VA Class:AM117

AHFS Class:

• Third Generation Cephalosporins 8:12.06.12

Generic Name(s):

• Cefixime

Chemical Name:

• [6 R -[6α,7β( Z )]]-7-[[(2-Amino-4-thiazoyl)[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Associated Monographs

• Cephalosporins General Statement

Cefixime is a semisynthetic, third generation cephalosporin antibiotic.1,2,3,4,6,7,13,23,57,60,75,83

Cefixime is used orally in adult and pediatric patients for the treatment of acute otitis media caused by susceptible bacteria;1,2,3,23,43,56,61,62,63,75 pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci);1,2,3,23,44,56,64,75 respiratory tract infections (e.g., acute exacerbations of chronic bronchitis, pneumonia†) caused by susceptible bacteria;1,2,3,23,44,56,64,70,72,75,137,166,180 and uncomplicated urinary tract infections caused by susceptible bacteria.1,2,40,51,64,74,75,182 The drug also has been used for the treatment of gonorrhea1,48,71,82,106,108,109,110,111,118,119,120,130 and infections caused by susceptible Salmonella †141,142 or Shigella †.139,148

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).3,40,43,56,62,63,64,75 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.3,75,102 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 .2,3,8,51,60,74,75,101 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.60

Prior to initiation of cefixime therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests.1,2 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.1,2

Acute Otitis Media

Cefixime is used in adults or children for the treatment of acute otitis media (AOM)1,2,3,23,43,56,61,62,63,75,138,164,165 caused by Haemophilus influenzae ,1,2,23,61,62,63 Moraxella catarrhalis ,1,2,23,61,62,63 Streptococcus pyogenes (group A β-hemolytic streptococci),1,2,23,62,63 or S. pneumoniae †.1,2,23,61,62,63

When anti-infective therapy is indicated for the treatment of AOM, the American Academy of Pediatrics (AAP) recommends high-dose amoxicillin or amoxicillin and clavulanate potassium as the drug of first choice for initial treatment.184 These experts recommend certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients who do not have a history of severe and/or recent penicillin-allergic reactions.184

In clinical studies in children 6 months to 16 years of age with AOM, 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.2,23,43,62,63,102,150,164 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;1,2 persistent effusions were present in 15% of patients and 17% were considered to be treatment failures.1 In studies in children with AOM, 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),43,61,63,165 oral amoxicillin and clavulanate potassium (40 mg of amoxicillin per kg daily in 3 equally divided doses),138 oral cefpodoxime proxetil (10 mg/kg once daily),149 or oral cefaclor (40 mg/kg daily given in 3 equally divided doses)62,150 for the treatment of infections caused by susceptible β-lactamase-producing M. catarrhalis or H. influenzae .2,61,165 Both the once- and twice-daily cefixime regimens appear to be equally effective in the treatment of AOM caused by susceptible organisms.2,56,61,75

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 .1,2,3,23,61,162,164,165 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.1,2,3,23,165 Because at least one case of pneumococcal bacteremia developed in a child who was receiving cefixime for the treatment of otitis media,170 some clinicians suggest that cefixime not be used for the treatment of otitis media known or suspected of being caused by S. pneumoniae .162 Although the clinical importance is unclear, staphylococci have been isolated from middle-ear fluid after treatment in a few patients receiving cefixime.61

For additional information regarding treatment of AOM, including information on diagnosis and management strategies, anti-infectives for initial treatment, duration of initial treatment, and anti-infectives after initial treatment failures, see Acute Otitis Media under Uses: Otitis Media, in the Cephalosporins General Statement 8:12.06.

Pharyngitis and Tonsillitis

Oral cefixime is used in the treatment of pharyngitis and tonsillitis caused by susceptible S. pyogenes (group A β-hemolytic streptococci).1,2,3,23,44,56,64,75 Although cefixime usually is effective in eradicating S. pyogenes from the nasopharynx,1,169 efficacy of the drug for prevention of subsequent rheumatic fever has not been established to date.1

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug's spectrum of activity, bacteriologic and clinical efficacy, potential adverse effects, ease of administration, patient compliance, and cost.86,152,154,155 No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.86

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, the AAP,82 Infectious Diseases Society of America (IDSA),152 American Heart Association (AHA),86 and others104,154,156 recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever. Other anti-infectives (e.g., oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic individuals.5,82,86,104,152

If an oral cephalosporin is used for the treatment of S. pyogenes pharyngitis and tonsillitis, a 10-day regimen of a first generation cephalosporin (cefadroxil, cephalexin) is preferred instead of other cephalosporins with broader spectrums of activity (e.g., cefaclor, cefdinir, cefixime, cefpodoxime, cefuroxime).82,86,152

Although 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,86,154,155,156,158,159,160,171 the IDSA and AHA state that use of cephalosporin regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis and tonsillitis cannot be recommended at this time.86,152

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 V161 and that a 5-day regimen of oral cefixime is at least as effective as the 10-day penicillin V regimen.171 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.171 Once-daily dosing with cefixime is as effective as twice-daily dosing in the treatment of pharyngitis and tonsillitis.2,56

Respiratory Tract Infections

Acute Sinusitis

Cefixime has been effective in a limited number of adults and children for the treatment of sinusitis† caused by S. pneumoniae , H. influenzae , M. catarrhalis , Escherichia coli †, H. parahaemolyticus †, or H. parainfluenzae †.2,3,44,64,75

When anti-infective therapy is indicated for the treatment of acute bacterial sinusitis, the IDSA recommends amoxicillin and clavulanate potassium and the AAP recommends either amoxicillin or amoxicillin and clavulanate potassium as the drug of choice for initial empiric treatment.192,193 Because of variable activity against S. pneumoniae and H. influenzae , the IDSA no longer recommends second or third generation oral cephalosporins for empiric monotherapy of sinusitis in adults or children.192 If an oral cephalosporin is used as an alternative for empiric treatment of acute bacterial sinusitis in children (e.g., in penicillin-allergic individuals), the IDSA and AAP recommend a combination regimen that includes a third generation cephalosporin (cefixime or cefpodoxime) and clindamycin (or linezolid).192,193

Acute and Chronic Bronchitis

Cefixime is used in adults or children for the treatment of acute exacerbations of chronic bronchitis1,2,23,72,75,103,180 caused by S. pneumoniae ,1,2,23,44,70,72,103 H. influenzae ,1,2,23,44,70,72,103 or M. catarrhalis †.2,44,70,72,103

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).180 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.44 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.2,23,70,72,103 However, the bacteriologic cure rate reported with cefixime in the treatment of lower respiratory tract infections has ranged from 54-100%,2,23,44,70,72,75,103 and some clinicians suggest that further study is needed to evaluate the drug's role in the treatment of these infections.75,102

Pneumonia

Oral cefixime has been effective when used in adults or children for the treatment of mild to moderate pneumonia, including community-acquired pneumonia†.137,166 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) and then changed to oral cefixime, as appropriate, allowing therapy to be completed on an outpatient basis.137,166

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)1,2,40,51,64,74,75,182 caused by susceptible E. coli 1,2,40,51,64,74,75,182 or Proteus mirabilis .1,2,40,51,74,75,182 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. †,2,51,64,74 C. diversus †,2,74 C. freundii †,2,74 Enterobacter spp. †,2,40,51 E. aerogenes †,2,40,74 E. agglomerans †,2,64 Klebsiella spp. †,2,40,51,182 K. pneumoniae †,2,64,74 Morganella morganii †,2 Proteus spp. †,2,51,64 or Serratia †.2,51,74 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)23,51,74 or oral amoxicillin (250 mg 3 times daily).23,40,75 The once- and twice-daily cefixime regimens were equally effective2,51,75 and resulted in a bacteriologic cure in about 90-100% of adults with uncomplicated UTIs.2,23,40,51,74,75 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).182

Cefixime has been effective in a few adults for the treatment of uncomplicated UTIs caused by gram-positive bacteria, including Staphylococcus epidermidis †,2 Staphylococcus spp. †,2,51 Streptococcus agalactiae †,2,40 nonhemolytic streptococci†,2,40,51 or Enterococcus faecalis †.2,40 However, treatment failures have occurred when cefixime was used in the treatment of UTIs caused by gram-positive bacteria,51 and some of these organisms (e.g., staphylococci, S. agalactiae , enterococci) have been isolated in urine either during or after therapy with the drug.2,51,74

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.3,75,102 For empiric therapy of acute, uncomplicated UTIs, co-trimoxazole, a fluoroquinolone, fosfomycin, or nitrofurantoin usually is recommended.104 Because cefixime is inactive in vitro against enterococci and staphylococci, the drug probably should not be used for empiric therapy of nosocomial UTIs.75,102 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.3,9

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†2,23,40,75 caused by susceptible Enterobacteriaceae , including E. coli .2,23 Response rates in patients with complicated UTIs receiving cefixime are not as good as those reported in patients with uncomplicated UTIs;23,40,75 bacteriologic cure rates in adults with complicated UTIs have been reported to be 67-100%.2,23,40 Further study is needed to evaluate efficacy of cefixime in the treatment of complicated UTIs.23

Gonorrhea and Associated Infections

Uncomplicated Gonorrhea

Cefixime is used for the treatment of uncomplicated gonorrhea.1,48,82,106,108,109,110,111,118,119,120,130,194,197 However, because of concerns related to recent reports of Neisseria gonorrhoeae with reduced susceptibility to cephalosporins, the US Centers for Disease Control and Prevention (CDC) states that cefixime is no longer recommended as first-line treatment for uncomplicated gonorrhea.197

For the treatment of uncomplicated urogenital, anorectal, or pharyngeal gonorrhea, the CDC states that a combination regimen that includes a single 250-mg IM dose of ceftriaxone and either oral azithromycin (single 1-g dose) or oral doxycycline (100 mg twice daily for 7 days) is the regimen of choice.197 If ceftriaxone is not available or cannot be used and the patient has urogenital or rectal† gonorrhea, the CDC recommends an alternative combination regimen that includes a single 400-mg dose of oral cefixime and either oral azithromycin (single 1-g dose) or oral doxycycline (100 mg twice daily for 7 days).197 If the patient has severe cephalosporin allergy, an alternative regimen of oral azithromycin (single 2-g dose) alone is recommended.197 Test-of-cure follow-up (culture or nucleic acid amplification test [NAAT]) should be performed 1 week after treatment in all patients who receive cefixime or other alternative regimens.197 If there is evidence of treatment failure, the CDC recommends that the patient receive a combination regimen that includes a single 250-mg IM dose of ceftriaxone and oral azithromycin (single 2-g dose) and that the case be reported to the CDC through local or state health departments.197

Although cefixime has been effective when given as a single 400- or 800-mg oral dose for the treatment of acute uncomplicated endocervical gonorrhea in women and urethral gonorrhea in men caused by penicillinase- and nonpenicillinase-producing N. gonorrhoeae ,1,2,23,48,71,106,108,109,110,111 N. gonorrhoeae with reduced susceptibility to cefixime, including some treatment failures, have been reported in the US and other countries with increasing frequency during the last decade.194,195,196,197,198 Because of the possibility of emergence of resistance and because bactericidal concentrations attained with a 400-mg dose of oral cefixime are lower and not as sustained as those provided by a single 250-mg IM dose of ceftriaxone,197 cefixime should only be used for the treatment of urogenital or rectal† gonococcal infections when ceftriaxone is unavailable or cannot be used and such patients should receive test-of-cure follow-up after treatment.197 In addition, cefixime is not recommended for the treatment of pharyngeal gonorrhea since it has only limited efficacy for the treatment of these infections.195,197

The CDC recommends that health-care providers treating gonorrhea remain vigilant for treatment failures (evidenced by persistent symptoms or a positive follow-up test despite treatment).197 If there is evidence of treatment failure, relevant clinical specimens should be cultured and in vitro susceptibility testing performed.197 In addition, an infectious disease specialist, an STD/HIV Prevention Training Center ([Web]), or the CDC (404-639-8659) should be consulted for treatment advice and the case should be reported to the CDC through local or state health departments within 24 hours of diagnosis.197 A test-of-cure should be performed 1 week after retreatment.197 For all patients with gonorrhea, clinicians should ensure that the patient's sexual partners from the preceding 60 days are evaluated promptly using cultures and treated with a recommended regimen if indicated.197

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.

Lyme Disease

Oral cefixime has been used in a limited number of patients for the treatment of Lyme disease†.181 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.181 However, other cephalosporins (ceftriaxone, cefotaxime, cefuroxime axetil) are recommended by the IDSA and others when a cephalosporin is used in the treatment of Lyme disease.185,185 (See Uses: Lyme Disease in the Cephalosporins General Statement 8:12.06.)

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 139,148 and, in one study, was more effective than ampicillin and sulbactam sodium for the treatment of these infections.148 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%.140 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 .82,163 Multiple-drug resistant strains of Shigella have been reported with increasing frequency.82 For susceptible strains, ampicillin or co-trimoxazole is effective; amoxicillin is less effective.82 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.82 Some clinicians state that the benefits of oral third generation cephalosporins (e.g., cefixime) in the treatment of shigellosis are unclear.82

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 †.141,142,189,190,191 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.82,104,146,147,163,174 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 (5 mg/kg twice daily) 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.141

Reconstitution and Administration

Cefixime is administered orally as capsules, conventional tablets, chewable tablets, or an oral suspension.1

Cefixime capsules and conventional tablets may be administered without regard to meals.1 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.1,2,3,26 (See Pharmacokinetics: Absorption.)

Cefixime chewable tablets must be chewed or crushed before swallowing.1

Reconstitution

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, 200, or 500 mg of cefixime per 5 mL.1 The water should be added to the powder in 2 equal portions and the bottle shaken well after each addition.1

The suspension should be shaken well just prior to administration of each dose.1

Dosage

Cefixime is commercially available as the trihydrate;1,2,83 potency of the drug is expressed in terms of cefixime1,83 (the free acid), calculated on the anhydrous basis.83

Cefixime may be administered once or twice daily.1,2,3,40,51,74,75 Once- and twice-daily regimens reportedly are similarly effective for the treatment of otitis media,2,56,61,75 tonsillitis,2,56 or uncomplicated urinary tract infections.2,51,75 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 infections70,72,75 or for complicated urinary tract infections†.75 Results of most studies indicate that the incidence of GI effects is similar with once- and twice-daily regimens.2,23,40,41,44,56 (See Cautions: GI Effects.)

Capsules containing 400 mg of cefixime are bioequivalent to conventional tablets containing 400 mg of the drug when administered under fasting conditions.1

Cefixime chewable tablets are bioequivalent to cefixime oral suspension.1

Cefixime conventional tablets and oral suspension are not bioequivalent.1 (See Pharmacokinetics: Absorption.)

Adult Dosage

Acute Otitis Media

The usual adult dosage of cefixime for the treatment of acute otitis media (AOM) is 400 mg once daily or 200 mg every 12 hours1 for 10-14 days.23,56,62,63

Only the chewable tablets or oral suspension should be used for the treatment of AOM; cefixime capsules and conventional tablets should not be used for the treatment of AOM.1

Pharyngitis and Tonsillitis

The usual adult dosage of cefixime for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) is 400 mg once daily or 200 mg every 12 hours for at least 10 days.1

Respiratory Tract Infections

The usual adult dosage of cefixime for the treatment of respiratory tract infections (acute exacerbations of chronic bronchitis) is 400 mg once daily or 200 mg every 12 hours.1 The usual duration of cefixime therapy for the treatment of upper respiratory tract infections is 5-10 days.44,64,72

Urinary Tract Infections

The usual adult dosage of cefixime for the treatment of urinary tract infections is 400 mg once daily or 200 mg every 12 hours.1 The usual duration of cefixime therapy for the treatment of uncomplicated urinary tract infectionsis 5-10 days.2,40,51,74

Gonorrhea and Associated Infections

A single 400-mg dose of cefixime is recommended for the treatment of uncomplicated urethral, endocervical, or rectal† gonorrhea in adults and adolescents.1,2,82,106,108,130,197 A single 800-mg dose of cefixime also has been used.2,23,48,106,109,194

If cefixime is used as an alternative for the treatment of uncomplicated urogenital or rectal† gonorrhea when ceftriaxone is not available or cannot be used, the US Centers for Disease Control and Prevention (CDC) recommends a single 400-mg dose of oral cefixime and either oral azithromycin (single 1-g dose) or oral doxycycline (100 mg twice daily for 7 days).197 Cefixime is not recommended by the CDC as first-line treatment for uncomplicated gonorrhea.197 (See Uses: Gonorrhea and Associated Infections.)

Lyme Disease

For the treatment of Lyme disease†, adults have received cefixime in a dosage of 200 mg daily for 100 days (administered with oral probenecid 500 mg 3 times daily).181

Pediatric Dosage

Children older than 12 years of age or those weighing more than 45 kg may receive the usual adult dosage of cefixime.1

General Pediatric Dosage

For pediatric patients beyond the neonatal period, the American Academy of Pediatrics (AAP) recommends a cefixime dosage of 8 mg/kg daily given in 1 or 2 divided doses for the treatment of mild to moderate infections.82 The AAP states that cefixime is inappropriate for the treatment of severe infections.82

The oral suspension containing 100 mg of cefixime per 5 mL is the preferred preparation for use in children weighing 5-7.5 kg; oral suspensions containing 100 or 200 mg of cefixime per 5 mL are the preferred preparations in those weighing 7.6-10 kg.1

Cefixime chewable tablets are not recommended in children weighing less than 10 kg.1

Acute Otitis Media

The usual dosage of cefixime for the treatment of AOM in children 6 months to 12 years of age is 8 mg/kg once daily or 4 mg/kg every 12 hours1 for 10-14 days.23,56,62,63

Only the chewable tablets or oral suspension should be used for the treatment of AOM; cefixime capsules and conventional tablets should not be used for the treatment of AOM.1

Pharyngitis and Tonsillitis

The usual dosage of cefixime for the treatment of group A β-hemolytic streptococcal pharyngitis and tonsillitis in children 6 months to 12 years of age is 8 mg/kg once daily or 4 mg/kg every 12 hours for at least 10 days.1

Respiratory Tract Infections

The usual dosage of cefixime for the treatment of acute exacerbations of chronic bronchitis in children 6 months to 12 years of age is 8 mg/kg once daily or 4 mg/kg every 12 hours.1 The usual duration of cefixime therapy for the treatment of upper respiratory tract infections is 5-10 days.44,64,72

For empiric treatment of acute bacterial sinusitis† in children, a cefixime dosage of 8 mg/kg daily given in 2 equally divided doses for 10-14 days has been recommended.192

Urinary Tract Infections

The usual dosage of cefixime for the treatment of uncomplicated urinary tract infections in children 6 months to 12 years of age is 8 mg/kg once daily or 4 mg/kg every 12 hours.1 The usual duration of cefixime therapy for the treatment of uncomplicated urinary tract infections is 5-10 days.2,40,51,74

Gonorrhea and Associated Infections

For the treatment of uncomplicated gonorrhea, the AAP recommends a single cefixime dose of 8 mg/kg (up to 400 mg) in prepubertal children weighing less than 45 kg or a single 400-mg dose in children 8 years of age or older weighing 45 kg or more.82

Cefixime should be used in conjunction with a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.82,197 Cefixime is not recommended by the CDC as first-line treatment for uncomplicated gonorrhea.197 (See Uses: Gonorrhea and Associated Infections.)

Shigellosis

For the treatment of shigellosis†, children have received cefixime in a dosage of 8 mg/kg daily for 5 days.139,148

Typhoid Fever

For the treatment of typhoid fever†, children 6 months to 16 years of age have received cefixime in a dosage of 5-10 mg/kg twice daily.141,142,189,190,191 Treatment usually is continued for 14 days;141,142,189 a high rate of treatment failure occurred when the drug was given for only 7 days.190

Dosage in Renal Impairment

In patients with creatinine clearances less than 60 mL/minute, dose and/or frequency of administration of cefixime should be modified in response to the degree of renal impairment.1 The manufacturer recommends that adults with creatinine clearances of 21-59 mL/minute and those undergoing hemodialysis receive a cefixime dosage of 260 mg daily administered as oral suspension, preferably as oral suspension containing 200 or 500 mg of cefixime per 5 mL; cefixime conventional tablets and chewable tablets are not recommended in these patients.1 The manufacturer also recommends that adults with creatinine clearances of 20 mL/minute or less and those undergoing continuous peritoneal dialysis receive a cefixime dosage of 200 mg daily as conventional tablets or chewable tablets, 172 mg daily as oral suspension containing 100 mg/5 mL, 176 mg daily as oral suspension containing 200 mg/5 mL, or 180 mg daily as oral suspension containing 500 mg/5 mL.1 Because cefixime is not substantially removed by hemodialysis or peritoneal dialysis,1,2,33,37,75 additional supplemental doses of the drug are not necessary during or after either procedure.33,75

Dosage in Geriatric Patients

Modification of the usual dosage of cefixime is not necessary in geriatric adults based on age,2,35,37 but may be required because of age-related decreases in renal function.35,37 (See Dosage and Administration: Dosage in Renal Impairment.)

Adverse effects reported with cefixime are similar to those reported with other cephalosporins.2,39,40,41,44 Cefixime generally is well tolerated;2,23,27,31,33,35,43,63,74,75 most adverse effects of the drug are transient and mild to moderate in severity.1,2,23,40,43,63,74,75,103 Adverse effects have been reported in up to 50% of patients receiving the drug2,40,44,74 but have been severe enough to require discontinuance in about 5% of patients.1,2,40,41

GI Effects

The most frequent adverse effects of cefixime involve the GI tract.1,2,23,27,30,35,40,41,43,44,62,63,64,74,75,103 Adverse GI effects have been reported in up to 30% of adults receiving tablets of the drug1,41 and have been mild in 20%, moderate in 5-9%, and severe in 2-3% of patients.1,2,23,41 Diarrhea1,2,33,40,41,43,44,51,56,63,64,67,75,103 or loose, frequent stools1,2,30,41,43,56,63,67,75 have been reported in up to 27%1,2,23,40,41,44,64,75,103 and abdominal pain,1,2,23,40,41,44,51,56,64,67,75 anorexia,30,40,51 nausea,1,2,23,40,41,44,51,63,64,74,75 vomiting,1,2,23,41,43,44,51,56,63,64,74 dyspepsia,1,2,23,40,41,44,51,75 flatulence,1,2,40,41,75 pruritus ani,67 and dry mouth41 have been reported in 1-11% of patients receiving the drug.1,23,41,51,75

Adverse GI effects generally appear during the first or second day of cefixime therapy23,41 and probably are direct effects of the drug and not the result of changes in bowel flora.23,39,41,67 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.23,41,75 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.23,51,75 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.2,23,40,41,44,56 Adverse GI effects generally respond to symptomatic treatment or resolve when cefixime therapy is discontinued.1,74 Rarely, these effects may be severe enough to require discontinuance of the drug.41,74,103

Severe diarrhea and/or colitis, which required hospitalization in some cases, has been reported rarely in patients receiving cefixime1,2,23,39,40,41,44,51,67,75,144,145 (i.e., in less than 2% of patients).23,41,75 (See Clostridium difficile-associated Diarrhea and Colitis under Cautions: GI Effects.)

Cefixime exerts several effects on normal bowel flora.2,23,38,39,67,75 Cefixime (200 mg twice daily or 400 mg once daily) given for 1-2 weeks reduces total bacterial counts of normal fecal anaerobic bacteria,2,23,39,67 including Clostridia , Bifidobacterium , and some Bacteroides .39,67 The drug also decreases bacterial counts of some normal fecal aerobic bacteria including some Enterobacteriaceae2,23,38,39,67 and streptococci.2,39,67 In some patients, however, cefixime therapy results in increased fecal counts of group D streptococci, principally Enterococcus faecalis (formerly Streptococcus faecalis ).2,39,67 Fecal flora generally returns to pretreatment levels within 2 weeks following discontinuance of cefixime.2,67

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,42,177,178

C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including cefixime, and may range in severity from mild diarrhea to fatal colitis.1,2,39,41,42,67C. difficile produces toxins A and B which contribute to the development of CDAD;1,42 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

CDAD should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy and managed accordingly.1,42,177,178 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1,42

If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile should be discontinued whenever possible.1,42,177,178 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,42,177,178 (See Cautions: Precautions and Contraindications.)

Nervous System Effects

Headache1,2,23,39,40,41,44,51,64,75 has been reported in up to 3-16%1,23,41,75 and dizziness,1,2,23,40,41,44,51,75 nervousness,2,40 insomnia,51 somnolence,40,41,44,51,56 malaise,44 and fatigue39,43,44 have been reported in up to 4% of patients receiving cefixime.1,23,41,75 Seizures have been reported in less than 2% of patients receiving cefixime.1 Several other cephalosporins also have been implicated in precipitating seizures, particularly in patients with renal impairment in whom the dosage was not reduced.1 If seizures occur during cefixime therapy, the drug should be discontinued and appropriate anticonvulsant therapy administered as indicated.1

Sensitivity Reactions

Hypersensitivity reactions have been reported in up to 7% of patients receiving cefixime1,2,23,40,41,75 and include rash,1,2,40,41,43,56,64,75 urticaria,1,41,43,44,62,63,75 drug fever,1,2,41,64 pruritus,1,2,39,40,41,44,75 and arthralgia.39,41

Anaphylaxis, angioedema, facial edema, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and serum sickness-like reactions1,41 have been reported in less than 2% of patients receiving cefixime.1

Hematologic Effects

Transient thrombocytopenia,1,2,41 thrombocytosis,41,74 leukopenia,1,2,41,64 leukocytosis,41 eosinophilia,1,2,30,33,41,72 and decreased hemoglobin concentration and hematocrit41 have been reported in less than 2% of patients receiving cefixime.1,41

Prolonged prothrombin time1,2 and prolonged partial thromboplastin time2,33,41 have been reported rarely.1,2,41 Patients with renal or hepatic impairment, poor nutritional status, prolonged anti-infective therapy, and previous anticoagulant therapy (stabilized) appear to be at risk.1

Neutropenia, pancytopenia, agranulocytosis, aplastic anemia, hemolytic anemia, and hemorrhage have been reported with other cephalosporins but have not been reported to date with cefixime.1

Hepatic Effects

Transient increases in AST (SGOT),1,2,33,41,62,72 ALT (SGPT),1,2,33,41,62,72 alkaline phosphatase,1,2,41 bilirubin,1,22 and LDH2 have been reported in less than 2% of patients receiving cefixime.1,41 Hepatitis1 and jaundice1 have been reported in less than 2% of patients receiving cefixime.1 Hepatic dysfunction, including cholestasis, also has been reported with other cephalosporins.1

Renal and Genitourinary Effects

Transient increases in BUN1,2,41,74 and serum creatinine1,2,41 concentrations and acute renal failure have been reported in less than 2% of patients receiving cefixime.1,41 Dysuria43 and pyuria64 have been reported rarely.

Genital pruritus,1,40,51 vaginitis,1,40 and vaginal candidiasis1,51 have been reported in less than 2% of patients receiving cefixime.1,40,51 Renal dysfunction and toxic nephropathy have been reported with other cephalosporins.1

Other Adverse Effects

Increased serum amylase concentrations have been reported in 1.5-5% of patients receiving cefixime;23,41 however, there was no apparent correlation between increased serum amylase concentrations and adverse GI effects in these patients.23,41

Precautions and Contraindications

Prior to initiation of cefixime therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.1 There is clinical and laboratory evidence of partial cross-allergenicity among β-lactam antibiotics including penicillins, cephalosporins, and cephamycins.1,172,173 Caution is advised.1 Cefixime is contraindicated in individuals who are hypersensitive to the drug or other cephalosporins.1 Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.173

To reduce development of drug-resistant bacteria and maintain effectiveness of cefixime and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, consider local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Patients should be advised that antibacterials (including cefixime) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefixime or other antibacterials in the future.1

As with other anti-infectives, prolonged use of cefixime may result in overgrowth of nonsusceptible organisms.1 Superinfection with gram-positive bacteria (e.g., staphylococci, enterococci) has occurred in patients receiving cefixime for the treatment of otitis media61 or urinary tract infections.2,51,74 Careful observation of the patient during cefixime therapy is essential.1 If suprainfection or superinfection occurs, appropriate therapy should be instituted.1

Because CDAD 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 or after cefixime therapy.1,42 (See Cautions: GI Effects.) Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

Because decreased prothrombin activity has been reported with cephalosporins, prothrombin time should be monitored in patients at risk (see Cautions: Hematologic Effects) and exogenous vitamin K administered as indicated.1

Individuals with phenylketonuria should be cautioned that cefixime chewable tablets containing 100, 150, and 200 mg of the drug contain aspartame (NutraSweet^®), which is metabolized in the GI tract to provide 3.3, 5, and 6.7 mg of phenylalanine, respectively.1

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.1,2,23,33,37,75 Patients undergoing dialysis should be monitored carefully during cefixime therapy.1 (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.1

The frequency of adverse GI effects (e.g., diarrhea, loose stools) reported in pediatric patients receiving cefixime oral suspension is similar to that reported in adults receiving cefixime tablets.1 Diarrhea or loose stools has been reported in up to 15% of children 6 months to 13 years of age receiving oral cefixime.2,41,75 CDAD has been reported rarely in children receiving cefixime.144 In 3 reported cases, the onset of symptoms (abdominal pain, diarrhea) occurred 4-14 days after the first dose of cefixime.144

Geriatric Precautions

Clinical studies did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1

Some evidence indicates that oral bioavailability of the drug may be increased in geriatric patients,1,2,35,37 but such increases are not considered clinically important.2,35,37 (See Pharmacokinetics: Absorption.)

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.35,37 (See Dosage and Administration: Dosage in Renal Impairment.)

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.1 The drug did not exhibit clastogenic potential in vivo in the mouse micronucleus test.1,2

Long-term animal carcinogenicity studies using cefixime have not been conducted to date.1,2

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice and rats using oral cefixime dosages up to 40 times the usual human dosage have not revealed evidence of harm to the fetus.1 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.1 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.1

Fertility

There was no evidence of impaired fertility or adverse effects on reproductive performance in rats receiving cefixime dosages up to 25 times the usual adult dosage.1

Lactation

Cefixime is distributed into milk in rats.36 Although the drug reportedly was not detected in milk following a single dose in lactating women in one study (see Pharmacokinetics: Distribution),2 it is not known whether cefixime is distributed into milk in humans.1 Therefore, consideration should be given to temporarily discontinuing nursing during therapy with the drug.1

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.32

Anticoagulants

Increased prothrombin time (with or without bleeding) has been reported following concomitant use of cefixime with an anticoagulant (e.g., warfarin).1

Carbamazepine

Concomitant administration of cefixime and carbamazepine has resulted in increased plasma carbamazepine concentrations.1 Carbamazepine concentrations should be monitored if the drug is used concomitantly with cefixime.1

Nifedipine

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 (AUC).143

Probenecid

Although specific information is unavailable, concomitant administration of probenecid reportedly increases peak serum concentrations and the AUC of cefixime and decreases renal clearance and volume of distribution of the drug.2

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.25 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.2 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,2 some clinicians state that this potential interaction may be clinically important in certain infections.102

Laboratory Test Interferences

Tests for Urinary Glucose or Ketones

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);1,2 however, glucose oxidase methods (e.g., Clinistix^®, Tes-Tape^®) are unaffected by the drug.1,2

Cefixime may cause false-positive results for ketones in urine if nitroprusside tests are used; this effect has not been reported with tests using nitroferricyanide.1

Immunohematology Tests

Although not reported to date with cefixime, positive direct antiglobulin (Coombs') test results have been reported in patients receiving other cephalosporins.1 This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving cefixime.

Acute Toxicity

The oral LD₅₀ of cefixime exceeds 10 g/kg in mice, rats, and rabbits.2 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.2

Limited information is available on the acute toxicity of cefixime in humans.2 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 drug1,2 and included mild to moderate adverse GI effects.2

If acute overdosage of cefixime occurs, the stomach should be emptied by gastric lavage.1,2 Cefixime is not removed in clinically important quantities by hemodialysis or peritoneal dialysis.1,2,33,37

Mechanism of Action

Cefixime is usually bactericidal in action.1,2,14,34,65,69,78 Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall.1,2,75 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 β-lactam antibiotics, indicate that cefixime has a high affinity for PBPs 3, 1a, and 1b of Escherichia coli .2,14,23,60,65,75 Since PBP 1b is a killing site for β-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.2,14,23,60,75 Cefixime has only low affinity for PBP 2 of staphylococci2,23,60,75 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 .2,9 At higher concentrations, direct lysis of the organisms may occur as well as spheroplast formation and rupture.2 Following in vitro exposure to cefixime, morphologic changes in β-lactamase-producing E. coli are the same as those seen in non-β-lactamase-producing strains of the organism.2 Lysis occurs in susceptible anaerobic bacteria following in vitro exposure to cefixime.2

For most susceptible organisms, the minimum bactericidal concentration (MBC) of cefixime is only 1-4 times higher than the minimum inhibitory concentration (MIC).2,8,14,15,20,23,60 However, for some strains of Enterobacter , Klebsiella , Morganella , Proteus , Providencia , and Serratia , the MBC may be 9-32 times higher than the MIC.14,60

Spectrum

Based on its spectrum of activity, cefixime is classified as a third generation cephalosporin.3,13,15,50,69,75 For information on the classification of cephalosporins and closely related β-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, ceftriaxone), cefixime has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.2,3,14,23,59,60,75 In vitro on a weight basis, however, cefixime usually is less active than many other currently available third generation cephalosporins against susceptible Enterobacteriaceae15,75,101 and is inactive in vitro against most strains of Enterobacter 60,75 and Pseudomonas .2,13,14,15,20,23,59,60,66,75,101 Although some other currently available third generation cephalosporins have some activity against staphylococci, cefixime usually is inactive against these organisms.1,2,3,13,14,18,20,23,59,60,69,75,78,101

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).9,13,60,75 There generally is little effect on in vitro susceptibility test results when the pH of the media is within the range of 5-8.9,13,60,75 In vitro activity of cefixime against Enterobacteriaceae is not affected by the presence of urine or serum.2,13,23,60,75

Inoculum size may affect in vitro susceptibility to cefixime.13,15,18,20,23,65 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.13,15,18,23,65

Strains of staphylococci resistant to penicillinase-resistant penicillins (methicillin-resistant [oxacillin-resistant] staphylococci) should be considered resistant to cefixime, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.132

For information on interpreting results of in vitro susceptibility testing (disk susceptibility tests, dilution susceptibility tests) when cefixime susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), see Spectrum: In Vitro Susceptibility Testing, in the Cephalosporins General Statement 8:12.06.

Gram-positive Aerobic Bacteria

Gram-positive Aerobic Cocci

Cefixime generally is active in vitro against Streptococcus pyogenes (group A β-hemolytic streptococci),1,2,3,13,14,20,23,50,59,60,66,77,78,79 S. agalactiae (group B streptococci),1,2,13,15,18,23,50,59,60,66,75 and groups C, F, and G streptococci.13,23,59,60,66 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 0.1-0.5 mcg/mL,2,3,13,14,20,23,50,59,60,66,75,78,161 and the MIC₉₀ reported for groups C, F, and G streptococci is 0.05-1 mcg/mL.23,59,60,66,75 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 ,3,75 but is less active than ampicillin or amoxicillin against these organisms.2,23

Cefixime is active in vitro against some strains of S. pneumoniae ;1,2,14,20,23,50,59,60,66,167,168 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).167,168 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.137,167,168

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.2,13,19,23,50,59,60,66,75 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.183 Enterococci, including Enterococcus faecalis (formerly S. faecalis ) and E. faecium (formerly S. faecium ), are resistant to cefixime.1,2,3,13,20,23,59,60,66,75

Unlike other currently available cephalosporins, cefixime is inactive in vitro against penicillinase-producing and nonpenicillinase-producing staphylococci, including Staphylococcus aureus ,1,2,3,13,14,18,20,23,59,60,66,75,78 S. epidermidis ,1,2,3,4,13,14,20,23,59,60,75,78 and S. saprophyticus .23,60 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.59,60,75 Like other cephalosporins, cefixime is inactive against methicillin-resistant (oxacillin-resistant) staphylococci.3,4,20,59,60,75,78

Gram-positive Aerobic Bacilli

Corynebacterium ,19,23 including JK strains of Corynebacterium JK ,13,19,60 generally are resistant to cefixime and have MIC₉₀s of 32 mcg/mL or greater.13,23,19,60 Listeria monocytogenes generally are resistant to cefixime in vitro.1,13,23,59,60,66,75

Gram-negative Aerobic Bacteria

Neisseria

Cefixime is active in vitro against Neisseria meningitidis ,2,3,13,20,59,60,75 and most strains of this organism are inhibited by cefixime concentrations of 0.01-0.06 mcg/mL.2,3,13,20,59,60,75

Cefixime is active in vitro against penicillinase-producing (PPNG) and nonpenicillinase-producing N. gonorrhoeae .1,2,3,11,14,23,59,60,75 The drug also is active in vitro against N. gonorrhoeae with chromosomally mediated resistance to penicillin (CMRNG) or plasmid-mediated tetracycline resistance (TRNG).2,11,60 The MIC₉₀ of cefixime reported for nonpenicillinase-producing N. gonorrhoeae , PPNG, or CMRNG usually has ranged from 0.001-0.06 mcg/mL.2,3,11,14,23,59,75 However, N. gonorrhoeae with reduced susceptibility to cefixime (MICs 0.25 mcg/mL or greater) have been reported in the US and other countries with increasing frequency during the last decade;194,195,196,197,198 treatment failures have been reported.194 (See Uses: Gonorrhea and Associated Infections.)

Haemophilus

Cefixime is active in vitro against most β-lactamase-producing and non-β-lactamase-producing strains of Haemophilus influenzae 1,2,3,8,10,13,14,18,20,23,50,59,65,66,68,75,76,77,78 and H. parainfluenzae .1,2,8,13 The MIC₉₀ reported for β-lactamase-producing and non-β-lactamase-producing H. influenzae is 0.015-0.25 mcg/mL.2,3,8,10,13,14,18,20,23,50,59,65,66,68,75,76,77,78

In vitro on a weight basis, cefixime is more active against β-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.2,23,60,75,76 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.2,8,17,23,60,68,76 However, some strains of non-β-lactamase-producing H. influenzae that are resistant to ampicillin and second generation cephalosporins also may have reduced susceptibility to cefixime.2,23

Moraxella catarrhalis

Cefixime is active in vitro against both β-lactamase- and non-β-lactamase-producing Moraxella catarrhalis ,1,2,3,13,20,23,58,59,66,75,77,78 and the MIC₉₀ of the drug reported for this organism is 0.03-0.4 mcg/mL.2,3,13,20,23,58,59,66,75,77,78 Cefixime is active in vitro against strains of M. catarrhalis resistant to ampicillin, cephalexin, and cefaclor.2,60,75

Enterobacteriaceae

Cefixime is active in vitro against most clinically important Enterobacteriaceae.15,21,23,59,60,75 With the exception of Citrobacter freundii , Enterobacter , Morganella morganii , and Serratia , the MIC₉₀ of cefixime for Enterobacteriaceae is generally 2 mcg/mL or less.1,15,21,23,50,59,60,66,75

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.23,60 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).2,14 Cefixime is active in vitro against strains of Salmonella typhi resistant to ampicillin, chloramphenicol, and/or co-trimoxazole.60

Pseudomonas

Some strains of Pseudomonas cepacia ,2,13,14,20,23,78 Ps. pseudomallei ,54 and Ps. stutzeri 60 are inhibited in vitro by cefixime concentrations of 1.56-8 mcg/mL. However, the MIC₉₀ of cefixime for Ps. aeruginosa 2,13,14,15,20,23,59,60,66,75 and for most other Pseudomonas , including Ps. fluorescens ,13,59 Ps. putida ,13,15,59 Ps. maltophilia ( Xanthomonas maltophilia ),13,20,59 and most strains of Ps. stutzeri ,13,15 usually exceeds 16 mcg/mL and these organisms are considered resistant to the drug.14,23,59,60,75

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.2,13,20,23,60,78 Aeromonas hydrophila generally is inhibited in vitro by cefixime concentrations of 0.01-4 mcg/mL.13,23,59,60,66 Some strains of Alcaligenes are inhibited in vitro by cefixime concentrations of 8 mcg/mL.60

Some strains of Campylobacter fetus subsp. jejuni are inhibited in vitro by cefixime concentrations of 1.6-8 mcg/mL,2,13,60,75 but many strains of the organism are resistant to the drug.2,13,23,75 Cefixime is active against Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ).22,114,115,121,122,123 The MIC₉₀ of cefixime for H. pylori has been reported as 0.25-0.5 mcg/mL.22,115

Cefixime concentrations of 12.5-16 mcg/mL inhibit some strains of Bordetella pertussis ;81 however, B. bronchiseptica 13 and B. parapertussis 81 are resistant to the drug. Pasteurella multocida is inhibited in vitro by cefixime1,2,12,23 concentrations of 0.012-1 mcg/mL.2,12,23

Achromobacter xylosoxidans 13,19,23 and Flavobacterium meningosepticum , F. adoratum , and F. indologenes are resistant to cefixime.13,23

Anaerobic Bacteria

Cefixime has only limited in vitro activity against anaerobic bacteria.2,14,23,59,60,75 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.2,14,23,59,60 Most strains of Bacteroides fragilis 1,2,14,15,23,59,75 and other Bacteroides species2,23,75 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.1,2,14,59,60,66,75,78

Chlamydia and Mycoplasma

Cefixime is inactive against Chlamydia trachomatis 2,11,23,59 and Ureaplasma urealyticum .2

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.80

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 β-lactamase stability1,2,13,14,21,23,60,75 and is stable against hydrolysis by many plasmid- and chromosomally mediated β-lactamases.2,13,14,21,23,60,66,75 The drug generally is more stable against inactivation by β-lactamases than are cefaclor, cefoxitin, cefuroxime, and cephalexin.13,21,79 Cefixime generally is not hydrolyzed by β-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).2,13,21,23,66,75 The drug is hydrolyzed by some β-lactamases produced by Enterobacter ,57,60 Klebsiella oxytoca ,57 Proteus vulgaris ,2,13 and Pseudomonas cepacia .2 The drug is hydrolyzed by Richmond-Sykes type I produced by Pseudomonas cepacia 60 and Ia produced by Citrobacter freundii and Enterobacter cloacae .13,21 The drug also is hydrolyzed by β-lactamases produced by Flavobacterium 2 and Bacteroides fragilis .2,13,14,23,57,60

Resistance to cefixime in staphylococci appears to be related to the drug's poor affinity for PBP 2 of these organisms.23,60,75 Resistance in enterococci and Listeria monocytogenes may also be related to poor binding of cefixime to the PBPs of these organisms.60,75 In vitro studies indicate that resistance to cefixime in C. freundii 60 and Enterobacter 60 apparently is related to factors that affect permeability of the organisms to the drug and also is related to the production of β-lactamases.60 Resistance to cefixime in Pseudomonas and Acinetobacter is related to permeability factors.60,75

Unlike some β-lactam anti-infectives (e.g., cefoxitin, imipenem), cefixime is a weak inducer of β-lactamases21 and does not derepress inducible, chromosomally mediated enzymes in C. freundii , E. cloacae , E. aerogenes , Providencia stuartii , Serratia liquefaciens , or S. marcescens .21 Cefixime does, however, induce β-lactamase production in some strains of Morganella morganii , but the drug remains active in vitro against these M. morganii strains following derepression of inducible β-lactamases.21

Pharmacokinetics

Absorption

Approximately 30-50% of a single dose of cefixime is absorbed following oral administration.1,2,75,100 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.2,100

Capsules containing 400 mg of cefixime are bioequivalent to conventional tablets containing 400 mg of the drug when administered under fasting conditions.1 Cefixime chewable tablets are bioequivalent to cefixime oral suspension.1 Cefixime conventional tablets and oral suspension are not bioequivalent;1 the oral suspension results in peak serum concentrations 25-50% higher than concentrations attained with the tablets.1

When cefixime is administered as conventional tablets or oral suspension, about 40-50% of a dose is absorbed whether the drug is given with or without food;1 however, the time to peak concentrations is increased approximately 0.8 hours when the drug is given with food.1 When cefixime is administered as capsules with food, absorption of the drug is decreased by approximately 15% based on area under the concentration-time curve (AUC) or approximately 25% based on peak serum concentrations.1

GI absorption of cefixime is not affected by concomitant administration of antacids.2,32,75 (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).1,2,26,30,31,35,37,100 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.2,3,31 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);1,2 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.1

In adults, peak serum concentrations of cefixime are approximately 25-50% higher when the drug is administered as an oral suspension rather than as tablets.1,100 When 200- or 400-mg doses of cefixime are administered to adults as an oral suspension, peak serum concentrations average 3 mcg/mL (range: 1-4.5 mcg/mL) or 4.6 mcg/mL (range: 1.9-7.7 mcg/mL), respectively.1 In the dosage range of 100-400 mg, the AUC in adults is approximately 10-25% higher with the oral suspension than with the tablets.1,100

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;23,37,75,100 there is some evidence that decreased GI absorption occurs with increasing dose.2,37 Studies in children using cefixime doses of 4-8 mg/kg also indicate that serum concentrations of cefixime are not directly dose proportional.37

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.2,23,29,30,75 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.2,29,30

Although the difference was not considered clinically important,2,35,37 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.1,35

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 3.5-4.5 hours after the dose average 2.18-2.44, 3.55-4.07, and 3.4-3.91 mcg/mL, respectively.37

Distribution

Information on distribution of cefixime is limited.1,34,75 Following oral administration, cefixime is distributed into bile,1,2 sputum,2,23 tonsils,23 maxillary sinus mucosa,23 middle ear discharge,23 blister fluid,2,75 and prostatic fluid.2 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.2

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 1.3-1.4 mcg/mL at 3-5 hours after the dose; concurrent serum concentrations of the drug averaged 2.5-3.2 mcg/mL.117

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 8-18.6 mg/kg and 134-190 mg/L, respectively.23 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.23

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.2

It is not known whether cefixime is distributed into CSF following oral administration.1

The apparent volume of distribution of cefixime in healthy adults averages 0.1 L/kg (range: 0.095-0.11 L/kg.31,75

Cefixime is approximately 65-70% bound to serum proteins,1,2,23,27,33,37,75 principally albumin,2 and such binding is not concentration dependent over the range of 0.5-30 mcg/mL.1,2,23,27,37 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.2,23

Cefixime crosses the placenta and is distributed in low concentrations into amniotic fluid and cord serum;2,23 cord serum concentrations may be 15-50% of concurrent maternal plasma concentrations.2,23

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.2 In a study in rats receiving cefixime via intraperitoneal infusion, only low concentrations of the drug were attained in the plasma of nursing pups.36

Elimination

The serum elimination half-life of cefixime in adults with normal renal function averages 2.4-4 hours.1,2,23,24,26,27,29,31,33,37,75,100 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.1 Serum half-life of cefixime is independent of dosage form1,100 and is not dose dependent.2

The serum half-life of cefixime is prolonged in patients with impaired renal function.1,2,23,33,37,75 In adults with moderate renal impairment (creatinine clearances of 20-40 mL/minute), serum half-life averages 6.4 hours.1 In adults with severe renal impairment (creatinine clearances of 5-20 mL/minute), half-life averages 11.5 hours.1

Cefixime is not substantially removed by hemodialysis or peritoneal dialysis.1 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.1 It is not known whether impaired hepatic function has an effect on the pharmacokinetics of cefixime.75

There is no evidence that cefixime is metabolized in vivo;1,2,23,30 no microbiologically active metabolites have been detected in serum or urine following oral administration of the drug.23,30,75

Cefixime is eliminated by renal and nonrenal mechanisms.1,2,23,24,26,27,29,30,31,37,52,75 Approximately 7-41% of a single oral dose of the drug is excreted unchanged in urine within 24 hours;1,2,23,24,26,27,29,31,37,75,100 the drug is excreted principally by glomerular filtration27,75 and to a lesser extent by tubular secretion.2 The remainder of the dose (up to 60%) is eliminated by nonrenal mechanisms.1,2,27,30,37,75 Studies in animals indicate that more than 10% of a single oral dose of cefixime is excreted unchanged in bile.1,2,52 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.30,67

Clearance of cefixime from serum averages 0.39-0.45 mL/minute per kg2,31 and renal clearance averages 27-43 mL/minute in healthy adults with normal renal function.2,24,26,27,29,37 Urinary concentrations of cefixime generally range from 2.2-103 mcg/mL during the first 2 hours and from 15.7-305 mcg/mL 6-8 hours after a single 200- or 400-mg oral dose of the drug.29,30,31

Only small amounts of cefixime are removed by hemodialysis or peritoneal dialysis; these amounts are not considered clinically important.1,2,33,37,75

Chemistry and Stability

Chemistry

Cefixime is a semisynthetic cephalosporin antibiotic.1,2,3,4,6,7,13,23,57,60,75,83 The drug is an oral aminothiazolyl methoxyimino cephalosporin.2,4,7,13,23,57,83 Cefixime is structurally similar to other oral (cefdinir, cefpodoxime proxetil, ceftibuten) or parenteral (cefotaxime, ceftazidime, ceftriaxone) cephalosporins that contain an aminothiazolyl side chain at position 7 of the cephalosporin nucleus.2,4,7,13,23,57,83 The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and the methoxyimino group imparts stability against hydrolysis by many β-lactamases.4,57,60,75 Like cefdinir, cefixime contains a vinyl moiety at position 3 of the cephalosporin nucleus.3,7,57,83 This vinyl moiety, which is a small uncharged group, is partially responsible for the GI absorption characteristics of cefixime.2,75 The vinyl moiety also may contribute to cefixime's potent bactericidal activity,60 although it appears to be partially responsible for the drug's poor in vitro activity against staphylococci.60

Cefixime is commercially available as the trihydrate;1,2,83 potency of the drug is expressed in terms of cefixime1,83 (the free acid), calculated on the anhydrous basis.83 Cefixime occurs as a white to slightly yellowish-white, nonhygroscopic, crystalline powder with a slight characteristic odor.2 The drug has a pK_a of 3.73.4 The aqueous solubility of cefixime is pH dependent.2 At room temperature, cefixime has solubilities in water of 0.5 mg/mL at pH 3.2 and 18 mg/mL at pH 4.2.2 Cefixime has a solubility of 8.3 mg/mL in alcohol at room temperature.2 Cefixime powder for oral suspension occurs as an off-white to pale yellow, strawberry-flavored powder.1 Following reconstitution, the suspension has a pH of 2.5-4.5.83

Stability

Cefixime capsules, conventional tablets, or chewable tablets should be stored at 20-25°C.1

Cefixime powder for oral suspension should be stored in tight containers at 20-25°C.1 After reconstitution, the oral suspension should be stored in a tight container and is stable for 14 days at room temperature or when refrigerated; any unused suspension should be discarded after 14 days.1

1. Lupin Pharma. Suprax^® (cefixime) tablets, capsules, chewable tablets, and powder for oral suspension prescribing information. Baltimore, MD; 2013 Mar.

2. Lederle. Suprax^® (cefixime) product monograph. Pearl River, NY; 1989 Jun.

3. Smith GH. Oral cephalosporins in perspective. DICP . 1990; 24:45-51. [PubMed 2405586]

4. Inamoto Y, Chiba T, Kamimura T et al. FK 482, a new orally active cephalosporin: synthesis and biological properties. J Antibiot . 1988; 41:828-30. [PubMed 3255303]

5. Cooper RJ, Hoffman JR, Bartlett JG et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: background. Ann Intern Med . 2001; 134:509-17. [PubMed 11255530]

6. Knoller J, Schonfeld W, Bremm KD et al. In vitro stability of cefixime (FK-027) in serum, urine and buffer. J Chromatogr . 1987; 389:312-6. [PubMed 3571358]

7. Namiki Y, Tanabe T, Kobayashi T et al. Degradation kinetics and mechanisms of a new cephalosporin, cefixime, in aqueous solution. J Pharm Sci . 1987; 76:208-14. [PubMed 3585736]

8. Kumar A. In vitro activity of cefixime (CL284635) and other antimicrobial agents against Haemophilus isolates from pediatric patients. Chemotherapy . 1988; 34:30-5. [PubMed 3258232]

9. Smith SM. Activity of cefixime (FK 027) for resistant gram-negative bacilli. Chemotherapy . 1988; 34:455-61. [PubMed 3243091]

10. Powell M. In vitro susceptibility of Haemophilus influenzae to cefixime. Antimicrob Agents Chemother . 1987; 31:1841-2. [PubMedCentral][PubMed 3501703]

11. Bowie WR, Shaw CE, Chan DGW et al. In vitro activity of difloxacin hydrochloride (A-56619), A-56620, and cefixime (CL 284,635; FK 027) against selected genital pathogens. Antimicrob Agents Chemother . 1986; 30:590-3. [PubMedCentral][PubMed 3098163]

12. Noel GJ. In vitro activities of selected new and long-lasting cephalosporins against Pasteurella multocida . Antimicrob Agents Chemother . 1986; 29:344-5. [PubMedCentral][PubMed 3087279]

13. Neu HC, Chin NX. Comparative in vitro activity and β-lactamase stability of FR 17027, a new orally active cephalosporin. Antimicrob Agents Chemother . 1984; 26:174-80. [PubMedCentral][PubMed 6333207]

14. Kamimura T, Kojo H, Matsumoto Y et al. In vitro and in vivo antibacterial properties of FK 027, a new orally active cephem antibiotic. Antimicrob Agents Chemother . 1984; 25:98-104. [PubMedCentral][PubMed 6561017]

15. Fuchs PC, Jones RN, Barry AL et al. In vitro evaluation of cefixime (FK027, FR17027, CL284635): spectrum against recent clinical isolates, comparative antimicrobial activity, β-lactamase stability, and preliminary susceptibility testing criteria. Diagn Microbiol Infect Dis . 1986; 5:151-62. [PubMed 3522088]

16. Fuchs PC, Barry AL. Cefixime disk susceptibility test criteria. J Clin Microbiol . 1986; 24:647-9. [PubMedCentral][PubMed 3771755]

17. Jorgensen JH, Doern GV, Thornsberry C et al. Susceptibility of multiply resistant Haemophilus influenzae to newer antimicrob agents. Diagn Microbiol Infect Dis . 1988; 9:27-32. [PubMed 3259490]

18. Cullmann W, Dick W, Stieglitz M et al. Comparative evaluation of orally active beta-lactam compounds in ampicillin-resistant gram-positive and gram-negative rods: role of beta lactamases on resistance. Chemotherapy . 1988; 34:202-15. [PubMed 3262045]

19. Counts GW, Baugher LK, Ulness BK et al. Comparative in vitro activity of the new oral cephalosporin cefixime. Eur J Clin Microbiol Infect Dis . 1988; 7:428-31. [PubMed 3137053]

20. Knapp CC, Sierra-Madero J. Antibacterial activities of cefpodoxime, cefixime, and ceftriaxone. Antimicrob Agents Chemother . 1988; 32:1896-8. [PubMedCentral][PubMed 3245701]

21. Sanders CC. β-lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance. Antimicrob Agents Chemother . 1989; 33:1313-7. [PubMedCentral][PubMed 2802558]

22. Garcia-Rodriguez JA, Garcia Sanchez JE, Garcia Garcia MI et al. In vitro activities of new oral β-lactams and macrolides against Campylobacter pylori. Antimicrob Agents Chemother. 1989; 33:1650-1.

23. Brogden RN. Cefixime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs . 1989; 38:524-50. [PubMed 2684593]

24. Faulkner RD, Sia LL, Barone JS et al. Bioequivalency of oral suspension formulations of cefixime. Biopharm Drug Dispos . 1989; 10: 205-11. [PubMed 2706319]

25. Bialer M, Wu WH, Faulkner RD et al. In vitro protein binding interaction studies involving cefixime. Biopharm Drug Dispos . 1988; 9:315-20. [PubMed 3395672]

26. Faulkner RD, Bohaychuk W, Haynes JD et al. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol . 1988; 34: 5225-8. [PubMed 3203716]

27. Faulkner RD, Fernandez P, Lawrence G et al. Absolute bioavailability of cefixime in man. J Clin Pharmacol . 1988; 28:700-6. [PubMed 3216036]

28. McAteer JA, Hiltke MF, Silber BM et al. Liquid-chromatographic determination of five orally active cephalosporins—cefixime, cefaclor, cefadroxil, cephalexin, and cephradine—in human serum. Clin Chem . 1987; 33:1788-90. [PubMed 3665031]

29. Faulkner RD, Bohaychuk W, Desjardins RE et al. Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state. J Clin Pharmacol . 1987; 27:807-12. [PubMed 3429686]

30. Nakashima M, Uematsu T, Takiguchi Y et al. Phase I study of cefixime, a new oral cephalosporin. J Clin Pharmacol . 1987; 27:425-31. [PubMed 3693588]

31. Brittain DC, Scully BE, Hirose T et al. The pharmacokinetic and bactericidal characteristics of oral cefixime. Clin Pharmacol Ther . 1985; 38:590-4. [PubMed 4053491]

32. Healy DP, Sahai JV, Sterling LP et al. Influence of an antacid containing aluminum and magnesium on the pharmacokinetics of cefixime. Antimicrob Agents Chemother . 1989; 33: 1994-7. [PubMedCentral][PubMed 2610509]

33. Guay DRP, Meatherall RC, Harding GK et al. Pharmacokinetics of cefixime (CL 284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrob Agents Chemother . 1986; 30:485-90. [PubMedCentral][PubMed 3777912]

34. Bergeron MG. Penetration of cefixime into fibrin clots and in vivo efficacy against Escherichia coli , Klebsiella pneumoniae , and Staphylococcus aureus . Antimicrob Agents Chemother . 1986; 30:913-6. [PubMedCentral][PubMed 3545070]

35. Faulkner RD, Bohaychuk W, Lanc RA et al. Pharmacokinetics of cefixime in the young and elderly. J Antimicrob Chemother . 1988; 21:787-94. [PubMed 3410802]

36. Halperin-Walega E, Batra VK, Tonelli AP et al. Disposition of cefixime in the pregnant and lactating rat: transfer to the fetus and nursing pup. Drug Metab Dispos . 1988; 16:130-4. [PubMed 2894941]

37. Faulkner RD, Yacobi A, Barone JS et al. Pharmacokinetic profile of cefixime in man. Pediatr Infect Dis . 1987; 6:963-70.

38. Daikos GL, Kathpalia SB, Sharifi R et al. Comparison of ciprofloxacin and beta-lactam antibiotics in the treatment of urinary tract infections and alteration of fecal flora. Am J Med . 1987; 82(Suppl 4A):290-4. [PubMed 3555050]

39. Finegold SM, Ingram-Drake L, Gee R et al. Bowel flora changes in humans receiving cefixime (CL 284,635) or cefaclor. Antimicrob Agents Chemother . 1987; 31:443-6. [PubMedCentral][PubMed 3579262]

40. Iravani A, Richard GA, Johnson D et al. A double-blind, multicenter, comparative study of the safety and efficacy of cefixime versus amoxicillin in the treatment of acute urinary tract infections in adult patients. Am J Med . 1988; 85(Suppl 3A):17-23. [PubMed 3048090]

41. Tally FP, Desjardins RE, McCarthy EF et al. Safety profile of cefixime. Pediatr Infect Dis . 1987; 6:976-80.

42. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

43. Leigh AP, Robinson D. A general practice comparative study of a new third-generation oral cephalosporin, cefixime, with amoxycillin in the treatment of acute paediatric otitis media. Br J Clin Pract . 1989; 43:140-3. [PubMed 2686744]

44. Kiani R, Johnson D. Comparative multicenter studies of cefixime and amoxicillin in the treatment of respiratory tract infections. Am J Med . 1988; 85(Suppl 3A):6-13. [PubMed 3048092]

45. Ellner JJ. Management of acute and chronic respiratory tract infections. Am J Med . 1988; 85(Suppl 3A):2-5. [PubMed 3048091]

46. Childs SJ. Management of urinary tract infections. Am J Med . 1988; 85(Suppl 3A): 14-6. [PubMed 3048089]

48. Megran DW, Lefebvre K, Willetts V et al. Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother . 1990; 34:355-7. [PubMedCentral][PubMed 2183719]

50. Krepel CJ, Schopf LR, Gordon RC et al. Comparative in vitro activity of cefixime with eight other antimicrobials against Enterobacteriaceae, streptococci, and Haemophilus influenzae . Curr Ther Res . 1988; 43:296-302.

51. Levenstein J, Summerfield PJF, Fourie S et al. Comparison of cefixime and co-trimoxazole in acute uncomplicated urinary tract infection: a double-blind general practice study. S Afr Med J . 1986; 70:455-60. [PubMed 3535127]

52. Yamanaka H, Chiba T, Kawabata K et al. Studies on β-lactam antibiotics: IX. Synthesis and biological activity of a new orally active cephalosporin, cefixime (FK027). J Antibiot . 1985; 38:1738-51. [PubMed 4093334]

53. Rossi R, Castellani P, Younes G et al. Activity of FCE 22891 compared with cefuroxime axetil and cefixime in pulmonary and subcutaneous infections in mice. J Antimicrob Chemother . 1989; 23(Suppl C):149-55. [PubMed 2732136]

54. Dance DAB, Wuthiekanun V, Chaowagul W et al. The antimicrobial susceptibility of Pseudomonas pseudomallei : emergence of resistance in vitro and during treatment. J Antimicrob Chemother . 1989; 24:295-309. [PubMed 2681116]

56. Scott HV, Pannowitz D. Cefixime: clinical trial against otitis media and tonsillitis. N Z Med J . 1990; 103:25-6. [PubMed 2406651]

57. Neu HC. β-Lactam antibiotics: structural relationships affecting in vitro activity and pharmacologic properties. Clin Infect Dis . 1986; 8(Suppl 3):S237-60.

58. Saito A, Yamaguchi K, Shigeno Y et al. Clinical and bacteriological evaluation of Branhamella catarrhalis in respiratory infections. Drugs . 1986; 31(Suppl 3):87-92. [PubMed 3488201]

59. Barry AL. Cefixime: spectrum of antibacterial activity against 16016 clinical isolates. Pediatr Infect Dis . 1987; 6: 954-7.

60. Neu HC. In vitro activity of a new broad spectrum, beta-lactamase-stable oral cephalosporin, cefixime. Pediatr Infect Dis . 1987; 6:958-62.

61. Howie VM. Bacteriologic and clinical efficacy of cefixime compared with amoxicillin in acute otitis media. Pediatr Infect Dis . 1987; 6:989-91.

62. Kenna MA, Bluestone CD, Fall P et al. Cefixime vs. cefaclor in the treatment of acute otitis media in infants and children. Pediatr Infect Dis . 1987; 6:992-6.

63. McLinn SE. Randomized, open label, multicenter trial of cefixime compared with amoxicillin for treatment of acute otitis media with effusion. Pediatr Infect Dis . 1987; 6:997-1001.

64. Risser WL, Barone JS, Clark PA et al. Noncomparative, open label, multicenter trial of cefixime for treatment of bacterial pharyngitis, cystitis and pneumonia in pediatric patients. Pediatr Infect Dis . 1987; 6:1002-6.

65. Mendelman PM, Henritzy LL, Chaffin DO et al. In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae . Antimicrob Agents Chemother . 1989; 33:1878-82. [PubMedCentral][PubMed 2610499]

66. Neu HC, Saha G. Comparative in vitro activity and β-lactamase stability of FK482, a new oral cephalosporin. Antimicrob Agents Chemother . 1989; 33:1795-800. [PubMedCentral][PubMed 2589845]

67. Nord CE, Movin G. Impact of cefixime on the normal intestinal microflora. Scand J Infect Dis . 1988; 20:547-52. [PubMed 3222669]

68. Machka K, Balg H, Braveny I. In vitro activity of new antibiotics against Haemophilus influenzae . Eur J Clin Microbiol Infect Dis . 1988; 7:812-4. [PubMed 3145871]

69. Nies BA. Comparative activity of cefixime and cefaclor in an in vitro model simulating human pharmacokinetics. Eur J Clin Microbiol . 1989; 8:558-61.

70. Beumer HM. Cefixime versus amoxicillin/clavulanic acid in lower respiratory tract infections. Int J Clin Pharmacol Ther . 1989; 27:30-3.

71. Kuhlwein A. Efficacy and safety of a single 400 mg oral dose of cefixime in the treatment of uncomplicated gonorrhea. Eur J Clin Microbiol Infect Dis . 1989; 8:261-2. [PubMed 2496996]

72. Dorow P. Safety and efficacy of cefixime versus cefaclor in respiratory tract infections. J Chemother . 1989; 1:257-60. [PubMed 2809693]

73. Faulkner RD, Sia LL, Look ZM et al. Bioequivalency of solid oral dosage forms of cefixime. Int J Pharm . 1988; 43:53-8.

74. Cox CE. Cefixime versus trimethoprim/sulfamethoxazole in treatment of patients with acute, uncomplicated lower urinary tract infections. Urology . 1989; 43:322-6.

75. Leggett NJ, Caravaggio C. Cefixime. DICP . 1990; 24:489-95. [PubMed 2188437]

76. Mortensen JE. Comparative in vitro activity of cefixime against Haemophilus influenzae isolates, including ampicillin-resistant, non-β-lactamase-producing isolates, from pediatric patients. Antimicrob Agents Chemother . 1990; 34:1456-8. [PubMedCentral][PubMed 2386375]

77. Liebowitz LD, Saunders J. In vitro susceptibility of upper respiratory tract pathogens to 13 oral antimicrobial agents. S Afr Med J . 1987; 72:385-8. [PubMed 3660122]

78. Matsui H, Hiraoka M, Inoue M et al. Antimicrobial activity and stability to β-lactmase of BMY-28271, a new oral cephalosporin ester. Antimicrob Agents Chemother . 1990; 34:555-61. [PubMedCentral][PubMed 2344162]

79. Jacoby GA. Activities of β-lactam antibiotics against Escherichia coli strains producing extended-spectrum β-lactamases. Antimicrob Agents Chemother . 1990; 34:858-62. [PubMedCentral][PubMed 2193623]

80. Agger WA, Callister SM. In vitro susceptibility of Borrelia burgdorferi to five oral cephalosporins and ceftriaxone. Antimicrob Agents Chemother . 1992; 36:1788-90. [PubMedCentral][PubMed 1416868]

81. Hoppe JE. In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to six new oral cephalosporins. Antimicrob Agents Chemother . 1990; 34:1442-3. [PubMedCentral][PubMed 2386374]

82. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

83. Food and Drug Administration. Antibiotic drugs; cefixime trihydrate; cefixime trihydrate tablets and cefixime trihydrate powder for oral suspension. (Docket No. 88N-0121). Fed Regist . 1988; 53:24256-9.

85. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling (Docket No. 89N-0474). Fed Regist . 1990; 55:46134-7.

86. Gerber MA, Baltimore RS, Eaton CB et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation . 2009; 119:1541-51. [PubMed 19246689]

97. Norrby SR. Adverse reactions and interactions with newer cephalosporin and cephamycin antibiotics. Medical Toxicol . 1986; 1:32-46.

98. Saxon A, Beall GN, Rohr AS et al. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med . 1987; 107: 204-15. [PubMed 3300459]

99. Lederle, Pearl River, NY: Personal communication.

100. Kees F, Naber KG, Sigl G et al. Relative bioavailability of three cefixime formulations. Arzneimittelforschung . 1990; 40:293-7. [PubMed 2346538]

101. Anon. Choice of cephalosporins. Med Lett Drugs Ther . 1990; 32:107-10. [PubMed 2243553]

102. Reviewers' comments (personal observations).

103. Verghese A, Roberson B, Kalbfleisch JH et al. Randomized comparative study of cefixime versus cephalexin in acute bacterial exacerbation of chronic bronchitis. Antimicrob Agents Chemother . 1990; 34:1041-4. [PubMedCentral][PubMed 2118322]

104. Anon. Drugs for bacterial infections. Med Lett Treat Guid . 2010; 8:43-52.

106. Handsfield HH, McCormack WM, Hook EW et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. N Engl J Med . 1991; 325:1337-41. [PubMed 1922235]

107. Markowitz M, Gerber MA. Treatment of streptococcal pharyngotonsillitis: reports of penicillin's demise are premature. J Pediatr . 1993; 123:679-85. [PubMed 8229474]

108. Plourde PJ, Tyndall M, Agoki E et al. Single-dose cefixime versus single-dose ceftriaxone in the treatment of antimicrobial-resistant Neisseria gonorrhoeae infection. J Infect Dis . 1992; 166:919-22. [PubMed 1527431]

109. Anon. Interim guidelines for the treatment of uncomplicated gonococcal infection. CMAJ . 1992; 146:1587-8. [PubMedCentral][PubMed 1571870]

110. Cates W Jr. Sexually transmitted diseases in the 1990's. N Engl J Med . 1991; 325:368-9.

111. Cates W Jr. Commentary on “Cefixime or ceftriaxone for gonorrhea?” ACP J Club . 1992; March-April:52. ( Ann Intern Med . vol 116, suppl 2). Comment on Handsfield HH, McCormack WM, Hook EW III, et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. N Engl J Med . 1991; 325:1337-41. [PubMed 1922235]

114. Tatsuta M, Ishikawa H, Iishi H et al. Reduction of gastric ulcer recurrence after suppression of Helicobacter pylori by cefixime. Gut . 1990; 31:973-6. [PubMedCentral][PubMed 2210464]

115. Westblom TU, Gudipati S. In vitro susceptibility of Helicobacter pylori to the new oral cephalosporins cefpodoxime, ceftibuten and cefixime. Eur J Clin Microbiol Infect Dis . 1990; 9:691-3. [PubMed 2226500]

117. Harrison CJ, Chartrand SA, Rodriguez W et al. Middle ear effuxion concentrations of cefixime during acute otitis media with effusion and otitis media with effusion. Pediatr Infect Dis J . 1997; 16:816-7. [PubMed 9271047]

118. Portilla I, Lutz B, Montalvo M et al. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. Sex Transm Dis . 1992; 19:94-8. [PubMed 1534422]

119. Dunnett DM. Cefixime in the treatment of uncomplicated gonorrhea. Sex Transm Dis . 1992; 19:92-3. [PubMed 1595018]

120. Asbach HW. Single dose oral administration of cefixime 400 mg in the treatment of acute uncomplicated cystitis and gonorrhoea. Drugs . 1991; 42(Suppl 4):10-3. [PubMed 1725148]

121. Loo VG, Sherman P. Helicobacter pylori infection in a pediatric population: in vitro susceptibilities to omeprazole and eight antimicrobial agents. Antimicrob Agents Chemother . 1992; 36:1133-5. [PubMedCentral][PubMed 1510406]

122. Ateshkadi A, Lam NP. Helicobacter pylori and peptic ulcer disease. Clin Pharm . 1993; 12:34-48. [PubMed 8428432]

123. Millar MR. Bactericidal activity of antimicrobial agents against slowly growing H. pylori . Antimicrob Agents Chemother . 1992; 36:185-7. [PubMedCentral][PubMed 1590687]

124. Blaser MJ. Helicobacter pylori : its role in disease. Clin Infect Dis . 1992; 15:386-91. [PubMed 1520782]

125. Murray DM, DuPont HL, Cooperstock M et al. Evaluation of new anti-infective drugs for the treatment of gastritis and peptic ulcer disease associated with infection by Helicobacter pylori . Clin Infect Dis . 1992; 15(Suppl 1):S268-73.

126. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med . 1991; 324:1043-8. [PubMed 2005942]

127. Graham DY. Evaluation of new anti-infective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

128. Murray DM, DuPont HL. Reply. (Evaluation of new anti-infective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17:294-5.

129. Marshall BJ. Campylobacter pylori : its link to gastritis and peptic ulcer disease. Clin Infect Dis . 1990; 12(Suppl 1):S87-93.

130. Workowski KA, Berman S, Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep . 2010; 59(RR-12):1-110.

132. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: Twenty-first informational supplement. CLSI document M100-S21. Wayne, PA; 2011.

133. Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis . 1992; 573-81.

134. Kelly CP, Pothoulakis C. Clostridium difficile colitis. N Engl J Med . 1994; 330:257-62. [PubMed 8043060]

135. Centers for Disease Control and Prevention. Decreased susceptibility of Neisseria gonorrhoeae to fluoroquinolone—Ohio and Hawaii, 1992-1994. MMWR Morb Mortal Wkly Rep . 1994; 43:325-7. [PubMed 8164636]

137. Markham A. Cefixime: a review of its therapeutic efficacy in lower respiratory tract infections. Drugs . 1995; 49:1007-22. [PubMed 7641600]

138. Gooch WM, Philips A, Rhoades R et al. Comparison of the efficacy and safety and acceptability of cefixime and amoxicillin/clavulanate in acute otitis media. Pediatr Infect Dis J . 1997; 16:S21-4. [PubMed 9041624]

139. Ashkenazi S, Amir J, Waisman Y et al. A randomized, double-blind study comparing cefixime and trimethoprim-sulfamethoxazole in the treatment of childhood shigellosis. J Pediatr . 1993; 123:817-21. [PubMed 8229498]

140. Salam MA, Seas C, Khan WA et al. Treatment of shigellosis: cefixime is ineffective in shigellosis in adults. Ann Intern Med . 1995; 123:505-8. [PubMed 7661494]

141. Bhutta ZA, Khan IA. Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone. Pediatr Infect Dis J . 1994; 13:990-4. [PubMed 7845753]

142. Girgis NI, Sultan Y, Hammad O et al. Comparison of the efficacy, safety and cost of cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella typhi septicemia in children. Pediatr Infect Dis J . 1995; 14:603-5. [PubMed 7567290]

143. Duverne C, Bouten A, Deslandes A et al. Modification of cefixime bioavailability by nefedipine in humans: involvement of the dipeptide carrier system. Antimicrob Agents Chemother . 1992; 36:2462-7. [PubMedCentral][PubMed 1489189]

144. Gremse DA, Dean PC, Farquhar DS et al. Cefixime and antibiotic-associated colitis. Pediatr Infect Dis J . 1994; 13:331-3. [PubMed 8036057]

145. Gales MA. Recognition of severe cefixime-induced diarrhea. Clin Pharm . 1993; 12:881. [PubMed 8137604]

146. Soe GB. Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins. Rev Infect Dis . 1987; 9:719-36. [PubMed 3125577]

147. Mermin JH, Townes JM, Gerber M et al. Typhoid fever in the United States, 1985-1994: changing risks of international travel and increasing antimicrobial resistance. Arch Intern Med . 1998; 158:633-8. [PubMed 9521228]

148. Helvaci M, Bektaslar D, Ozkaya B et al. Comparative efficacy of cefixime and ampicillin-sulbactam in shigellosis in children. Acta Paediatr Jpn . 1998; 40:131-4. [PubMed 9581302]

149. Asmar BI, Dajani AS, Del Beccaro MA et al. Comparison of cefpodoxime proxetil and cefixime in the treatment of acute otitis media in infants and children. Pediatrics . 1994; 94:847-52. [PubMed 7971000]

150. Rodriguez WJ, Khan W, Sait T et al. Cefixime vs. cefaclor in the treatment of acute otitis media in children: a randomized, comparative study. Pediatr Infect Dis J . 1993; 12:70-4. [PubMed 8417429]

152. Shulman ST, Bisno AL, Clegg HW et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis . 2012; 55:1279-82. [PubMed 23091044]

154. Pichichero ME. Shortened course of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis. Pediatr Infect Dis J . 1997; 16:680-95. [PubMed 9239773]

155. Tack KJ, Henry DC, Gooch WM et al. Five-day cefdinir treatment for streptococcal pharyngitis. Antimicrob Agents Chemother . 1998; 42:1073-5. [PubMedCentral][PubMed 9593129]

156. Pichichero ME. Cephalosporins are superior to penicillin for treatment of streptococcal tonsillopharyngitis: is the difference worth it? Pediatr Infect Dis . 1993; 12:268-74.

157. Dajani AS, Kessler SL, Mendelson R et al. Cefpodoxime proxetil vs. penicillin V in pediatric streptococcal pharyngitis/tonsillitis. Pediatr Infect Dis J . 1993; 12:275-9. [PubMed 8483620]

158. Aujard Y, Boucot I, Brahimi N et al. Comparative efficacy and safety of four-day cefuroxime axetil and ten-day penicillin treatment of group A beta-hemolytic streptococcal pharyngitis in children. Pediatr Infect Dis J . 1995; 14:295-300. [PubMed 7603811]

159. Mehra S, Van Moerkerke M, Welck J et al. Short course therapy with cefuroxime axetil for group A streptococcal tonsillopharyngitis in children. Pediatr Infect Dis J . 1998; 17:452-7. [PubMed 9655533]

160. Milatovic D. Evaluation of cefadroxil, penicillin and erythromycin in the treatment of streptococcal tonsillopharyngitis. Pediatr Infect Dis J . 1991; 10:S61-3. [PubMed 1945599]

161. Block SL, Hedrick JA. Comparative study of the effectiveness of cefixime and penicillin V for the treatment of streptococcal pharyngitis in children and adolescents. Pediatr Infect Dis J . 1992; 11:919-25. [PubMed 1454432]

162. Friedland IR. Cefixime therapy for otitis media. Pediatr Infect Dis J . 1993; 12:544-5. [PubMed 8345993]

163. Nataro JP. Treatment of bacterial enteritis. Pediatr Infect Dis J . 1998; 17:420-22. [PubMed 9613658]

164. Bluestone CD. Review of cefixime in the treatment of otitis media in infants and children. Pediatr Infect Dis J . 1993; 12:75-82. [PubMed 8417430]

165. Owen MJ, Anwar R, Nguyen HK et al. Efficacy of cefixime in the treatment of acute otitis media in children. Am J Dis Child . 1993; 147:81-6. [PubMed 8418608]

166. Ramirez JA, Srinath L, Ahkee S et al. Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med . 1995; 155:1273-6. [PubMed 7778957]

167. Spangler SK, Jacobs MR. In vitro susceptibilities of 185 penicillin-susceptible and - resistant pneumococci to WY-49605 (SUN/SY 555%), a new oral penem, compared with those to penicillin G, amoxicillin, amoxicillin-clavulanate, cefixime, cefaclor, cefpodoxime, cefuroxime, and cefdinir. Antimicrob Agents Chemother . 1994; 38:2902-4. [PubMedCentral][PubMed 7695280]

168. Thorburn CE, Knott SJ. In vitro activities of oral β-lactams at concentrations achieved in humans against penicillin-susceptible and -resistant pneumococci and potential to select resistance. Antimicrob Agents Chemother . 1998; 42:1973-9. [PubMedCentral][PubMed 9687392]

169. Davies HD, Low DE, Schwartz B et al. Evaluation of short-course therapy with cefixime or rifampin for eradication of pharyngeally carried group A streptococci. Clin Infect Dis . 1995; 21:1294-6. [PubMed 8589159]

170. Ottolini M, Ascher D, Cieslak T et al. Pneumococcal bacteremia during oral treatment with cefixime for otitis media. Pediatr Infect Dis J . 1991; 10:467-8. [PubMed 1852543]

171. Adam D, Hostalek U. 5-day cefixime therapy for bacterial pharyngitis and/or tonsillitis: comparison with 10-day penicillin V therapy. Cefixime Study Group. Infection . 1995; 23(Suppl 2):S83-6. [PubMed 8537138]

172. Kishiyam JL. The cross-reactivity and immunology of β-lactam antibiotics. Drug Saf . 1994; 10:318-27. [PubMed 8018304]

173. Thompson JW. Adverse effects of newer cephalosporins: an update. Drug Saf . 1993; 9:132-42. [PubMed 8397890]

174. Zenilman JM. Typhoid fever. JAMA . 1997; 278:847-8. [PubMed 9293994]

177. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

178. American Society of Health. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

180. Lorenz J. Comparison of 5-day and 10-day cefixime in the treatment of acute exacerbation of chronic bronchitis. Chemotherapy . 1998; 44(Suppl):15-8. [PubMed 9797418]

181. Oksi J, Nikoskelainen J. Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated lyme borreliosis. Eur J Clin Microbiol Infect Dis . 1998; 17:715-9. [PubMed 9865985]

182. Hoberman A, Wald ER, Hickey RW et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics . 1999; 104:79-86. [PubMed 10390264]

183. Aracil B, Gomez-Garces JL. A study of susceptibility of 100 clinical isolates belonging to the Streptococcus milleri group to 16 cephalosporins. J Antimicrob Chemother . 1999; 43:399-402. [PubMed 10223596]

184. Lieberthal AS, Carroll AE, Chonmaitree T et al. The diagnosis and management of acute otitis media. Pediatrics . 2013; 131:e964-99. [PubMed 23439909]

185. Wormser GP, Dattwyler RJ, Shapiro ED et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis . 2006; 43:1089-134. [PubMed 17029130]

189. Memon IA, Billoo AG, Memon HI. Cefixime: an oral option for the treatment of multidrug-resistant enteric fever in children. South Med J . 1997; 90:1204-7. [PubMed 9404906]

190. Cao XT, Kneen R, Nguyen TA et al. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. Pediatr Infect Dis J . 1999; 18:245-8. [PubMed 10093945]

191. Girgis NI, Kilpatrick ME, Farid Z et al. Cefixime in the treatment of enteric fever in children. Drugs Exp Clin Res . 1993; 19:47-9. [PubMed 8223140]

192. Chow AW, Benninger MS, Brook I et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis . 2012; 54:e72-e112. [PubMed 22438350]

193. Wald ER, Applegate KE, Bordley C et al. Clinical Practice Guideline for the Diagnosis and Management of Acute Bacterial Sinusitis in Children Aged 1 to 18 Years. Pediatrics . 2013; :. [PubMed 23796742]

194. Allen VG, Mitterni L, Seah C et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada. JAMA . 2013; 309:163-70. [PubMed 23299608]

195. Kirkcaldy RD, Bolan GA, Wasserheit JN. Cephalosporin-resistant gonorrhea in North America. JAMA . 2013; 309:185-7. [PubMed 23299612]

196. Centers for Disease Control and Prevention (CDC). Cephalosporin susceptibility among Neisseria gonorrhoeae isolates--United States, 2000-2010. MMWR Morb Mortal Wkly Rep . 2011; 60:873-7. [PubMed 21734634]

197. Centers for Disease Control and Prevention (CDC). Update to CDC's Sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep . 2012; 61:590-4. [PubMed 22874837]

198. Kirkcaldy RD, Zaidi A, Hook EW et al. Neisseria gonorrhoeae antimicrobial resistance among men who have sex with men and men who have sex exclusively with women: the Gonococcal Isolate Surveillance Project, 2005-2010. Ann Intern Med . 2013; 158:321-8. [PubMed 23460055]