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 caused by susceptible bacteria; acute otitis media caused by susceptible bacteria; pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-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 b-lactamase-producing strains), Moraxella (formerly Branhamella) catarrhalis (including b-lactamase-producing strains), Streptococcus pyogenes (group A b-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 b-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 b-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 b-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 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 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.
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 b-lactamase- and non-b-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. For additional information on current recommendations for the treatment of gonorrhea and associated infections, see Uses: Gonorrhea and Associated Infections, in Ceftriaxone 8:12.06.12.
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 cephalosporins (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. (See Uses: Lyme Disease in the Cephalosporins General Statement 8:12.06.)
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 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. (See Cautions: GI Effects.) 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. (See Dosage and Administration: Dosage in Renal Impairment.)
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 b-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%1, 2, 23, 40, 41, 44, 64, 75, 103 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%1, 23, 41, 75 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 AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, and LDH2 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 BUN1, 2, 41, 74 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 b-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. (See Cautions: GI Effects.) 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 continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis.
Patients undergoing dialysis should be monitored carefully during cefixime therapy. (See Dosage and Administration: Dosage in Renal Impairment.)
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. (See Dosage and Administration: Dosage in Renal Impairment.)
Some evidence also indicates that oral bioavailability of the drug may be increased in geriatric patients, but such increases reportedly are not clinically important. (See Pharmacokinetics: Absorption.)
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, Fertitlity 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 (see Pharmacokinetics: Distribution), 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 area under the plasma concentration-time curve. 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 Toxcicity
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. For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06.
Studies evaluating the binding of cefixime to penicillin-binding proteins (PBPs), the target enzymes of b-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 b-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 5.60 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 b-lactamase-producing E. coli are the same as those seen in non-b-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. Spectrum Based on its spectrum of activity, cefixime is classified as a third 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 third generation cephalosporins (e.g., cefdinir, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone), cefixime has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins. In vitro on a weight basis, however, cefixime usually is less active than many other currently available third generation cephalosporins against susceptible Enterobacteriaceae and is inactive in vitro against most strains of Enterobacter and Pseudomonas.
Although some other currently available third generation cephalosporins have some activity against staphylococci, cefixime usually is inactive against these organisms.
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.
If results indicate that a clinical isolate has intermediate susceptibility to cefixime, 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 cefixime, 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 also should be considered resistant to cefixime, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.
Disk Susceptibility Tests
When the disk-diffusion procedure is used to test susceptibility to cefixime, a disk containing 5 mcg of cefixime should be used. The cephalosporin class disk containing 30 mcg of cephalothin should not be used to test susceptibility to cefixime.
When the disk-diffusion susceptibility test is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterobacteriaceae with growth inhibition zones of 19 mm or greater are susceptible to cefixime, those with zones of 16-18 mm be have intermediate susceptibility, and those with zones of 15 mm or less are resistant to the drug.
When disk-diffusion susceptibility testing of Haemophilus is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), isolates with growth inhibition zones of 21 mm or greater should be considered susceptible to cefixime. Because of limited data on resistant strains of these organisms, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to cefixime be submitted to a reference laboratory for further testing. When disk-diffusion susceptibility testing is performed according to the NCCLS standardized procedures using GC agar (with 1% defined growth supplement), N. gonorrhoeae with growth inhibition zones of 31 mm or greater should be considered susceptible to cefixime.
Because of limited data on resistant strains of these organisms, NCCLS recommends that any N. gonorrhoeae isolate that appears to be nonsusceptible to cefixime be submitted to a reference laboratory for further testing. Interpretive criteria are not available to determine susceptibility of Streptococcus pneumoniae to cefixime using the cefixime 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 cefixime.
Dilution Susceptibility Tests
When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterobacteriaceae with MICs of 1 mcg/mL or less are susceptible to cefixime, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.
When dilution susceptibility testing for Haemophilus is performed according to the NCCLS standardized procedure using HTM, Haemophilus with MICs of 1 mcg/mL or less should be considered susceptible to cefixime.
Because of limited data on resistant strains of these organisms, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to cefixime be submitted to a reference laboratory for further testing.
When dilution susceptibility testing for N. gonorrhoeae is performed according to the NCCLS standardized procedure using GC agar base (with 1% defined growth supplement), isolates with an MIC of 0.25 mcg/mL or less should be considered susceptible to cefixime. Because of limited data on resistant strains of these organisms, NCCLS recommends that any N. gonorrhoeae isolate that appears to be nonsusceptible to cefixime be submitted to a reference laboratory for further testing. NCCLS states that S. pneumoniae found to be susceptible to penicillin using the NCCLS standardized broth dilution procedure can be considered susceptible to cefixime.
Gram-positive Aerobic Bacteria
Gram-positive Aerobic Cocci
Cefixime generally is active in vitro against Streptococcus pyogenes (group A b-hemolytic streptococci), S. agalactiae (group B streptococci), and groups C, F, and G streptococci. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of cefixime reported for S. pyogenes and S. agalactiae is 0.1-0. mcg/mL, and the MIC90 reported for groups C, F, and G streptococci is 0.05-1 mcg/mL. In vitro on a weight basis, cefixime is either equally or more active than most first and second generation cephalosporins (e.g., cephalexin, cefadroxil, cefaclor, cefuroxime) against S. pyogenes, but is less active than ampicillin or amoxicillin against these organisms.
Cefixime is active in vitro against some strains of S. pneumoniae; however, in vitro on a weight basis, the drug generally is less active against this organism than some other oral cephalosporins (e.g., cefdinir, cefpodoxime, cefprozil, cefuroxime).
While penicillin-susceptible S. pneumoniae may be inhibited in vitro by cefixime concentrations of 4 mcg/mL or less, the MIC90 of cefixime reported for strains of S. pneumoniae that have intermediate resistance to penicillin (relatively resistant) and strains that are highly resistant to penicillin is 16-32 mcg/mL and these strains are considered resistant to cefixime.
Nonenterococcal group D streptococci (e.g., S. bovis) and viridans streptococci (e.g., S. mitis) generally require cefixime concentrations of 1-32 mcg/mL for in vitro inhibition, and most strains are considered resistant to the drug. In one study, the MIC50 and MIC90 of cefixime for the S. milleri group of viridans streptococci (S. anginosus, S. constellatus, S. intermedius) were 4 and 8 mcg/mL, respectively.
Enterococci, includingEnterococcus faecalis (formerly S. faecalis) and E. faecium (formerly S. faecium), are resistant to cefixime. Unlike other currently available cephalosporins, cefixime is inactive in vitro against penicillinase-producing and nonpenicillinase-producing staphylococci, including Staphylococcus aureus, S. epidermidis, and S. saprophyticus. Although some staphylococci may be inhibited in vitro by cefixime concentrations of 3-16 mcg/mL, most strains require high concentrations of cefixime for in vitro inhibition and are considered resistant to the drug.
Like other cephalosporins, cefixime is inactive against methicillin-resistant staphylococci.
Gram-Positive Aerobic Bacilli
Corynebacterium, including JK strains of Corynebacterium JK, generally are resistant to cefixime and have MIC90s of 32 mcg/mL or greater. Listeria monocytogenes generally are resistant to cefixime in vitro.
Gram-negative Aerobic Bacteria
Neisseria
Cefixime is active in vitro against Neisseria meningitidis, and most strains of this organism are inhibited by cefixime concentrations of 0.01-0.06 mcg/mL. Cefixime is active in vitro against penicillinase-producing (PPNG) and nonpenicillinase-producing N. gonorrhoeae. The drug also is active in vitro against N. gonorrhoeae with chromosomally mediated resistance to penicillin (CMRNG) or plasmid-mediated tetracycline resistance (TRNG). The MIC90 of cefixime for nonpenicillinase-producing N. gonorrhoeae, PPNG, or CMRNG is 0.001-0.06 mcg/mL. In vitro on a weight basis, cefixime is as active as ceftriaxone against PPNG and CMRNG.
Haemophilus
Cefixime is active in vitro against most b-lactamase-producing and non-b-lactamase-producing strains of Haemophilus influenzae and H. parainfluenzae. The MIC90 reported for b-lactamase-producing and non-b-lactamase-producing H. influenzae is 0.015-0.25 mcg/mL. In vitro on a weight basis, cefixime is more active against b-lactamase-producing H. influenzae than is cefaclor, cephalexin, cefuroxime, or amoxicillin and clavulanate potassium, but may be equally or slightly less active than is ciprofloxacin, ceftriaxone, or co-trimoxazole against these organisms.
Cefixime is active in vitro against multiple-drug resistant strains of H. influenzae that are resistant to ampicillin, chloramphenicol, tetracycline, co-trimoxazole, cefaclor, and/or erythromycin. However, some strains of non-b-lactamase-producing H. influenzae that are resistant to ampicillin and second generation cephalosporins also may have reduced susceptibility to cefixime.
Moraxella catarrhalis
Cefixime is active in vitro against both b-lactamase- and non-b-lactamase-producing Moraxella (formerly Branhamella) catarrhalis, and the MIC90 of the drug reported for this organism is 0.03-0. mcg/mL. Cefixime is active in vitro against strains of M. catarrhalis resistant to ampicillin, cephalexin, and cefaclor.
Enterobacteriaceae
Cefixime is active in vitro against most clinically important Enterobacteriaceae.
With the exception of Citrobacter freundii, Enterobacter, Morganella morganii, and Serratia, the MIC90 of cefixime for Enterobacteriaceae is generally 2 mcg/mL or less. In vitro on a weight basis, cefixime is equally or less active than other third generation cephalosporins (e.g., cefotaxime, ceftriaxone) or ciprofloxacin against Enterobacteriaceae. Cefixime is active in vitro against many strains of E. coli, Citrobacter freundii, K. pneumoniae, and P. mirabilis resistant to other anti-infectives (e.g., aminoglycosides, tetracycline, ampicillin, amoxicillin, cefaclor, cephalexin).
Cefixime is active in vitro against strains of Salmonella typhi resistant to ampicillin, chloramphenicol, and/or co-trimoxazole. The following table includes MIC50s and MIC90s of cefixime reported for Enterobacteriaceae: Organism MIC50 (mcg/mL) MIC90 (mcg/mL) Citrobacter spp. C. amalonaticus 0.25-0. 1-1. C. diversus 0.06-0. 0.06-0. C. freundii 1-3. 2-128 Enterobacter spp. 3.27-4 20-32 E. aerogenes 0.4-16 8-100 E. agglomerans 0.05-0. 8-32 E. cloacae 0.1-16 8-128 Escherichia coli 0.1-0. 0.12-2 Hafnia alvei 0.4-4 2-32 Klebsiella spp. 0.08-0. 0.25-0. K. oxytoca 0.013-0. 0.05-4 K. pneumoniae 0.025-0. 0.05-0. Morganella morganii 0.39-8 4-32 Proteus spp. P. mirabilis 0.01-0. 0.01-0. P. vulgaris 0.01-0. 0.05-2 Providencia spp. 0.125-0. 0.5-16 P. rettgeri 0.01-0. 0.05-2 P. stuartii 0.01-0. 0.12-2 Serratia spp. 0.5-2 8-64 S. marcescens 0.25-3. 2-128 Salmonella spp. 0.05-0. 0.2-0. S. enteritidis 0.125-0. 0.34-0. S. typhi 0.02-0. 0.06 Shigella spp. 0.12-0. 0.25-0. Yersinia enterocolitica 0.25-1 1-4
Pseudomonas
Some strains of Pseudomonas cepacia, Ps. pseudomallei, and Ps. stutzeri are inhibited in vitro by cefixime concentrations of 1.56-8 mcg/mL. However, the MIC90 of cefixime for Ps. aeruginosa and for most other Pseudomonas, including Ps. fluorescens, Ps. putida, Ps. maltophilia (Xanthomonas maltophilia), and most strains of Ps. stutzeri, usually exceeds 16 mcg/mL and these organisms are considered resistant to the drug.
Other Gram-negative Aerobic Bacteria
Cefixime has some in vitro activity against Acinetobacter; however, the MIC90 reported for A. calcoaceticus var. lwoffi and A. calcoaceticus var. anitratus generally ranges from 3.1-100 mcg/mL. Aeromonas hydrophila generally is inhibited in vitro by cefixime concentrations of 0.01-4 mcg/mL. Some strains of Alcaligenes are inhibited in vitro by cefixime concentrations of 8 mcg/mL.
Some strains of Campylobacter fetus subsp. jejuni are inhibited in vitro by cefixime concentrations of 1.6-8 mcg/mL, but many strains of the organism are resistant to the drug. Cefixime is active against Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis). The MIC90 of cefixime for H. pylori has been reported as 0.25-0.5 mcg/mL. Cefixime concentrations of 12.-16 mcg/mL inhibit some strains of Bordetella pertussis; however, B. bronchiseptica and B. parapertussis are resistant to the drug. Pasteurella multocida is inhibited in vitro by cefixime concentrations of 0.012-1 mcg/mL.
Achromobacter xylosoxidans and Flavobacterium meningosepticum, F. adoratum, and F. indologenes are resistant to cefixime.
Anaerobic Bacteria
Cefixime has only limited in vitro activity against anaerobic bacteria. Some strains (45-91% of those tested) of Lactobacillus, Peptococcus, Peptostreptococcus, Actinomyces, Propionibacterium, Fusobacterium, and Veillonella are inhibited in vitro by cefixime concentrations of 1-4 mcg/mL. Most strains of Bacteroides fragilis and other Bacteroides species are resistant to cefixime in vitro. Although some Clostridium are inhibited in vitro by cefixime concentrations of 1.56-8 mcg/mL, most strains of Clostridia (including C. difficile) are considered resistant to the drug.
Chlamydia and Mycoplasma
Cefixime is inactive against Chlamydia trachomatis and Ureaplasma urealyticum.
Spirochetes
Cefixime has some activity against Borrelia burgdorferi, the causative organism of Lyme disease, and concentrations of 0.8 mcg/mL reportedly inhibit the organism in vitro. Resistance For information on possible mechanisms of bacterial resistance to cephalosporins, see Resistance in the Cephalosporins General Statement 8:12.06. Cefixime has a high degree of b-lactamase stability and is stable against hydrolysis by many plasmid- and chromosomally mediated b-lactamases.
The drug generally is more stable against inactivation by b-lactamases than are cefaclor, cefoxitin, cefuroxime, cephalexin, and cephradine. Cefixime generally is not hydrolyzed by b-lactamases classified as Richmond-Sykes types Ia (P99), III (TEM-1, TEM-2, SHV-1), IV (K-1), and V (OXA-2, OXA-3, PSE-1, PSE-4, PSE-4). The drug is hydrolyzed by some b-lactamases produced by Enterobacter, Klebsiella oxytoca, Proteus vulgaris, and Pseudomonas cepacia.
The drug is hydrolyzed by Richmond-Sykes type I produced byPseudomonas cepacia and Ia produced by Citrobacter freundii and Enterobacter cloacae.
The drug also is hydrolyzed by b-lactamases produced by Flavobacterium and Bacteroides fragilis. Resistance to cefixime in staphylococci appears to be related to the drug’s poor affinity for PBP 2 of these organisms. R
esistance in enterococci and Listeria monocytogenes may also be related to poor binding of cefixime to the PBPs of these organisms. In vitro studies indicate that resistance to cefixime in C. freundii and Enterobacter apparently is related to factors that affect permeability of the organisms to the drug and also is related to the production of b-lactamases.
Resistance to cefixime in Pseudomonas and Acinetobacter is related to permeability factors. Unlike some b-lactam anti-infectives (e.g., cefotetan, cefoxitin, imipenem), cefixime is a weak inducer of b-lactamases and does not derepress inducible, chromosomally mediated enzymes in C. freundii, E. cloacae, E. aerogenes, Providencia stuartii, Serratia liquefaciens, or S. marcescens.
Cefixime does, however, induce b-lactamase production in some strains of Morganella morganii, but the drug remains active in vitro against these M. morganii strains following derepression of inducible b-lactamases.
Pharmacokinetics
In many of the studies described in the Pharmacokinetics section, cefixime was administered as capsules (which are not currently available in the US) or as an oral solution (which differs from the oral suspension currently marketed in the US).
Although there are some differences in pharmacokinetic parameters between the formulations, results of controlled, cross-over studies in healthy adults indicate that the capsules used in these studies essentially are bioequivalent to cefixime tablets (no longer commercially available in the US) and that the oral solution, but not the oral syrup, used in these studies essentially is bioequivalent to the currently marketed oral suspension of the drug. Of these oral dosage forms, the syrup has been the least bioavailable to date.
The manufacturer states that currently available tablets of cefixime are not bioequivalent to the currently available oral suspension since the oral suspension is absorbed more completely than the tablets. (See Pharmacokinetics: Absorption.)
Absorption
Approximately 30-50% of a single dose of cefixime is absorbed following oral administration. Studies in rats indicate that the drug is absorbed from the upper and middle part of the small intestine and probably is transported across the intestinal membrane by a dipeptide carrier system.
Presence of food in the GI tract decreases the rate of absorption of cefixime but generally does not affect the extent of absorption of the drug. GI absorption of cefixime is not affected by concomitant administration of antacids. (See Drug Interactions: Antacids.)
Following oral administration of a single 200- or 400-mg dose of cefixime as capsules, tablets, or oral suspension, the time to peak serum concentrations averages 3.1-4.4 hours (range: 2-6 hours). In one study in healthy, fasting adults, time to peak serum concentrations of cefixime was dose dependent and averaged 2.7, 3.4, 3.9, and 4.3 hours following a single 50-, 100-, 200-, and 400-mg oral dose, respectively.
Following oral administration of a single 200- or 400-mg tablet of cefixime, peak serum concentrations average 2 mcg/mL (range: 1-4 mcg/mL) or 3.7 mcg/mL (range: 1.3-7.7 mcg/mL); serum concentrations average 1.5 or 2.7 mcg/mL, respectively, 6 hours after the dose and average 0.4 or 0.6 mcg/mL, respectively, 12 hours after the dose.
Peak serum concentrations of cefixime are approximately 15-50% higher when the drug is administered as an oral suspension rather than as tablets. When 200- or 400-mg doses of cefixime are administered as an oral suspension, peak serum concentrations average 3-3.4 mcg/mL (range: 1-4. mcg/mL) and 4.6 mcg/mL (range: 1.9-7. mcg/mL), respectively. In the dosage range of 100-400 mg, the areas under the concentration-time curves (AUCs) are approximately 10-25% higher with the oral suspension than with the tablets.
This lack of bioequivalence between dosage forms should be considered if the oral suspension is substituted for tablets; the manufacturer states that tablets theoretically should not be substituted for the oral suspension for the treatment of otitis media.
Studies in healthy adults using cefixime doses of 100 mg to 2 g given as capsules or an oral solution or suspension indicate that peak serum concentrations and AUCs increase with increasing dose but are not directly dose proportional; there is some evidence that decreased GI absorption occurs with increasing dose.
Studies in children using cefixime doses of 4- to 8-mg/kg also indicate that serum concentrations of cefixime are not directly dose proportional.
There is no evidence that cefixime accumulates in serum or urine of patients with normal renal function following multiple doses of the drug given once or twice daily. In one study in healthy adults receiving 400 mg once daily or 200 mg twice daily as cefixime capsules, peak serum concentrations and AUCs determined after 8 and 14-15 days of therapy were similar to those reported on the first day of therapy.
Although the difference was not considered clinically important, one study in geriatric patients older than 64 years of age receiving 400-mg doses of cefixime once daily for 5 days indicated that peak serum concentrations of cefixime were 20-26% higher and AUCs were approximately 40-42% higher in these geriatric adults than in healthy adults 18-35 years of age. In pediatric patients 6 months to 6 years of age or older receiving a single 4-, 6-, or 8-mg/kg dose of cefixime as an oral suspension, serum concentrations of the drug 3.5-4. hours after the dose average 2.18-2.44,55-4.07, and 3.4-3. mcg/mL, respectively.
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.
In children 3 months to 5 years of age with acute otitis media with effusion or with otitis media with effusion that required tympanostomy tube placement, a single 8-mg/kg oral dose of cefixime resulted in middle ear fluid concentrations averaging 1.3-1. mcg/mL at 3-5 hours after the dose; concurrent serum concentrations of the drug averaged 2.5-3.2 mcg/mL. In cholecystectomized patients who received a single 100-, 200-, or 400-mg oral dose of cefixime, concentrations of the drug in gallbladder tissue and bile 3.5-12 hours after the dose averaged 8-18. mg/kg and 134-190 mg/L, respectively.
In one patient with a biliary tract infection who received a single 200-mg dose of cefixime, concentrations of the drug in common duct bile were 0.3 mg/L 1.5 hours after the dose and 99 mg/L 4.5 hours after the dose. Cefixime concentrations in prostatic fluid are reported to range from less than 0.01 to 0.83 mcg/mL in samples obtained 1-3 hours after a single 200- or 400-mg oral dose of the drug.
It is not known whether cefixime is distributed into CSF following oral administration. The apparent volume of distribution of cefixime in healthy adults averages 0.1 L/kg (range: 0.095-0.11 L/kg.
Cefixime is approximately 65-70% bound to serum proteins, principally albumin, and such binding is not concentration dependent over the range of 0.5-30 mcg/mL. The fraction of free cefixime in plasma may be slightly greater in patients with impaired renal function than in those with normal renal function, but this generally is not considered clinically important.
Cefixime crosses the placenta and is distributed in low concentrations into amniotic fluid and cord serum; cord serum concentrations may be 15-50% of concurrent maternal plasma concentrations. In one study in women who received a single 100-mg oral dose of cefixime, the drug reportedly was not detected in milk when samples were obtained 1-6 hours after the dose. In a study in rats receiving cefixime via intraperitoneal infusion, only low concentrations of the drug were attained in the plasma of nursing pups.
Elimination
The serum elimination half-life of cefixime in adults with normal renal function averages 2.4-4 hours. Although not reported in published studies, the manufacturer states that the serum elimination half-life of cefixime may range up to 9 hours in some healthy adults.
Serum half-life of cefixime is independent of dosage form and is not dose-dependent. The serum half-life of cefixime is prolonged in patients with impaired renal function. In adults with creatinine clearances of 21-60 mL/minute per 1.73 m, serum half-life averages about 7 hours. In adults with creatinine clearances of 5-20 mL/minute per 1.73 m, half-life averages 11. hours.
In one study in a limited number of adults undergoing hemodialysis and receiving 400-mg oral doses of cefixime, pharmacokinetics of the drug were similar to those reported for patients with creatinine clearances of 21-60 mL/minute. It is not known whether impaired hepatic function has an effect on the pharmacokinetics of cefixime. Cefixime is eliminated by renal and nonrenal mechanisms. There is no evidence that cefixime is metabolized in vivo; no microbiologically active metabolites have been detected in serum or urine following oral administration of the drug.
Approximately 7-41% of a single oral dose of the drug is excreted unchanged in urine within 24 hours; the drug is excreted principally by glomerular filtration and to a lesser extent by tubular secretion. T
he remainder of the dose (up to 60%) is eliminated by nonrenal mechanisms. Studies in animals indicate that up to 10% of a single oral dose of cefixime is excreted unchanged in bile. Fecal concentrations of cefixime in healthy adults may range from 0.237-1.55 g/kg following usual oral doses of the drug as capsules or tablets.
Clearance of cefixime from serum averages 0.39-0. mL/minute per kg and renal clearance averages 27-43 mL/minute in healthy adults with normal renal function.
Urinary concentrations of cefixime generally range from 2.2-103 mcg/mL during the first 2 hours and from 15.-305 mcg/mL 6-8 hours after a single 200- or 400-mg oral dose of the drug. Only small amounts of cefixime are removed by hemodialysis or peritoneal dialysis; these amounts are not considered clinically important.
Chemistry and Stability
Chemistry
Cefixime is a semisynthetic cephalosporin antibiotic. The drug is an oral aminothiazolyl methoxyimino cephalosporin.
Cefixime is structurally similar to other oral (cefdinir, cefpodoxime proxetil, ceftibuten) or parenteral (cefotaxime, ceftazidime, ceftizoxime, ceftriaxone) cephalosporins that contain an aminothiazolyl side chain at position 7 of the cephalosporin nucleus.
The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and the methoxyimino group imparts stability against hydrolysis by many b-lactamases. Like cefdinir, cefixime contains a vinyl moiety at position 3 of the cephalosporin nucleus. This vinyl moiety, which is a small uncharged group, is partially responsible for the GI absorption characteristics of cefixime.
The vinyl moiety also may contribute to cefixime’s potent bactericidal activity, although it appears to be partially responsible for the drug’s poor in vitro activity against staphylococci. 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. Cefixime occurs as a white to slightly yellowish-white, nonhygroscopic, crystalline powder with a slight characteristic odor. The drug has a pKa of 3.73. The aqueous solubility of cefixime is pH dependent.
At room temperature, cefixime has solubilities in water of 0.5 mg/mL at pH 3.2 and 18 mg/mL at pH 4.2. Cefixime has a solubility of 8.3 mg/mL in alcohol at room temperature.Cefixime powder for oral suspension occurs as an off-white to cream-colored, strawberry-flavored powder. Following reconstitution, the suspension has a pH of 2.5-4.5.
Stability
Cefixime powder for oral suspension should be stored in tight containers at 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. Cefixime is stable in serum or urine specimens for at least 1 month at -20 to -70°C. In vitro in serum, cefixime loses almost 50% of its potency within 7 days at 4°C. Although the drug is stable in urine for up to 24 hours at 37°C, the drug is unstable in vitro in serum at this temperature and loses up to 15% of its potency after 8 hours at 37°C.
Preparations
Cefixime Oral For suspension 100 mg/5 mL (of anhydrous Suprax®, (with sucrose) cefixime) Wyeth
| Dosage forms of Cefixime: | ||
|---|---|---|
| Suprax 100 mg/5ml Suspension | Suprax 400 mg Tablet | Suprax 20 mg/ml Suspension |
Synonyms of Cefixime:
Cefixim, Cefixima [Spanish], Cefixime Anhydrous, Cefiximum [Latin]
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Therapeutic classes of Cefixime:
Anti-Bacterial Agents, Cephalosporins
Delivery
Australia, Canada, Mexico, New Zealand, USA, Europe [Belgium, France, Norway, Holland, Ireland, Spain, Switzerland, Great Britain (UK), Italy] and etc.