Suprax (Cefixime)

Cefixime

Cefixime is a semisynthetic, third-generation cephalosporin antibiotic.

Uses

Cefixime is used orally in adult and pediatric patients for the treatment of uncomplicated urinary tract infections (UTIs) caused by susceptible bacteria; acute otitis media caused by susceptible bacteria; pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A beta-hemolytic streptococci); and respiratory tract infections (e.g., acute bronchitis, acute exacerbations of chronic bronchitis, pneumonia) caused by susceptible bacteria.

The drug also is used for the treatment of uncomplicated gonorrhea and has been used in the treatment of infections caused by susceptible Salmonella or Shigella. Because cefixime has a long serum half-life and can be administered once or twice daily, some clinicians suggest that the drug may be particularly useful when patient compliance is a concern (e.g., in the treatment of otitis media).

Although cefixime is an effective alternative to other anti-infective agents for the treatment of many infections, the drug offers no clear advantage (except for a convenient dosage regimen) over other equally effective, less expensive anti-infectives available for the treatment of uncomplicated urinary tract infections or upper and lower respiratory tract infections. In addition, use of cefixime as empiric therapy in some infections (e.g., urinary tract infections, respiratory tract infections, soft tissue infections) is limited by its spectrum of activity since the drug is inactive against staphylococci, enterococci, and Pseudomonas aeruginosa.

Because cefixime is inactive against most anaerobic bacteria, the drug is ineffective in and should not be used alone if a mixed aerobic-anaerobic bacterial infection is suspected. Prior to initiation of cefixime therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests. Cefixime therapy may be started pending results of susceptibility tests, but should be discontinued and other appropriate anti-infective therapy substituted if the organism is found to be resistant to cefixime.

Urinary Tract Infections

Uncomplicated Urinary Tract Infections

Cefixime generally has been effective when used in men, women, or children for the treatment of uncomplicated urinary tract infections (UTIs) caused by susceptible strains of Escherichia coli or Proteus mirabilis.

The drug also has been effective when used in a limited number of adults or children for the treatment of uncomplicated UTIs caused by other gram-negative bacteria, including Citrobacter spp., C. diversus, C. freundii, Enterobacter spp., E. aerogenes, E. agglomerans, Klebsiella spp., K. pneumoniae, Morganella morganii, Proteus spp., or Serratia. In controlled studies in men and women with uncomplicated UTIs caused by susceptible gram-negative bacteria, oral cefixime (400 mg once daily or 200 mg twice daily) was as effective as oral co-trimoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole every 12 hours) or oral amoxicillin (250 mg 3 times daily).

The once- and twice-daily cefixime regimens were equally effective and resulted in a bacteriologic cure in about 90-100% of adults with uncomplicated UTIs. In a study in pediatric patients 1-24 months of age with urinary tract infections, a 14-day regimen of oral cefixime (16 mg/kg on day 1 followed by 8 mg/kg once daily) was as effective as a 14-day regimen that included a parenteral drug (IV cefotaxime 200 mg/kg daily given in 4 divided doses for 3 days or until the child is afebrile for 24 hours) followed by oral cefixime (8 mg/kg once daily).

Cefixime has been effective in a few adults for the treatment of uncomplicated UTIs caused by gram-positive bacteria, including Staphylococcus epidermidis, Staphylococcus spp., Streptococcus agalactiae, nonhemolytic streptococci, or Enterococcus faecalis (formerly Streptococcus faecalis). However, treatment failures have occurred when cefixime was used in the treatment of UTIs caused by gram-positive bacteria, and some of these organisms (e.g., staphylococci, S. agalactiae, enterococci) have been isolated in urine either during or after therapy with the drug.

Some clinicians suggest that cefixime offers no advantage over other equally effective, less expensive anti-infective agents (e.g., sulfisoxazole, amoxicillin, co-trimoxazole) for the treatment of uncomplicated UTIs.

For empiric therapy of acute, uncomplicated UTIs, co-trimoxazole, a fluoroquinolone, fosfomycin, nitrofurantoin, or an oral cephalosporin usually is recommended. Because cefixime is inactive in vitro against enterococci and staphylococci, the drug probably should not be used for empiric therapy of nosocomial UTIs. It has been suggested that cefixime be reserved for the treatment of UTIs caused by multidrug-resistant gram-negative bacteria (e.g., E. coli) and used as an alternative to co-trimoxazole, amoxicillin and clavulanate potassium, norfloxacin, and ciprofloxacin for these infections.

Some clinicians suggest that certain oral third-generation cephalosporins (cefdinir, cefixime, cefpodoxime proxetil, ceftibuten) are one of several alternatives that can be used for the outpatient treatment of recurrent UTIs or UTIs acquired in hospitals or nursing homes since these infections are likely to be caused by multidrug-resistant gram-negative bacilli; however, these cephalosporins are not appropriate for the treatment of more severely ill patients hospitalized with UTIs. The most appropriate agent for the treatment of UTIs should be selected based on the severity of the infection and results of culture and in vitro susceptibility testing.

Complicated Urinary Tract Infections

Cefixime has been used with some success in a limited number of adults for the treatment of pyelonephritis and other complicated UTIs caused by susceptible Enterobacteriaceae, including E. coli. Response rates in patients with complicated UTIs receiving cefixime are not as good as those reported in patients with uncomplicated UTIs; bacteriologic cure rates in adults with complicated UTIs have been reported to be 67-100%. Further study is needed to evaluate efficacy of cefixime in the treatment of complicated UTIs.

Otitis Media

Acute Otitis Media

Cefixime is used in adults or children for the treatment of acute otitis media caused by Haemophilus influenzae (including beta-lactamase-producing strains), Moraxella (formerly Branhamella) catarrhalis (including beta-lactamase-producing strains), Streptococcus pyogenes (group A beta-hemolytic streptococci), or S. pneumoniae. In clinical studies in children 6 months to 16 years of age with otitis media, a 10-day regimen of oral cefixime produced a favorable clinical response (e.g., clinical cure or improvement with absence of fever, irritability, otalgia, and tympanic membrane erythema with or without middle ear effusion) in 83-100% and a presumptive bacteriologic cure in 60-97% of patients.

At 2-4 weeks after cefixime therapy, a clinical cure was still evident in 71-77% of children with H. influenzae infections, 84-100% of those with M. catarrhalis infections, and 69-82% of those with S. pneumoniae infections; persistent effusions were present in 15% of patients and 17% were considered to be treatment failures. In studies in children with acute otitis media, oral cefixime (8 mg/kg once daily or 4 mg/kg twice daily) was as effective as oral amoxicillin (20 or 40 mg/kg daily given in 3 equally divided doses), oral amoxicillin and clavulanate potassium (40 mg of amoxicillin per kg daily in 3 equally divided doses), oral cefpodoxime proxetil (10 mg/kg once daily), or oral cefaclor (40 mg/kg daily given in 3 equally divided doses) for the treatment of infections caused by susceptible beta-lactamase-producing M. catarrhalis or H. influenzae. Both the once- and twice-daily cefixime regimens appear to be equally effective in the treatment of acute otitis media caused by susceptible organisms.

There is some evidence that cefixime is less effective than some other anti-infective agents for the treatment of otitis media caused by S. pneumoniae. In some studies where results were stratified according to causative organism, the bacteriologic response reported for cefixime in infections caused by S. pneumoniae was lower than that reported for amoxicillin. Because at least one case of pneumococcal bacteremia developed in a child who was receiving cefixime for the treatment of otitis media, some clinicians suggest that cefixime not be used for the treatment of otitis media known or suspected of being caused by S. pneumoniae. Although the clinical importance is unclear, staphylococci have been isolated from middle-ear fluid after treatment in a few patients receiving cefixime.

Pharyngitis and Tonsillitis

Oral cefixime is used in the treatment of pharyngitis and tonsillitis caused by susceptible S. pyogenes (group A beta-hemolytic streptococci). Although cefixime 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 open-label, randomized studies in pediatric patients with S. pyogenes pharyngitis and tonsillitis indicate that a 10-day regimen of oral cefixime is more effective than a 10-day regimen of oral penicillin V and that a 5-day regimen of oral cefixime is at least as effective as the 10-day penicillin V regimen.

The bacteriologic eradication rate was 94% in those who received a 10-day regimen of oral cefixime, 82.6% in those who received a 5-day regimen of oral cefixime, and 77-88% in those who received a 10-day regimen of oral penicillin V. Once-daily dosing with cefixime is as effective as twice-daily dosing in the treatment of pharyngitis and tonsillitis.

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 beta-hemolytic streptococci in 100% of patients.

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the US Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (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 intramuscular (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 to be alternative agents.

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 should 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 beta-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.

Respiratory Tract Infections

Acute and Chronic Bronchitis

Cefixime is used in adults or children for the treatment of acute bronchitis and acute exacerbations of chronic bronchitis caused by S. pneumoniae or beta-lactamase- and non-beta-lactamase-producing strains of H. influenzae or M. catarrhalis.

The drug also has been effective in a limited number of adults and children for the treatment of other respiratory tract infections, including sinusitis and pneumonia, caused by these organisms or by E. coli, H. parahaemolyticus, or H. parainfluenzae. There is some evidence that 5- or 10-day regimens of oral cefixime (400 mg once daily) are equally effective in patients with acute exacerbation of chronic bronchitis; in one study, the clinical and bacteriologic response rates reported with a 5-day regimen were 88-91 and 69-74%, respectively, and those reported with the 10-day regimen were 88-91 and 53-82%, respectively (intent-to-treat analysis).

In one study in adults, cefixime (400 mg once daily) was as effective as oral amoxicillin (500 mg 3 times daily) for the treatment of lower respiratory tract infections caused by susceptible organisms. Other controlled studies in adults indicate that cefixime (200 mg twice daily or 400 mg once daily) was as effective as oral amoxicillin and clavulanate potassium (500 mg/125 mg 3 times daily), oral cefaclor (500 mg 3 times daily), or oral cephalexin (250 mg 4 times daily) for the treatment of these infections. However, the bacteriologic cure rate reported with cefixime in the treatment of lower respiratory tract infections has ranged from 54-100%, and some clinicians suggest that further study is needed to evaluate the drug's role in the treatment of these infections.

Pneumonia

Oral cefixime has been effective when used in adults or children for the treatment of mild to moderate pneumonia, including community-acquired pneumonia. When used in the treatment of hospitalized patients with community-acquired pneumonia, therapy was initiated with a parenteral third-generation cephalosporin (e.g., ceftriaxone, cefotaxime, ceftizoxime) and then changed to oral cefixime, as appropriate, allowing therapy to be completed on an outpatient basis.

Gonorrhea and Associated Infections

Uncomplicated Gonorrhea

Cefixime is used for the treatment of uncomplicated gonorrhea. A single 400- or 800-mg oral dose of cefixime has been used to treat acute uncomplicated endocervical gonorrhea in women and urethral gonorrhea in men caused by penicillinase- and nonpenicillinase-producing Neisseria gonorrhoeae.

While experience is limited, cefixime also probably would be effective for uncomplicated infections caused by plasmid-mediated, tetracycline-resistant strains (TRNG) or strains with chromosomally mediated resistance (CMRNG). Single oral doses (400 or 800 mg) of cefixime appear to be as effective as single 250-mg IM doses of ceftriaxone in the treatment of uncomplicated gonorrhea.

The CDC states that cefixime has an antimicrobial spectrum similar to that of ceftriaxone, but the 400-mg oral cefixime dose does not provide bactericidal concentrations that are as high and sustained as those provided by a 125-mg IM dose of ceftriaxone.

In a randomized, multicenter study in men and women with uncomplicated gonorrhea who received a single 400- or 800-mg oral dose of cefixime or a single 250-mg IM dose of ceftriaxone, the bacteriologic cure rate 3-10 days after treatment was 96, 98, or 98%, respectively.

Although a single 800-mg oral dose of cefixime has been effective when used alone in a limited number of men for the treatment of anorectal or pharyngeal gonorrhea, efficacy of the drug for the treatment of gonococcal infections at these sites has not been clearly established. The CDC and most clinicians recommend that uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

Alternative regimens that are recommended by the CDC for the treatment of uncomplicated gonorrhea in adults and adolescents include a single IM dose of spectinomycin, a single IM dose of certain cephalosporins (ceftizoxime, cefotaxime, cefoxitin), or a single oral dose of certain fluoroquinolones (gatifloxacin, lomefloxacin, norfloxacin), given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia.

The AAP states that data are insufficient to date concerning efficacy of oral cephalosporins for the treatment of uncomplicated gonorrhea or other gonococcal infections in children and, until further information on oral therapy is available, a parenteral cephalosporin (e.g., ceftriaxone) or IM spectinomycin should be used for the treatment of gonococcal infections in children who weigh less than 45 kg.

However, based on experience in adults, the AAP states that use of cefixime can be considered for the treatment of uncomplicated gonorrhea in young children provided that follow-up can be assured. The AAP and CDC state that children with uncomplicated gonorrhea who weigh 45 kg or more generally can receive regimens recommended for adults and adolescents.

Disseminated Gonococcal Infections

Cefixime is used for follow-up in the treatment of disseminated gonococcal infections. The CDC currently recommends that treatment of disseminated gonococcal infections in adults and adolescents be initiated with a multiple-dose regimen of IM or IV ceftriaxone or, alternatively, a multiple-dose parenteral regimen of certain IV cephalosporins (cefotaxime, ceftizoxime), certain IV fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin), or IM spectinomycin.

The initial parenteral regimen should be continued for 24-48 hours after improvement begins; therapy can then be switched to oral cefixime, oral ciprofloxacin, oral ofloxacin, or oral levofloxacin and continued to complete at least 1 week of treatment. The CDC recommends that the patient be hospitalized for initial treatment, especially when compliance may be a problem, when the diagnosis is uncertain, or when the patient has purulent synovial effusions or other complications.

Patients should be examined for clinical evidence of endocarditis and meningitis; the recommended regimen for these infections is IV ceftriaxone.

An anti-infective regimen effective for presumptive treatment of chlamydia should be given in conjunction with the regimen for disseminated gonococcal infections unless appropriate testing has been performed to exclude this infection.

Typhoid Fever and Other Salmonella Infections

Oral cefixime has been used in children for the treatment of typhoid fever (enteric fever) or septicemia caused by multidrug-resistant strains of Salmonella typhi. Multidrug-resistant strains of S. typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) have been reported with increasing frequency, and fluoroquinolones (e.g., ciprofloxacin, ofloxacin) and third-generation cephalosporins (e.g., ceftriaxone, cefotaxime) are considered the agents of first choice for the treatment of typhoid fever or other severe infections known or suspected to be caused by these strains. In a study in children 6 months to 13 years of age with typhoid fever caused by multidrug-resistant S. typhi who were randomized to receive a 14-day regimen of oral cefixime (10 mg/kg daily in 2 divided doses) or IV ceftriaxone (65 mg/kg once daily), the time to defervescence was 8.3 days in those who received cefixime and 8 days in those who received ceftriaxone; the relapse rate was 5 and 14%, respectively.

Shigellosis

Oral cefixime (8 mg/kg daily for 5 days) has been effective when used in children for the treatment of shigellosis caused by susceptible Shigella and, in one study, was more effective than ampicillin and sulbactam sodium for the treatment of these infections. However, in a study in adults with shigellosis who received oral cefixime (400 mg once daily for 5 days), the clinical response rate to the drug was only 53% and the bacteriologic eradication rate was 40%. Anti-infective therapy generally is indicated in addition to fluid and electrolyte replacement for the treatment of severe cases of shigellosis since anti-infectives appear to shorten the duration of diarrhea and the period of fecal excretion of Shigella. Multiple-drug resistant strains of Shigella have been reported with increasing frequency. For susceptible strains, ampicillin or co-trimoxazole is effective; amoxicillin is less effective.

A fluoroquinolone or, alternatively, a parenteral third-generation cephalosporin (e.g., ceftriaxone) are considered the agents of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown or strains resistant to ampicillin and co-trimoxazole are likely. Some clinicians state that the benefits of oral third-generation cephalosporins (e.g., cefixime) in the treatment of shigellosis are unclear.

Lyme Disease

Oral cefixime has been used in a limited number of patients for the treatment of Lyme disease. In an open, randomized study in patients with disseminated Lyme borreliosis, oral cefixime (200 mg daily with oral probenecid 500 mg 3 times daily) given for 100 days was as effective as a regimen of IV ceftriaxone (2 g daily given for 14 days) followed by oral amoxicillin (500 mg 3 times daily with oral probenecid 500 mg 3 times daily) given for 100 days.

However, other cephalosporins (cefotaxime, ceftriaxone, cefuroxime axetil) usually are recommended when a cephalosporin is used in the treatment of Lyme disease.

Dosage and Administration

Reconstitution and Administration

Cefixime is administered orally and may be given without regard to meals. Cefixime may be administered once or twice daily. Once- and twice-daily regimens reportedly are similarly effective for the treatment of uncomplicated urinary tract infections, tonsillitis, or otitis media, and either regimen may be used in these infections. However, some clinicians suggest that a twice-daily regimen be used in the treatment of otitis media until further study is done to more fully evaluate efficacy of the once-daily regimen.

Relative efficacy of the 2 regimens has not been evaluated in other infections, and some clinicians suggest that twice-daily dosing may be preferable for the treatment of some lower respiratory tract infections or for complicated urinary tract infections. In a few studies in adults, adverse gastrointestinal (GI) effects were reported more frequently in those receiving 400 mg of cefixime once daily than in those receiving 200 mg twice daily; however, results of most studies indicate that the incidence of GI effects is not affected by dosing frequency.

Cefixime 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 100 mg of cefixime per 5 mL.

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

The suspension should be shaken well just prior to administration of each dose. The manufacturer states that cefixime oral suspension should be used for the treatment of otitis media and that cefixime tablets should not be substituted for the oral suspension in the treatment of this infection. However, tablets no longer are commercially available in the US. In addition, the increased bioavailability of cefixime when given as an oral suspension should be taken into consideration if the oral suspension is substituted for the tablet.

Dosage

Cefixime is commercially available as the trihydrate; potency of the drug is expressed in terms of cefixime (the free acid), calculated on the anhydrous basis.

Adult Dosage

The usual adult dosage of cefixime is 400 mg daily. This dosage may be given as a single 400-mg tablet daily or 200 mg (as tablets; no longer commercially available in the US) may be given every 12 hours.

Modification of the usual dosage of cefixime generally is not necessary in geriatric adults, unless renal function is substantially impaired.

Gonorrhea and Associated Infections

For the treatment of uncomplicated gonorrhea caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism, adults should receive a single 400-mg dose of cefixime. Higher single doses of cefixime (e.g., 800 mg) also have been used.

When cefixime is used for the treatment of disseminated gonococcal infections following an initial parenteral regimen, the CDC recommends that adults receive 400 mg twice daily to complete at least 1 week of treatment.

Unless the presence of coexisting chlamydial infection has been excluded by appropriate testing, cefixime therapy for uncomplicated or disseminated gonococcal infections should be administered in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

Pediatric Dosage

Children older than 12 years of age or those weighing more than 50 kg may receive the usual adult dosage of cefixime. The usual dosage of cefixime for children 6 months to 12 years of age is 8 mg/kg daily. This dosage may be given as a single daily dose or 4 mg/kg may be given every 12 hours.

Duration of Therapy

The duration of cefixime therapy depends on the type of infection, but therapy with the drug generally should be continued for at least 48-72 hours after the patient becomes afebrile or evidence of eradication of the infection is obtained.

The usual duration of cefixime therapy is 5-10 days for the treatment of uncomplicated urinary tract infections or upper respiratory tract infections and 10-14 days for the treatment of lower respiratory tract infections.

For the treatment of otitis media, the usual duration of therapy is 10-14 days; a shorter duration of therapy (e.g., 5-7 days) may be effective but has not been fully evaluated in controlled clinical studies. If cefixime is used in the treatment of infections caused by group A beta-hemolytic streptococci, therapy should be continued for at least 10 days to decrease the risk of rheumatic fever or glomerulonephritis.

Dosage in Renal Impairment

Modification of usual dosage of cefixime generally is not necessary in patients with creatinine clearances exceeding 60 mL/minute. In patients with creatinine clearances of 60 mL/minute or less, dose and/or frequency of administration of cefixime should be modified in response to the degree of renal impairment.

Adults with creatinine clearances of 21-60 mL/minute or those undergoing renal hemodialysis should receive 75% of the usual cefixime dosage (i.e., 300 mg daily at the usual dosing interval), and adults with creatinine clearances less than 20 mL/minute or those undergoing continuous ambulatory peritoneal dialysis (CAPD) should receive 50% of the usual cefixime dosage (i.e., 200 mg) at the usual dosing interval.

Alternatively, some clinicians suggest that adults with creatinine clearances less than 20 mL/minute receive the usual dose of cefixime at twice the usual dosing interval. Because cefixime is not substantially removed by hemodialysis or peritoneal dialysis, additional supplemental doses of the drug are not necessary during or after either procedure.

Cautions

Adverse effects reported with cefixime are similar to those reported with other cephalosporins. Cefixime generally is well tolerated; most adverse effects of the drug are transient and mild to moderate in severity.

Adverse effects have been reported in up to 50% of patients receiving the drug but have been severe enough to require discontinuance in about 5% of patients.

GI Effects

The most frequent adverse effects of cefixime involve the GI tract. Adverse GI effects have been reported in up to 30% of adults receiving tablets (no longer commercially available in the US) of the drug and have been mild in 20%, moderate in 5-9%, and severe in 2-3% of patients.

Diarrhea or loose, frequent stools have been reported in up to 27%, and abdominal pain, anorexia, nausea, vomiting, dyspepsia, flatulence, pruritus ani, and dry mouth have been reported in 1-11% of patients receiving the drug. The frequency of adverse GI effects in pediatric patients receiving cefixime oral suspension reportedly is comparable to that in adults receiving tablets of the drug.

Adverse GI effects generally appear during the first or second day of cefixime therapy and probably are direct effects of the drug and not the result of changes in bowel flora. In both adults and children, up to 80% of reported cases of diarrhea or loose stools have occurred within the first 4 days of cefixime therapy. In a few studies, adverse GI effects appeared to be more frequent in patients receiving 400 mg of cefixime once daily than in those receiving 200 mg of the drug twice daily. However, results of most other studies in both adults and children indicate that the incidence of GI effects is similar with both regimens and is not affected by dosing frequency.

Adverse GI effects generally respond to symptomatic treatment or resolve when cefixime therapy is discontinued. Rarely, these effects may be severe enough to require discontinuance of the drug. Severe diarrhea and/or colitis, which required hospitalization in some cases, has been reported rarely in patients receiving cefixime (i.e., in less than 2% of patients).

Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by toxin-producing clostridia resistant to cefixime, may occur during or following discontinuance of cefixime therapy and ranges in severity from mild to life-threatening. C. difficile and/or its toxin has been isolated from the feces of patients who developed diarrhea and/or colitis in association with cefixime therapy.

Mild cases of colitis may respond to discontinuance of cefixime alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary.

If colitis is moderate to severe or is not relieved by discontinuance of cefixime, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered. Cefixime exerts several effects on normal bowel flora.

Cefixime (200 mg twice daily or 400 mg once daily) given for 1-2 weeks reduces total bacterial counts of normal fecal anaerobic bacteria, including clostridia, Bifidobacterium, and some Bacteroides. The drug also decreases bacterial counts of some normal fecal aerobic bacteria including some Enterobacteriaceae and streptococci. In some patients, however, cefixime therapy results in increased fecal counts of group D streptococci, principally Enterococcus faecalis (formerly Streptococcus faecalis). Fecal flora generally returns to pretreatment levels within 2 weeks following discontinuance of cefixime.

Nervous System Effects

Headache has been reported in up to 3-16% and dizziness, nervousness, insomnia, somnolence, malaise, and fatigue have been reported in up to 4% of patients receiving cefixime. Seizures have been reported in less than 2% of patients receiving cefixime. Several other cephalosporins also have been implicated in precipitating seizures, particularly in patients with renal impairment in whom the dosage was not reduced. If seizures occur during cefixime therapy, the drug should be discontinued and appropriate anticonvulsant therapy administered as indicated.

Sensitivity Reactions

Hypersensitivity reactions have been reported in up to 7% of patients receiving cefixime and include rash, urticaria, drug fever, pruritus, and arthralgia. Anaphylaxis, angioedema, facial edema, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and serum sickness-like reactions have been reported in less than 2% of patients receiving cefixime. If a hypersensitivity reaction occurs during cefixime therapy, the drug should be discontinued. Severe acute hypersensitivity reactions should be treated with appropriate therapy (e.g., epinephrine, oxygen, antihistamines, corticosteroids, airway management) as indicated.

Hematologic Effects

Transient thrombocytopenia, thrombocytosis, leukopenia, leukocytosis, eosinophilia, and decreased hemoglobin concentration and hematocrit have been reported in less than 2% of patients receiving cefixime. Prolonged prothrombin time and prolonged partial thromboplastin time also have been reported rarely. Positive direct antiglobulin (Coombs') test results, neutropenia, pancytopenia, agranulocytosis, aplastic anemia, hemolytic anemia, and hemorrhage have been reported with other cephalosporins but have not been reported to date with cefixime.

Hepatic Effects

Transient increases in aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), alkaline phosphatase, bilirubin, and lactate dehydrogenase (LDH) have been reported in less than 2% of patients receiving cefixime. Hepatitis and jaundice have been reported in less than 2% of patients receiving cefixime. Hepatic dysfunction, including cholestasis, also has been reported with other cephalosporins.

Renal and Genitourinary Effects

Transient increases in blood urea nitrogen (BUN) and serum creatinine concentrations and acute renal failure have been reported in less than 2% of patients receiving cefixime.

Dysuria and pyuria have been reported rarely. Genital pruritus, vaginitis, and vaginal candidiasis have been reported in less than 2% of patients receiving cefixime. Renal dysfunction and toxic nephropathy have been reported with other cephalosporins.

Other Adverse Effects

Increased serum amylase concentrations have been reported in 1.5-5% of patients receiving cefixime; however, there was no apparent correlation between increased serum amylase concentrations and adverse GI effects in these patients.

Precautions and Contraindications

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

Cefixime is contraindicated in individuals who are hypersensitive to the drug or other cephalosporins and should be used with caution in individuals who are hypersensitive to penicillins.

Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.

Although it has not been definitely proven that allergic reactions to antibiotics are more frequent in atopic individuals, the manufacturer states that cefixime should be used with caution in individuals with a history of allergy, particularly to drugs. As with other anti-infective agents, prolonged use of cefixime may result in overgrowth of nonsusceptible organisms.

Superinfection with gram-positive bacteria (e.g., staphylococci, enterococci) has occurred in patients receiving cefixime for the treatment of otitis media or urinary tract infections. Careful observation of the patient during cefixime therapy is essential.

If suprainfection or superinfection occurs, appropriate therapy should be instituted. Cefixime should be used with caution in patients with a history of GI disease, particularly colitis.

Because C. difficile-associated diarrhea and colitis has been reported with the use of cefixime or other cephalosporins, it should be considered in the differential diagnosis of patients who develop diarrhea during cefixime therapy. Because serum concentrations of cefixime are higher and more prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of the drug should be decreased in patients with impaired renal function, including those undergoing CAPD or hemodialysis.

Patients undergoing dialysis should be monitored carefully during cefixime therapy.

Pediatric Precautions

Safety and efficacy of cefixime in children younger than 6 months of age have not been established. The incidence of adverse GI effects, including diarrhea and loose stools, in children receiving cefixime oral suspension reportedly is comparable to that reported in adults receiving tablets of the drug.

Diarrhea or loose stools has been reported in up to 15% of children 6 months to 13 years of age receiving oral cefixime. C. difficile-associated diarrhea and colitis has been reported rarely in children receiving cefixime. In 3 reported cases, the onset of symptoms (abdominal pain, diarrhea) occurred 4-14 days after the first dose of cefixime.

Geriatric Precautions

Because renal function decreases with age and may be impaired in geriatric patients, the possibility that adjustment of cefixime dosage may be necessary in this age group should be considered.

Some evidence also indicates that oral bioavailability of the drug may be increased in geriatric patients, but such increases reportedly are not clinically important.

Mutagenicity and Carcinogenicity

Cefixime was not mutagenic when tested in vitro or in vivo in bacteria or mammalian cells for the ability to cause point mutations, induce unscheduled DNA synthesis, or cause chromosome aberrations. The drug did not exhibit clastogenic potential in vivo in the mouse micronucleus test. Long-term animal carcinogenicity studies using cefixime have not been conducted to date.

Pregnancy, Fertility and Lactation

Reproduction studies in mice and rats using oral cefixime dosages up to 400 times the usual human dosage have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using cefixime in pregnant women, and the drug should be used during pregnancy only when clearly needed. Use of cefixime during labor and delivery has not been studied to date, and the drug should be used in these circumstances only when clearly needed.

There was no evidence of impaired fertility or adverse effects on reproductive performance in rats receiving cefixime dosages up to 125 times the usual adult dosage. Cefixime is distributed into milk in rats. Although the drug reportedly was not detected in milk following a single dose in lactating women in one study, it currently is not known whether cefixime is distributed into milk in humans. Therefore, cefixime should be used with caution in nursing women, and consideration should be given to temporarily discontinuing nursing during therapy with the drug.

Drug Interactions

Antacids

Results of a study in healthy men indicate that administration of an antacid containing aluminum hydroxide and magnesium hydroxide either simultaneously with or 2 hours before or after a single 400-mg oral dose of cefixime has no clinically important effects on the pharmacokinetics of the anti-infective agent.

Probenecid

Although specific information is unavailable, concomitant administration of probenecid reportedly increases peak serum concentrations and the area under the serum concentration-time curve (AUC) of cefixime and decreases renal clearance and volume of distribution of the drug.

Salicylates

In one in vitro study in pooled serum, salicylic acid apparently displaced cefixime from protein binding sites, resulting in more than a 50% increase in concentrations of free cefixime; this effect appeared to be concentration-dependent.

Concomitant administration of a 650-mg oral dose of aspirin and a 400-mg oral dose of cefixime in healthy adult men did not appear to affect protein binding, serum half-life, or renal clearance of cefixime but did result in a 20-25% decrease in peak serum concentrations and AUCs of the anti-infective agent.

Although the manufacturer states that this effect was not considered clinically important since serum concentrations of cefixime remained higher than the MIC values reported for most susceptible organisms, some clinicians state that this potential interaction may be clinically important in certain infections.

Anticoagulants

Increased prothrombin time with or without bleeding has been reported following concomitant use of cefixime with an anticoagulant (e.g., warfarin).

Other Drugs

Concomitant administration of cefixime and carbamazepine may result in increased plasma carbamazepine concentrations. Concomitant administration of cefixime and nifedipine increases oral bioavailability of cefixime as a result of higher peak plasma concentrations and AUC. In vitro in pooled serum, acetaminophen, heparin, phenytoin, diazepam, ibuprofen, or furosemide had no clinically important effects on the in vitro protein binding of cefixime.

Laboratory Test Interferences

Tests for Urinary Glucose

Like most cephalosporins, cefixime may cause false-positive results in urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest®, Fehling's solution); however, glucose oxidase methods (e.g., Clinistix®, Tes-Tape®) are unaffected by the drug.

Immunohematology Tests

Although not reported to date with cefixime, positive direct antiglobulin (Coombs') test results have been reported in patients receiving other cephalosporins. This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving cefixime.

Urinary Ketones

Cefixime may cause false-positive results for urinary ketones when tests using nitroprusside are used; this should not occur when tests using nitroferricyanide are used.

Acute Toxicity

The oral LD50 of cefixime exceeds 10 g/kg in mice, rats, and rabbits. In dogs, LD50 determinations have been limited by emesis, which occurred when cefixime doses of 320 mg/kg or greater were used in these animals.

Limited information is available on the acute toxicity of cefixime in humans. In healthy adults who received cefixime in single doses up to 2 g, adverse effects were similar to those seen with usual doses of the drug and included mild to moderate adverse GI effects. If acute overdosage of cefixime occurs, the stomach should be emptied by gastric lavage. Cefixime is not removed in clinically important quantities by hemodialysis or peritoneal dialysis.

Mechanism of Action

Cefixime is usually bactericidal in action. Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall.

Studies evaluating the binding of cefixime to penicillin-binding proteins (PBPs), the target enzymes of beta-lactam antibiotics, indicate that cefixime has a high affinity for PBPs 3, 1a, and 1b of Escherichia coli. Since PBP 1b is a killing site for beta-lactam anti-infectives, cefixime's high affinity for this site may be a major factor in the drug's potent bactericidal activity against this organism. Cefixime has only low affinity for PBP 2 of staphylococci and little or no affinity for PBP 4 or 5. In vitro studies indicate that low concentrations of cefixime usually cause the formation of filamentous cells in susceptible E. coli or Klebsiella pneumoniae.

At higher concentrations, direct lysis of the organisms may occur as well as spheroplast formation and rupture. Following in vitro exposure to cefixime, morphologic changes in beta-lactamase-producing E. coli are the same as those seen in non-beta-lactamase-producing strains of the organism. Lysis occurs in susceptible anaerobic bacteria following in vitro exposure to cefixime.

For most susceptible organisms, the minimum bactericidal concentration (MBC) of cefixime is only 1-4 times higher than the minimum inhibitory concentration (MIC). However, for some strains of Enterobacter, Klebsiella, Morganella, Proteus, Providencia, and Serratia, the MBC may be 9-32 times higher than the MIC.

In Vitro Susceptibility Testing

Results of in vitro cefixime susceptibility tests are not usually affected by the pH of the media or the presence of certain cations (e.g., calcium, magnesium, sodium). There generally is little effect on in vitro susceptibility test results when the pH of the media is within the range of 5-8. In vitro activity of cefixime against Enterobacteriaceae is not affected by the presence of urine or serum. Inoculum size may affect in vitro susceptibility to cefixime. MICs of most susceptible organisms are not greatly affected when the size of the inoculum is increased from 10³ to 10⁵ colony-forming units (CFU) per mL; however, MICs of some Enterobacteriaceae may be 15-500 times higher when the size of the inoculum is increased from 10³ to 10⁷ CFU.

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 cefixime, 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.

Distribution

Information on distribution of cefixime is limited.

Following oral administration, cefixime is distributed into bile, sputum, tonsils, maxillary sinus mucosa, middle ear discharge, blister fluid, and prostatic fluid. Sputum concentrations may be 2-10% of concurrent serum concentrations; in one study, a single 200-mg oral dose of cefixime resulted in sputum concentrations of 0.03-0.12 mcg/mL.

It is not known whether cefixime is distributed into cerebrospinal fluid (CSF) following oral administration.

Stability

Cefixime powder for oral suspension should be stored in tight containers at 59–86°F (15–30°C). After reconstitution, refrigeration of cefixime oral suspension is not required; the suspension should be stored in a tight container and is stable for 14 days at room temperature or when refrigerated, and any unused suspension should be discarded after this period.