) suggest that use of these oral fluoroquinolones in the outpatient treatment of CAP be reserved for when other anti-infectives are ineffective or cannot be used or when highly penicillin-resistant S. pneumoniae (i.e., penicillin MICs 4 mcg/mL or greater) are identified as the cause of infection. For inpatient treatment of CAP patients who require hospitalization in an ICU or non-ICU setting, various parenteral regimens are recommended. (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections, in the Cephalosporins General Statement 8:12.06.

Acute Otitis Media

Oral cefprozil is used in children 6 months through 12 years of age for the treatment of acute otitis media caused by S. pneumoniae, H. influenzae (including b-lactamase-producing strains), or M. catarrhalis (including b-lactamase-producing strains). Results of controlled clinical studies in children 6 months to 17 years of age with clinically and/or microbiologically confirmed acute otitis media indicate that a 10-day regimen of oral cefprozil generally is as effective as a 10-day regimen of oral cefaclor, oral cefixime, oral amoxicillin and clavulanate potassium, or oral ceftibuten. In published studies, the overall clinical response rate to a 10-day regimen of oral cefprozil in pediatric patients with acute otitis media has been 83-97% and the bacteriologic eradication rate has been 84-95%.

Although the clinical and bacteriologic response rates to oral cefprozil in pediatric patients with acute otitis media generally have been similar to those reported with oral amoxicillin and clavulanate potassium, the manufacturer cautions that, in patients with otitis media caused by b-lactamase-producing bacteria, cefprozil therapy may be associated with a slightly lower bacteriologic eradication rate than therapy with an anti-infective agent that contains a specific b-lactamase inhibitor (i.e., amoxicillin and clavulanate potassium) and that the possibility of reduced overall efficacy should be weighed carefully against local susceptibility patterns for common pathogens encountered in this infection when considering use of cefprozil for the treatment of otitis media.

In one study in children 6 months to 12 years of age with acute otitis media with middle ear effusion, including patients with recurrent otitis media (i.e., 4 or more prior episodes of acute otitis media within the last 12 months or 3 or more prior episodes within the last 6 months) or persistent acute otitis media (i.e., symptoms of otalgia and signs of middle ear inflammation despite the fact that anti-infective agent therapy was given within the last 7 days), the overall clinical response rate to 10 days of oral cefprozil therapy (30 mg/kg daily) was 78%.

When results of children with acute otitis media caused by a single identified pathogen were stratified according to the causative organism, the clinical response rate to cefprozil was 91% in those with otitis media caused by M. catarrhalis, 77-81% in those with otitis media caused by S. pneumoniaeor H. influenzae, and 71% in those with otitis media caused by S. pyogenes.

Cefprozil has been effective for the treatment of acute otitis media in pediatric patients when administered in a 5-day regimen, and there is some evidence that the 5-day regimen may be as effective as the usually recommended 10-day regimen for the treatment of acute otitis media in certain pediatric patients without a history of recurrent infections. In one controlled study in children 3 months to 14 years of age with acute otitis media who were randomized to receive 5 or 10 days of oral cefprozil (30 mg/kg daily given in 2 divided doses), a satisfactory clinical response (cure or improvement) was attained in 94.% of those who received the 5-day regimen and 96.% of those who received the 10-day regimen. However, in the subgroup of patients with a history of 3 or more prior episodes of acute otitis media, the clinical response rate was 100% in those who received the 10-day regimen versus 70% in those who received the 5-day regimen.

Further study is needed to evaluate use of a 5-day regimen of oral cefprozil for the treatment of acute otitis media. Some clinicians caution that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of acute otitis media in children younger than 2 years of age or for patients with underlying disease, recurrent or persistent acute otitis media, or perforated tympanic membranes and spontaneous purulent drainage. For additional information regarding treatment of acute otitis media, see Acute Otitis Media under Uses: Otitis Media, in the Cephalosporins General Statement 8:12.06.

Pharyngitis and Tonsillitis

Oral cefprozil is used in adults and children 2 years of age or older for the treatment of pharyngitis and tonsillitis caused by susceptible S. pyogenes (group A b-hemolytic streptococci). Although cefprozil usually is effective in eradicating S. pyogenes from the nasopharynx, substantial data to establish efficacy of the drug for prophylaxis of subsequent rheumatic fever are not available to date.

Results of randomized, multicenter studies in pediatric patients with streptococcal pharyngitis or tonsillitis indicate that a 10-day regimen of oral cefprozil is more effective than a 10-day regimen of oral penicillin V. In one study in children 3-18 years of age with streptococcal pharyngitis or tonsillitis randomized to receive 10 days of oral cefprozil (7.5 mg/kg twice daily) or 10 days of oral penicillin V (16. mg/kg 3 times daily), the clinical response rate (cure or improvement) was 95.% in those who received cefprozil versus 88.% in those who received penicillin V; the bacteriologic eradication rates were 89 or 84.%, respectively.

A 10-day regimen of oral cefprozil has been used effectively to eradicate S. pyogenes in pediatric patients who failed to respond to a 10-day regimen of oral penicillin V. In an open, randomized study in adults and adolescents 12 years of age or older with acute streptococcal pharyngitis, a 10-day regimen of oral cefprozil (500 mg once daily) was at least as effective as a 10-day regimen of oral cefaclor (250 mg 3 times daily); the clinical response rate was 85% for both drugs and the bacteriologic eradication rate was 91% in those who received cefprozil and 95% in those who received cefaclor.

In another study in adults and children 2 years of age or older randomized to receive oral cefprozil or oral cefaclor, the overall clinical response rate was 80% in those who received cefprozil and 72% in those who received cefaclor; the bacteriologic eradication rates were 83 and 76%, respectively. Selection of an anti-infective agent regimen for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug’s spectrum of activity as well as the regimen’s bacteriologic and clinical efficacy, potential adverse effects, ease of administration and patient compliance, and cost. No regimen has been found to date that effectively eradicates group A b-hemolytic streptococci in 100% of patients.

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the CDC, American Academy of Pediatrics (AAP),American Academy of Family Physicians (AAFP), IDSA, American Heart Association (AHA), American College of Physicians-American Society of Internal Medicine (ACP-ASIM), and others consider natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) the treatment of choice for streptococcal pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste. Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternatives.

There is some evidence that bacteriologic and clinical cure rates reported with 10-day regimens of certain oral cephalosporins (e.g., cefaclor, cefadroxil, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, cefuroxime axetil, ceftibuten, cephalexin) are slightly higher than those reported with the 10-day oral penicillin V regimen. In addition, there is some evidence that a shorter duration of therapy with certain oral cephalosporins (e.g., a 5-day regimen of cefadroxil, cefdinir, cefixime, or cefpodoxime proxetil or a 4- or 5-day regimen of cefuroxime axetil) achieves bacteriologic and clinical cure rates equal to or greater than those achieved with the traditional 10-day oral penicillin V regimen.

Based on these results, some clinicians suggest that oral cephalosporins be included as agents of choice for the treatment of S. pyogenes pharyngitis and tonsillitis.

However, the IDSA states that first generation cephalosporins can be used for the treatment of pharyngitis in patients hypersensitive to penicillins (except those with immediate-type hypersensitivity to b-lactam anti-infectives) but that cephalosporins appear to offer no advantage over penicillins since they have a broader spectrum of activity and generally are more expensive. In addition, because of limited data to date, the IDSA states that use of cephalosporin regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis cannot be recommended at this time.

Cefprozil

Skin and Skin Structure Infections

Oral cefprozil is used in adults and children 2 years of age or older for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) and S. pyogenes.

The drug also has been effective when used in a limited number of patients for the treatment of uncomplicated skin and skin structure infections caused by S. epidermidis, S. saprophyticus, group B or G streptococci, Escherichia coli, or Klebsiella pneumoniae. Prior to initiation of cefprozil therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests.

Abscesses should be surgically drained if indicated. Results of multicenter, randomized studies in adults and children 2 years of age or older with mild to moderate bacterial skin and skin structure infections (e.g., carbuncle, cellulitis, folliculitis, furuncle, impetigo, infecteddermatitis, paronychia, pyoderma, superficial abscess, wound infection) indicate that 5-10 days of therapy with oral cefprozil (250 mg twice daily or 500 mg once daily in adults; 20 mg/kg once daily in children) is at least as effective as 5-10 days of therapy with oral cefaclor (250 mg 3 times daily in adults or 20 mg/kg daily in 3 doses). A satisfactory clinical response was attained in 93-95% of patients who received cefprozil and in 78-92% of patients who received cefaclor; the bacteriologic eradication rates were 86-91% and 74-89%, respectively.

Dosage and Administration

Reconstitution and Administration

Cefprozil is administered orally.

Administration of cefprozil tablets or oral suspension with food does not affect the extent of absorption or peak plasma concentrations of the drug. Cefprozil powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the container to provide a suspension containing 125 or 250 mg of cefprozil per 5 mL.

The water should be added in 2 equal portions and the bottle shaken after each addition.

Dosage

Dosage of cefprozil, which is commercially available for oral use as the monohydrate, is expressed in terms of anhydrous cefprozil.

Adult Dosage

Respiratory Tract Infections

For the treatment of acute sinusitis in adults and adolescents 13 years of age or older, the usual dosage of cefprozil is 250 or 500 mg every 12 hours for 10 days; the higher dosage should be used to treat moderate to severe sinusitis.

For the treatment of secondary bacterial infections of acute bronchitis and acute bacterial exacerbations of chronic bronchitis, the usual dosage of cefprozil for adults and adolescents 13 years of age or older is 500 mg every 12 hours for 10 days.

For the outpatient treatment of acute community-acquired pneumonia (CAP) in immunocompetent adults, some clinicians recommend that cefprozil be given in a dosage of 500 mg twice daily.

The duration of CAP therapy depends on the causative pathogen, illness severity at the onset of anti-infective therapy, response to treatment, comorbid illness, and complications. CAP secondary to S. pneumoniae generally can be treated for 7-10 days or 72 hours after the patient becomes afebrile. CAP caused by bacteria that can necrose pulmonary parenchyma generally should be treated for at least 2 weeks.

Patients chronically treated with corticosteroids also may require at least 2 weeks of therapy.

Pharyngitis and Tonsillitis

The usual dosage of cefprozil for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci) in adults and adolescents 13 years of age or older is 500 mg once daily for 10 days.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections in adults and adolescents 13 years of age or older, the usual dosage of cefprozil is 250 or 500 mg every 12 hours or 500 mg once daily for 10 days.

Pediatric Dosage

Children 13 years of age or older may receive the usual adult dosage of cefprozil.

Respiratory Tract Infections

For the treatment of acute sinusitis in children 6 months through 12 years of age, the usual dosage of cefprozil is 7.5 or 15 mg/kg every 12 hours for 10 days; the higher dosage should be used to treat moderate to severe infections.

Acute Otitis Media

For the treatment of acute otitis media in children 6 months through 12 years of age, the usual dosage of cefprozil is 15 mg/kg every 12 hours for 10 days.

Pharyngitis and Tonsillitis

The usual dosage of cefprozil for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A b-hemolytic streptococci) in children 2 through 12 years of age is 7.5 mg/kg every 12 hours for 10 days. Skin and Skin Structure Infections For the treatment of uncomplicated skin and skin structure infections in children 2 through 12 years of age, the usual dosage of cefprozil is 20 mg/kg once daily for 10 days.

Dosage in Renal and Hepatic Impairment

Modification of the usual dosage of cefprozil does not appear to be necessary in patients with creatinine clearances of 30 mL/minute or greater. In patients with creatinine clearances less than 30 mL/minute, dose but not frequency of administration of cefprozil should be modified; such patients should receive 50% of the usual cefprozil dose.

Because the drug is partially removed by hemodialysis, cefprozil should be administered to patients undergoing hemodialysis after the end of the dialysis period. Modification of usual dosage of cefprozil is not necessary in patients with hepatic impairment.

Cautions

Adverse effects reported with cefprozil are similar to those reported with other cephalosporins. (See Cautions in the Cephalosporins General Statement 8:12.06.) Cefprozil generally is well tolerated; most adverse effects are transient and mild to moderate in severity. Adverse effects have been severe enough to require discontinuance in about 2% of patients. The most frequent adverse effects of cefprozil involve the GI tract. In young children, diarrhea, vomiting, and rash (principally in the diaper area) appear to be most common, while in adults, diarrhea and nausea appear to be most common.

GI Effects

Nausea is one of the most common adverse effects of cefprozil, occurring in 3.5% of patients receiving the drug.

Diarrhea or loose stools have occurred in 2.9% of patients receiving cefprozil. The incidence of diarrhea with cefprozil appears to be comparable to that with cefaclor but less than that with amoxicillin and clavulanate potassium, and possibly some other oral cephalosporins.

Vomiting and abdominal pain or discomfort each have occurred in 1% of patients. Dyspepsia, flatulence, glossitis, and mouth pain have been reported rarely in patients receiving cefprozil; a causal relationship to the drug has not been established.

Adverse GI effects may be severe enough to result in discontinuance of cefprozil.

Cefprozil

Colitis, including Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by toxin-producing clostridia, has occurred rarely in patients receiving cefprozil. C. difficile-associated diarrhea and colitis may occur during or following discontinuance of the drug and may range in severity from mild to life-threatening.

Mild cases of diarrhea and colitis may respond to discontinuance of cefprozil alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic and toxin studies and treatment with fluid, electrolyte, and protein supplementation as indicated. If C. difficile-associated diarrhea and colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.

Dermatologic and Sensitivity Reactions

Rash occurred in 0.9% of patients receiving cefprozil in clinical studies. In young children, rash associated with cefprozil therapy most commonly is a diaper rash rather than a sensitivity reaction.

Urticaria and pruritus have been reported rarely.

Anaphylaxis, serum-sickness-like reactions, erythema, exanthema, erythema multiforme, erythema nodosum, and Stevens-Johnson syndrome also have been reported rarely; however, a causal relationship with cefprozil has not been established.

Sensitivity reactions (e.g., rash, urticaria) have been reported more frequently in children than in adults.Such reactions usually occur within a few days after initiation of therapy and subside within a few days after discontinuance of the drug. Toxic epidermal necrolysis has been reported with cephalosporins. If a severe hypersensitivity reaction occurs during cefprozil therapy, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

Nervous System Effects

Dizziness has been reported in 1% of patients receiving cefprozil. Hyperactivity, headache, nervousness, insomnia, confusion, and somnolence each have been reported in less than 1% of patients receiving the drug. Lightheadedness has been reported rarely.

Although seizures have not been reported in patients receiving cefprozil, several cephalosporins have been implicated in precipitating seizures, particularly in patients with renal impairment in whom the dosage was not reduced. If seizures associated with cefprozil therapy occur, the drug should be discontinued and anticonvulsant therapy administered if clinically indicated.

Hepatic Effects

Increases in serum AST (SGOT) and ALT (SGPT) concentrations have been reported in 2% of patients receiving cefprozil. Elevations in serum alkaline phosphatase and bilirubin concentrations also have been reported in 0.2% and less than 0.1%, respectively, of patients receiving the drug. Cholestatic jaundice has been reported rarely in patients receiving cefprozil. Increases in serum LDH concentrations have been reported in patients receiving cephalosporins.

Hematologic Effects

Eosinophilia has been reported in 2.3% of patients receiving cefprozil. Decreased leukocyte count has been reported in 0.2% of patients receiving the drug. Although a causal relationship has not been established, neutropenia, thrombocytopenia, prolonged partial thromboplastin time, thrombocytosis,prolonged prothrombin time, prolonged prothrombin ratio, and decreased hematocrit have been reported rarely in patients receiving cefprozil. Other adverse hematologic effects reported in patients receiving cephalosporins include positive antiglobulin (Coombs’) test results, agranulocytosis, aplastic anemia, pancytopenia, hemolytic anemia, and hemorrhage.

Renal Effects

Elevated BUN and serum creatinine concentrations each have been reported in 0.1% of patients receiving cefprozil. Adverse renal effects reported in patients receiving cephalosporins include renal dysfunction and toxic nephropathy.

Other Adverse Effects

Vaginitis and genital pruritus have been reported in 1.6% of patients receiving cefprozil. Leukorrhea and vaginal candidiasis have been reported infrequently. Diaper rash and superinfection have been reported in 1.5% of patients receiving the drug. Although a causal relationship to cefprozil has not been established, fever, chills, sweating, tinnitus, visual field defects, generalized pain, back pain, leg pain, angioedema, and crying have been reported rarely.

Precautions and Contraindications

Prior to initiation of cefprozil therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cefprozil, other cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among b-lactam antibiotics including penicillins, cephalosporins, and cephamycins.

Cefprozil is contraindicated in patients with known hypersensitivity to cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins. Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.

If a hypersensitivity reaction occurs during cefprozil therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen as indicated. As with other anti-infective agents, prolonged use of cefprozil may result in overgrowth of nonsusceptible organisms.

Careful observation of the patient during cefprozil therapy is essential. If superinfection occurs, appropriate therapy should be initiated.

Because Clostridium difficile-associated diarrhea and colitis has been reported with the use of cefprozil, it should be considered in the differential diagnosis of patients who develop diarrhea during cefprozil therapy.

Cefprozil should be used with caution in patients with a history of GI disease, especially colitis. In patients with known or suspected renal impairment, careful observation and appropriate laboratory studies should be performed prior to and during cefprozil therapy. Because plasma concentrations of cefprozil may be higher and more prolonged in these patients, doses and/or frequency of administration should be decreased. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

The manufacturer states that cephalosporins, including cefprozil, should be used with caution in patients receiving potent diuretics (e.g., furosemide), since concomitant use of these drugs may adversely affect renal function. Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that the oral suspension of cefprozil contains aspartame (NutraSweet®) which is metabolized to phenylalanine in the GI tract following oral administration.

Positive direct and indirect antiglobulin (Coombs’) test results have been reported in patients receiving a cephalosporin. (See Cautions: Hematologic Effects, in the Cephalosporins General Statement 8:12.06.) Patients receiving a cephalosporin, including cefprozil, may show a false-positive result in urine glucose determinations using cupric sulfate (e.g., Benedict’s solution, Fehling’s solution, Clinitest®). Urinary glucose determinations using glucose oxidase methods (e.g., Clinistix®, Tes-Tape®) are unaffected by the drugs. A false-negative result may occur in the ferricyanide test for blood glucose. Cefprozil does not interfere with the alkaline picrate method used to determine plasma or urinary creatinine concentrations.

Pediatric Precautions

The manufacturer states that safety and efficacy of cefprozil for the treatment of acute otitis media or acute sinusitis in children younger than 6 months of age or the treatment of pharyngitis and tonsillitis or uncomplicated skin and skin structure infections in children younger than 2 years of age have not been established. The manufacturer cautions that drug accumulation secondary to prolonged elimination has been reported in neonates receiving other cephalosporins. Sensitivity reactions (e.g., rash, urticaria) have been reported more frequently in children than in adults. The most common adverse effects occurring in children receiving cefprozil are similar to those seen in adults and include diarrhea, nausea, vomiting, and rash.

Geriatric Precautions

Of the more than 4500 adults who received cefprozil in clinical studies, 14% were 65 years of age or older, while 5% were 75 years of age and older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Cefprozil is known to be substantially excreted by the kidney, and the risk of cefprozil-induced toxicity may be greater in patients with renal impairment. Because geriatric patients may have decreased renal function, initial dosage should be selected carefully and it may be useful to monitor renal function.

Mutagenicity and Carcinogenicity

Mutagenesis studies performed in appropriate prokaryotic and eukaryotic cells in vitro or in vivo have not shown cefprozil to be mutagenic. Long-term in vivo studies have not been performed to date to evaluate the carcinogenic potential of the drug.

Pregnancy, Fertitlity and Lactation

Reproduction studies in mice, rats, or rabbits using oral cefprozil in dosages 8.5, 18.5, or 0.8 times, respectively, the maximum daily human dose (1 g) based upon mg/m2 have not revealed evidence of harm to the fetus.

There are no adequate and well-controlled studies to date using cefprozil in pregnant women or during labor and delivery, and the drug should be used during pregnancy or labor and delivery only when clearly needed. Reproduction studies in male or female rats receiving oral cefprozil in dosages up to 18. times the maximum recommended human dosage have not revealed evidence of impaired fertility.

Because trace concentrations of cefprozil (less than 0.3% of a dose) are distributed into milk, the drug should be used with caution in nursing women. Spectrum Based on its spectrum of activity, cefprozil is classified as a second generation cephalosporin. For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

Like other currently available second generation cephalosporins (e.g., cefaclor, cefamandole, cefuroxime), cefprozil is active in vitro against both gram-positive and gram-negative bacteria. The drug generally is more active in vitro against gram-negative bacteria than first generation cephalosporins, but has a narrower spectrum of activity against gram-negative bacteria than third generation cephalosporins. The spectrum of activity of cefprozil is similar to that of cefaclor; however, in vitro on a weight basis, cefprozil may be more active against susceptible organisms than cefaclor.

In Vitro Susceptibility Testing

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to cefprozil, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.

If results indicate that a clinical isolate has intermediate susceptibility to cefprozil, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.

This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretations, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to cefprozil, the strain is not inhibited by systemic concentrations of the drug achievable with normal dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.

Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to cefprozil, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug. In addition, NCCLS recommends that b-lactamase-negative, ampicillin-resistant (BLNAR) strains of H. influenzae be considered resistant to cefprozil despite the fact that results of in vitro susceptibility tests may indicate that these strains are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to cefprozil, a disk containing 30 mcg of cefprozil should be used. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterobacteriaceae with growth inhibition zones of 18 mm or greater are susceptible to cefprozil, those with zones of 15-17 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing for Haemophilus is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 18 mm or greater are susceptible to cefprozil, those with zones of 15-17 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug. Interpretive criteria are not available to determine susceptibility of streptococci to cefprozil using the cefprozil disk; however, NCCLS states that S. pneumoniae found to be susceptible to penicillin using the NCCLS standardized disk-diffusion procedure and a 1-mcg oxacillin disk can be considered susceptible to cefprozil. In addition, other Streptococcus (b-hemolytic streptococci, viridans streptococci) found to be susceptible to penicillin using the standardized disk procedure can be considered susceptible to cefprozil.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterobacteriaceae with MICs of 8 mcg/mL or less are susceptible to cefprozil, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing of Haemophilus is performed according to NCCLS standardized procedures using HTM, Haemophilus with MICs of 8 mcg/mL or less are susceptible to cefprozil, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug. When broth dilution susceptibility testing for S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood), S. pneumoniae with MICs of 2 mcg/mL or less are susceptible to cefprozil, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.

NCLLS states that S. pneumoniae and other streptococci (b-hemolytic streptococci, viridans streptococci) that are found to be susceptible to penicillin using NCCLS standardized dilution procedures can be considered susceptible to cefprozil.

Pharmacokinetics

Some of the pharmacokinetic data described in the Pharmacokinetics section were derived from studies that involved cefprozil capsules (not commercially available in the US); however, these capsules, cefprozil oral solution (not commercially available in the US), commercially available cefprozil film-coated tablets, and commercially available cefprozil oral suspension have been shown to be bioequivalent when administered under fasting conditions.

Results of high-pressure liquid chromatographic (HPLC) assays that distinguish between the cis- and trans-isomers of cefprozil indicate that the pharmacokinetics of the isomers are identical and the proportions of cis- and trans-cefprozil in plasma and urine are similar to those contained in commercially available preparations of the drug (i.e., approximately a 9:1 ratio). In adults with normal renal function, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of cefprozil increase in proportion to the dose over the dosage range of 250 mg to 1 g, and there is no evidence that the drug accumulates in plasma following multiple oral doses (up to 1 g every 8 hours for 8-10 days).

Results of pharmacokinetic studies indicate that the AUC of cefprozil reported in healthy geriatric adults (i.e., adults 65 years of age or older) is 35-60% higher than that reported in younger healthy adults (20-40 years of age) and that the average AUC in adult females is 15-20% higher than that reported in adult males. Studies in adults with impaired renal function indicate that the pharmacokinetics of cefprozil are affected by the degree of renal impairment and that plasma half-life of the drug increases with decreasing renal impairment. The plasma half-life of cefprozil is increased slightly in patients with hepatic impairment, but this does not necessitate a change in dosage of the drug.

Absorption

Following oral administration of cefprozil in fasting adults, bioavailability of the drug is approximately 90-95%. Studies using commercially available cefprozil tablets or oral suspension indicate that presence of food in the GI tract does not affect the extent of absorption or peak plasma concentrations of the drug; however, compared with administration in the fasting state, the time to peak plasma concentrations may be prolonged by 15-45 minutes when the drug is administered with food.

Results of a crossover study using cefprozil capsules (not commercially available in the US) indicate that bioavailability of the drug is not affected by concomitant administration of an antacid containing magnesium hydroxide and aluminum hydroxide. In healthy, fasting adults who receive a single 250-mg, 500-mg, or 1-g oral dose of cefprozil as capsules, peak plasma concentrations are attained within 1.5 hours and average 6.1, 10., or 18. mcg/mL, respectively; plasma concentrations 8 hours after the dose average 0.2, 0.4, or 1 mcg/mL, respectively.

In pediatric patients 8 months to 8 years of age who received a single 15- or 30-mg/kg oral dose of cefprozil as the oral suspension, peak plasma concentrations were attained within 1.2-1. hours and averaged 11. or 15. mcg/mL, respectively.

In pediatric patients 6 months to 12 years of age who received a single 7.5-, 15-, or 30-mg/kg oral dose of the drug as the oral suspension, peak plasma concentrations were attained within 1-2 hours; plasma concentrations averaged 3.99, 8.47, or 17. mcg/mL, respectively, 2 hours after the dose and 0.91, 2.75, or 8.66 mcg/mL, respectively, 4 hours after the dose.

Distribution

The steady-state volume of distribution of cefprozil is estimated to be 0.23 L/kg in healthy adults with normal renal function.

Following oral administration, cefprozil is distributed into various body tissues and fluids including blister fluid, middle ear fluid, and tonsillar and adenoidal tissue. In pediatric patients with chronic otitis media with effusion who received a single 15- or 20-mg/kg oral dose of cefprozil as the oral suspension, concentrations of the drug in middle ear fluid collected within 6 hours of the dose ranged from 0.06-4. or 0.17-8. mcg/mL, respectively; concurrent plasma concentrations ranged from 0.38-15. or 1.28-21. mcg/mL, respectively.

In children 2-14 years of age undergoing elective tonsillectomy and/or adenoidectomy who received a single 7.5- or 20-mg/kg dose of cefprozil as the oral suspension, concentrations of the drug in tonsillar or adenoidal tissue ranged from 37-47 or 46-82% of concurrent plasma concentrations, respectively. Information on distribution of cefprozil into CSF is not available.

Cefprozil is distributed into milk in low concentrations following oral administration (i.e., in concentrations less than 0.3% of the dose). In a study in women who received a single 1-g dose of oral cefprozil, concentrations of the drug in breast milk over the next 24 hours ranged from 0.25-3. mcg/mL. Cefprozil is 35-45% bound to plasma proteins; binding is independent of drug concentration over the range of 2-20 mcg/mL.

Elimination

In adults with normal renal function, the plasma half-life of cefprozil averages 1-1. hours and renal clearance of the drug averages 1.78-2.53 mL/minute per kg. The plasma half-life of the drug in pediatric patients 6 months to 12 years of age averages 0.94-2.1 hours.

Cefprozil is eliminated principally in urine by glomerular filtration and tubular secretion. Approximately 54-70% of a single oral dose of the drug is eliminated unchanged in urine within 24 hours. In adults with normal renal function who receive a single 250-mg, 500-mg, or 1-g oral dose of cefprozil, concentrations of the drug in urine over the first 4 hours following the dose average 700, 1000, and 2900 mcg/mL, respectively.

Renal clearance of the drug following a single 1-g dose of cefprozil reportedly is 40% lower in healthy adults 65 years of age and older than in healthy adults 20-40 years of age. The plasma half-life of cefprozil is prolonged in patients with renal impairment and, depending on the degree of impairment, may average 5.2-5.9 hours.

In a study in patients with hepatic impairment who received a single 1-g oral dose of cefprozil, the plasma half-life of the drug averaged 2.2 hours.

Cefprozil is removed by hemodialysis.

Chemistry and Stability

Chemistry

Cefprozil is a semisynthetic cephalosporin antibiotic.

The drug is an oral cephalosporin structurally similar to cefaclor; however, cefprozil contains a p-hydroxyphenyl group at position 7 of the cephalosporin nucleus and contains a 1-propenyl group at position 3 instead of the chloride contained in cefaclor.

Cefprozil is an isomeric mixture of the cis- and trans-isomers of the drug in approximately a 9:1 ratio. Both isomers have similar antibacterial activity against gram-positive bacteria; however, the cis-isomer is 8-9 times more active against gram-negative bacteria than thetrans-isomer.

Cefprozil is commercially available as the monohydrate; potency is calculated on the anhydrous basis. Cefprozil occurs as a white to yellowish powder. The drug is slightly soluble in water and practically insoluble in alcohol.

Cefprozil has a pKas of about 2.7, 7.4, and 9.7. Following reconstitution, cefprozil oral suspension containing 125 or 250 mg of cefprozil per 5 mL occurs as a pink, bubble-gum-flavored suspension.

Stability

Cefprozil tablets should be stored at 15-30°C and cefprozil powder for oral suspension should be stored at 15-25°C.

Following reconstitution, cefprozil oral suspension should be stored in a tight container and is stable for 14 days when refrigerated; any unused suspension should be discarded after this period.

For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of cefprozil, see the Cephalosporins General Statement 8:12.06.

Preparations

Cefprozil Oral For suspension 125 mg (of anhydrous Cefzil®, (with aspartame) cefprozil) per 5 mL Bristol-Myers Squibb 250 mg (of anhydrous Cefzil®, (with aspartame) cefprozil) per 5 mL Bristol-Myers Squibb Tablets, film- 250 mg (of anhydrous Cefzil®, Bristol-Myers coated cefprozil) Squibb 500 mg (of anhydrous Cefzil®, Bristol-Myers cefprozil) Squibb

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