Cefuroxime Axetil, Cefuroxime Sodium

Cefuroxime Axetil, Cefuroxime Sodium

Cefuroxime is a semisynthetic, second generation cephalosporin antibiotic.

Uses

Cefuroxime axetil is used orally for the treatment of mild to moderate respiratory tract infections (i.e., acute maxillary sinusitis, acute exacerbations of chronic bronchitis, secondary infections of acute bronchitis, community-acquired pneumonia) caused by susceptible bacteria; acute bacterial otitis media; pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci); mild to moderate uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including b-lactamase-producing strains) or S. pyogenes; and uncomplicated urinary tract infections caused by Escherichia coli or Klebsiella pneumoniae.

Cefuroxime axetil also is used orally for the treatment of uncomplicated gonorrhea and for the treatment of early Lyme disease manifested as erythema migrans caused by Borrelia burgdorferi.

The manufacturer of Ceftin® (cefuroxime axetil) oral suspension states that safety and efficacy of the suspension have been established only for the treatment of pharyngitis and tonsillitis, acute otitis media, and impetigo caused by susceptible bacteria. Cefuroxime sodium is used parenterally in the treatment of lower respiratory tract infections (including pneumonia), serious skin and skin structure infections, genitourinary tract infections, bone and joint infections, septicemia, and meningitis caused by susceptible organisms.

Cefuroxime sodium also has been used parenterally for perioperative prophylaxis. Because cefuroxime, like other second generation cephalosporins, generally is less active against susceptible gram-positive cocci than are first generation cephalosporins, most clinicians state that cefuroxime probably should not be used in the treatment of infections caused by gram-positive bacteria when a penicillin or a first generation cephalosporin could be used. In addition, because cefuroxime generally is less active in vitro against Enterobacteriaceae than third generation cephalosporins, some clinicians state that a third generation drug such as cefotaxime, ceftizoxime, or ceftriaxone generally is preferred if a parenteral cephalosporin is indicated in the treatment of infections known or suspected to be caused by these gram-negative bacteria.

Prior to initiation of cefuroxime therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. If cefuroxime is started pending results of susceptibility tests, it should be discontinued if the causative organism is found to be resistant to the drug. In serious infections when the causative organism is unknown, concomitant therapy with an aminoglycoside may be indicated pending results of in vitro susceptibility tests.

Respiratory Tract Infections

Cefuroxime axetil is used orally for the treatment of mild to moderate respiratory tract infections, including acute maxillary sinusitis caused by susceptible Streptococcus pneumoniae or Haemophilus influenzae (non-b-lactamase-producing strains only) and acute exacerbations of chronic bronchitis and secondary infections of acute bronchitis caused by susceptible S. pneumoniae, H. influenzae (non-b-lactamase-producing strains only), or H. parainfluenzae (non-b-lactamase-producing strains only).

The manufacturer states that insufficient data exist to establish efficacy of cefuroxime axetil in the treatment of acute bacterial maxillary sinusitis that is known or suspected to be caused by b-lactamase-producing strains of H. influenzae or Moraxella (formerly Branhamella) catarrhalis.

Cefuroxime sodium is used parenterally for the treatment of lower respiratory tract infections, including pneumonia, caused by susceptible S. pneumoniae, Staphylococcus aureus (penicillinase- and nonpenicillinase-producing strains), S. pyogenes (group A b-hemolytic streptococci), H. influenzae (including ampicillin-resistant strains), Escherichia coli, and Klebsiella.

Community-acquired Pneumonia

Oral cefuroxime axetil is used for the treatment of mild to moderate community-acquired pneumonia (CAP).

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

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

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

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

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

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

The US Centers for Disease Control (CDC) suggests that use of these oral fluoroquinolones in the outpatient treatment of CAP be reserved for when other anti-infectives are ineffective or cannot be used or when highly penicillin-resistant S. pneumoniae (i.e., penicillin MICs 4 mcg/mL or greater) are identified as the cause of infection.

For inpatient treatment of CAP patients who require hospitalization in an ICU or non-ICU setting, various parenteral regimens are recommended for empiric therapy.

A sequential regimen of parenteral cefuroxime sodium (given for 48-72 hours) followed by oral cefuroxime axetil (given for 7 days) has been used effectively for the treatment of community-acquired pneumonia in adults. However, other parenteral cephalosporins (cefotaxime, ceftriaxone) are recommended by the ATS and IDSA if cephalosporins are included in parenteral regimens for the empiric treatment of CAP. (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections, in the Cephalosporins General Statement 8:12.06.

Acute Otitis Media

Cefuroxime axetil is used orally for the treatment of acute otitis media caused by S. pneumoniae, H. influenzae (including b-lactamase-producing strains), M. catarrhalis (including b-lactamase-producing strains), or S. pyogenes.

Results of controlled clinical studies in children 3 months to 12 years of age with acute otitis media indicate that a 10-day regimen of oral cefuroxime axetil is as effective or more effective than a 10-day regimen of oral cefaclor, oral amoxicillin, or oral amoxicillin and clavulanate potassium. In published studies, the overall clinical response rate to a 10-day regimen of oral cefuroxime axetil in pediatric patients with acute otitis media has ranged from 62-94%.

Cefuroxime axetil also has been effective for the treatment of acute otitis media in pediatric patients when administered in a 5-day regimen. In a randomized study in children 3 months to 12 years of age with acute otitis media, a satisfactory bacteriologic response (cure or presumed cure) was obtained in 92% of those who received a 5-day regimen of cefuroxime axetil (30 mg/kg daily given in 2 divided doses), 84% of those who received a 10-day regimen or cefuroxime axetil (30 mg/kg daily given in 2 divided doses), or 95% of those who received a 10-day regimen of amoxicillin and clavulanate potassium (40 mg/kg daily given in 3 divided doses).

There is evidence from a randomized study in children 6-36 months of age with acute otitis media that a 5-day regimen of oral cefuroxime axetil is as effective as and may be better tolerated than an 8- or 10-day regimen of oral amoxicillin and clavulanate potassium. Some clinicians caution that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of acute otitis media in children younger than 2 years of age or for patients with underlying disease, recurrent or persistent acute otitis media, or perforated tympanic membranes and spontaneous purulent drainage.

Pharyngitis and Tonsillitis

Cefuroxime axetil is used orally for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A b-hemolytic streptococci). Although cefuroxime usually is effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever remains to be established.

A 10-day regimen of oral cefuroxime axetil is at least as effective as a 10-day regimen of oral penicillin V for the treatment of S. pyogenes pharyngitis and tonsillitis. In addition, results of a prospective, randomized study in children 2-15 years of age indicate that a 4-day regimen of oral cefuroxime axetil (20 mg/kg of cefuroxime in 2 divided doses daily) is as effective as a 10-day regimen of oral penicillin V (45 mg/kg daily in 3 divided doses).

The clinical response rate was 94.% in those who received the 4-day cefuroxime regimen and 96.% in those who received the 10-day penicillin regimen; 30 days after treatment, the bacteriologic relapse rate was 2.8 and 2.3%, respectively. Selection of an anti-infective agent regimen for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug’s spectrum of activity as well as the regimen’s bacteriologic and clinical efficacy, potential adverse effects, ease of administration and patient compliance, and cost. No regimen has been found to date that effectively eradicates group A b-hemolytic streptococci in 100% of patients.

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

Other anti-infectives (e.g., oral cephalosporins, oral macrolides) are considered alternative agents. There is some evidence that bacteriologic and clinical cure rates reported with 10-day regimens of certain oral cephalosporins (e.g., cefaclor, cefadroxil, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, cefuroxime axetil, ceftibuten, cephalexin) are slightly higher than those reported with the 10-day oral penicillin V regimen.

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

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

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

Gonorrhea and Associated Infections

IM cefuroxime sodium has been used in conjunction with oral probenecid for the treatment of uncomplicated gonorrhea and disseminated gonococcal infections caused by penicillinase-producing strains of Neisseria gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism.

Cefuroxime axetil has been used orally for the treatment of uncomplicated urethral and endocervical gonorrhea caused by PPNG or nonpenicillinase-producing strains of N. gonorrhoeae and for the treatment of uncomplicated rectal gonorrhea in females caused by nonpenicillinase-producing strains of the organism.

However, IM cefuroxime sodium and oral cefuroxime axetil are not included in the current CDC recommendations for uncomplicated or disseminated gonococcal infections. In a study comparing efficacy of a single 1-g oral dose of cefuroxime or a single 500-mg oral dose of ciprofloxacin in adults with uncomplicated gonorrhea caused by PPNG, both regimens appeared to be equally effective in eradicating urethral, endocervical, and rectal infections in women (eradication rate: 97-99%); however, the eradication rate in men with uncomplicated urethral infections was 93% in those who received cefuroxime axetil and 100% in those who received ciprofloxacin.

While only a limited number of patients in the study had pharyngeal gonococcal infections, the single-dose oral cefuroxime axetil regimen appeared to be slightly less effective than the single-dose oral ciprofloxacin. In a study in women with uncomplicated gonorrhea who received a single 1-g oral dose of cefuroxime, the cure rate ranged from 96-99% in those with urethral, endocervical, or rectal infections; in those with pharyngeal gonorrhea, the cure rate with cefuroxime was 60%.

The CDC and many clinicians recommend that uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

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

The CDC states that, although a single 1-g oral dose of cefuroxime axetil may be effective for the treatment of uncomplicated gonorrhea, the drug offers no advantage over cefixime when an oral cephalosporin is indicated for the treatment of gonorrhea. There has been less clinical experience with cefuroxime axetil, and it has a less favorable pharmacokinetics profile and lower antibacterial activity against N. gonorrhoeae, and may be less effective for the treatment of pharyngeal infections. In addition, the CDC states that oral cephalosporins have not been adequately evaluated for the treatment of gonococcal infections in children.

Lyme Disease

Cefuroxime axetil is used orally in the treatment of early Lyme disease manifested as erythema migrans. Lyme disease is a spirochetal disease caused by tick-borne Borrelia burgdorferi. The IDSA, AAP, and other clinicians currently recommend oral cefuroxime axetil as an alternative to first-line therapy with doxycycline or amoxicillin for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular (AV) heart block. The IDSA states that cefuroxime axetil is an effective agent, that because of its greater cost, is recommended for patients with early Lyme disease who are allergic to or intolerant of doxycycline or amoxicillin.

For information on the manifestations of Lyme disease and details about the efficacy of various anti-infective regimens in early or late Lyme disease, seeLyme Disease in Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.24.

Efficacy of cefuroxime axetil for the treatment of early Lyme disease has been evaluated in studies that included adults and pediatric patients 12 years of age or older with physician-documented erythema migrans (with or without systemic manifestations of infection), and results of these studies indicate that the drug is as effective as oral doxycycline in producing resolution of erythema migrans and preventing the development of manifestations of late Lyme disease.

The clinical diagnosis of early Lyme disease in study patients was validated objectively by a blinded expert who examined available photographs of skin lesions taken before therapy and/or by serologic evidence of antibodies specific to B. burgdorferiidentified using enzyme-linked immunosorbent assay (ELISA) and Western immunoblot.

Patients were randomized to receive oral cefuroxime axetil (500 mg of cefuroxime twice daily) or oral doxycycline (100 mg 3 times daily) for 20 days and evaluated during treatment (days 8-12) and posttreatment (days 1-5, 1 month, and then at 3-month intervals for up to 1 year). In patients who were evaluated at 1 month posttreatment, a satisfactory clinical response consisting of either clinical success (defined as resolution of erythema migrans and other manifestations of infection within 5 days posttreatment and maintained through follow-up at 1 month posttreatment) or clinical improvement (defined as resolution of erythema migrans within 5 days posttreatment with incomplete resolution of other manifestations of infection at that time but further improvement or complete resolution of manifestations by follow-up at 1 month posttreatment) was attained in 91 or 93% of patients who received cefuroxime axetil or doxycycline, respectively.

Clinical success was attained in 72 or 73% of patients receiving cefuroxime axetil or doxycycline, respectively; clinical improvement was attained in 19% of patients receiving either drug. In patients evaluated at 1 year, a satisfactory clinical outcome consisting of success (defined as the absence of signs or symptoms of late Lyme disease throughout the 1-year follow-up) or clinical improvement (defined as the presence of some signs or symptoms consistent with late Lyme disease but no objective evidence of active disease throughout the 1-year follow-up) was attained in 84 or 87% of patients who received cefuroxime axetil or doxycycline, respectively.

Success at 1 year was attained in 73% of patients receiving either drug; clinical improvement was attained in 10% of patients receiving cefuroxime axetil and 13% of patients receiving doxycycline.

Meningitis

Parenteral cefuroxime has been used in neonates, children, and adults for the treatment of meningitis caused by susceptible S. pneumoniae, H. influenzae (including ampicillin-resistant strains), N. meningitidis, or S. aureus (penicillinase- and nonpenicillinase-producing strains); however, cefuroxime is not considered a drug of choice for these infections. Treatment failures have been reported when cefuroxime was used in the treatment of meningitis, especially in meningitis caused by H. influenzae. In addition, while results of some studies in pediatric patients with meningitis indicate that the clinical cure rate with IV cefuroxime is similar to that reported for IV ceftriaxone, the bacteriologic response to cefuroxime appears to be slower, which may increase the risk for hearing loss and neurologic sequelae. In a study in children 44 days to 16 years of age with acute bacterial meningitis who were randomized to receive empiric therapy with IV ceftriaxone (100 mg/kg once daily) or IV cefuroxime (240 mg/kg daily in 4 doses), all patients in both groups were considered clinically cured; however, the rate of sterilization of CSF after the first 18-36 hours of therapy was higher in those who received ceftriaxone (98%) than in those who received cefuroxime (88%). When a cephalosporin is indicated for the treatment of bacterial meningitis, a parenteral third generation cephalosporin (usually ceftriaxone or cefotaxime) generally is recommended.

Perioperative Prophylaxis

IV cefuroxime sodium is used for perioperative prophylaxis in patients undergoing clean-contaminated or potentially contaminated surgery. There is evidence that perioperative prophylaxis with an appropriate anti-infective agent can decrease the incidence of infection, particularly wound infection, after certain procedures; however, such prophylaxis usually is recommended only for procedures with a high rate of infection, procedures involving implantation of prosthetic material, and procedures in which the consequences of infection are especially serious.

Cardiac Surgery

There is evidence that perioperative prophylaxis can decrease the incidence of infection after cardiac surgery.

Results of a pooled analysis of published, randomized, controlled studies indicate that perioperative prophylaxis reduces the incidence of infection after permanent pacemaker implantation.

For perioperative prophylaxis in patients undergoing cardiac surgery (e.g., prosthetic valve, coronary artery bypass, other open-heart surgery, pacemaker or defibrillator implant), some clinicians recommend IV cefazolin or IV cefuroxime sodium. Although routine use of vancomycin for perioperative prophylaxis is not recommended, vancomycin may be considered an alternative for perioperative prophylaxis in cardiac surgery patients hypersensitive to b-lactam anti-infectives or at institutions where methicillin-resistant S. aureus and S. epidermidis frequently cause wound infection.

Results of several studies indicate that perioperative use of IV cefuroxime sodium can decrease the incidence of infection in patients undergoing open-heart surgery, including coronary bypass surgery.

Although in one limited study in patients undergoing coronary artery bypass surgery or cardiac valve replacement, cefuroxime sodium was slightly more effective than cefazolin in reducing the incidence of postoperative wound infections, results of a prospective double-blind study in patients undergoing cardiac surgery indicate that cefazolin may be more effective than cefuroxime in preventing sternal wound infections.

Noncardiac Thoracic Surgery

Some clinicians state that, although perioperative prophylaxis is used routinely in pulmonary surgery, there is little data to support such prophylaxis. In one randomized, double-blind study in patients undergoing noncardiac thoracic surgery, a single preoperative dose of cefazolin decreased the incidence of postoperative surgical site infection, but did not affect the incidence of postoperative empyema or nosocomial pneumonia. There is evidence that multiple doses of a cephalosporin can prevent infection after closed-tube thoracostomy for chest trauma; however, insertion of chest tubes for other indications, such as spontaneous pneumothorax, does not require prophylaxis.

For perioperative prophylaxis in patients undergoing noncardiac thoracic surgery, some clinicians recommend IV cefazolin or IV cefuroxime sodium. Although routine use of vancomycin for perioperative prophylaxis is not recommended, vancomycin may be considered an alternative for perioperative prophylaxis in noncardiac thoracic surgery patients who are hypersensitive to b-lactam anti-infectives or at institutions where methicillin-resistant S. aureus and S. epidermidis frequently cause wound infection.

Other Procedures

IV cefuroxime sodium has been effective when used perioperatively to reduce the incidence of infection in patients undergoing GI surgery, obstetric and gynecologic surgery (e.g., vaginal hysterectomy), or orthopedic surgery (e.g., hip replacement). However, other anti-infectives (e.g., cefazolin, cefotetan, cefoxitin) generally are the preferred drugs for perioperative prophylaxis in patients undergoing GI, orthopedic, vascular, or gynecologic and obstetric surgery.(See Uses: Perioperative Prophylaxis, in the Cephalosporins General Statement 8:12.06.)

Timing and Number of Doses

When perioperative prophylaxis is indicated in patients undergoing clean-contaminated or potentially contaminated surgery, administration of an anti-infective should be timed to ensure that bactericidal concentrations of the drug are established in serum and tissues by the time the initial surgical incision is made; therapeutic concentrations of the drug should then be maintained in serum and tissues throughout the operation and until, at most, a few hours after the incision is closed.

With many anti-infectives (e.g., cefazolin), a single dose given no more than 30 minutes before the incision provides adequate tissue concentrations throughout the procedure. If cefuroxime sodium is used prophylactically, the manufacturers recommend that the drug should usually be given just prior to surgery (approximately 30-60 minutes before the initial incision) to ensure adequate cefuroxime tissue concentrations at the time of surgery.

If surgery is prolonged (more than 4 hours) or major blood loss occurs, it may be advisable to administer one or more additional doses during the procedure; for prolonged procedures some clinicians suggest that intraoperative doses be administered every 4-8 hours for the duration of the procedure.

Although anti-infective prophylaxis regimens reported in published studies often include 1 or 2 postoperative doses in addition to the preoperative dose, many clinicians state that postoperative doses generally are unnecessary. If signs of infection occur following surgery, specimens should be obtained for identification of the causative organism and appropriate therapy instituted.

Dosage and Administration

Reconstitution and Administration

Cefuroxime axetil is administered orally. Cefuroxime sodium is administered by direct IV or deep IM injection or by IV infusion. The drug should be given IV rather than IM in patients with septicemia or other severe or life-threatening infections or in patients with lowered resistance, particularly if shock is present.

Cefuroxime axetil powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a suspension containing 125 or 250 mg of cefuroxime (as cefuroxime axetil) per 5 mL of suspension.

After tapping the bottle to thoroughly loosen the powder for oral suspension, the water should be added in one portion and the suspension agitated well. The suspension should be agitated well just prior to each use and the cap replaced securely after each opening.

Although cefuroxime axetil film-coated tablets may be given orally without regard to meals, administration with food maximizes bioavailability of the drug. Cefuroxime axetil oral suspension must be administered with food. In children aged 3 months to 12 years who are unable to swallow tablets, cefuroxime may be administered as the commercially available oral suspension.

Alternatively, commercially available cefuroxime axetil tablets have been crushed and mixed with food (e.g., applesauce, ice cream); however, crushed tablets of the drug have a strong, persistent taste, and the manufacturer currently states that the drug should not be administered in this manner. (See Cautions: Pediatric Precautions.) Cefuroxime axetil tablets also have been allowed to disintegrate in a small amount (60-90 mL) of beverage such as apple juice or milk, and the beverage stirred and ingested immediately; disintegration of the tablets is optimal when the beverage is at room temperature.

This has been followed by ingestion of additional amounts of the beverage without the drug. Limited data from a study conducted by the manufacturer suggest that cefuroxime axetil is stable for 2 hours at room temperature when added as single 125- or 250-mg tablets to 40 mL of Tropicana® orange juice, Welch’s® grape juice, or Nestle’s® chocolate milk. However, extemporaneous preparation of an oral suspension of the drug intended for multiple dosing currently is not recommended since stability information for more prolonged periods currently is not available and because the drug is commercially available as an oral suspension.

Although administration of crushed tablets of the drug via a nasogastric or other feeding tube has not been studied to date, if this method of administration is used, the pieces of film coating should be removed from the crushed tablets prior to mixing with a liquid to minimize the risk of forming a plug in the tube.

The child’s tolerance of the taste of cefuroxime axetil should be ascertained by the clinician and parent, preferably when prescription of the drug is being considered (e.g., while the child is still in the physician’s office).

Intermittent IV Injection

For direct intermittent IV injection, the manufacturer of Zinacef® states that 8 or 16 mL of sterile water for injection should be added to a vial labeled as containing 750 mg or 1.5 g of cefuroxime, respectively, to provide solutions containing approximately 90 mg/mL; the entire contents of the vial should be withdrawn for each dose.

The manufacturer of Kefurox® states that a vial labeled as containing 750 mg or 1.5 g of the drug should be reconstituted by adding 7 or 14 mL, respectively, of sterile water for injection to provide solutions containing approximately 100 mg/mL; the entire contents of the 750-mg or 1.5-g vial should be withdrawn for each dose.

The appropriate dose should then be injected directly into a vein over a 3- to 5-minute period or injected slowly into the tubing of a freely flowing compatible IV solution.

Intermittent or Continuous IV Infusion

For intermittent or continuous IV infusion, 100 mL of sterile water for injection, 5% dextrose injection, 0.9% sodium chloride injection, or other compatible IV solution may be added to an infusion pack labeled as containing 750 mg or 1.5 g of cefuroxime to provide solutions containing approximately 7.5 or 15 mg/mL, respectively.

Alternatively, reconstituted solutions of cefuroxime may be added to glass or PVC IV containers containing a compatible IV solution. ADD-Vantage® vials labeled as containing 750 mg or 1.5 g of cefuroxime or the 7.5-g pharmacy bulk package should be reconstituted according to the manufacturer’s directions. The pharmacy bulk package is not intended for direct IV infusion; doses of the drug from the reconstituted bulk package must be further diluted in a compatible IV infusion solution prior to administration.

Thawed solutions of the commercially available frozen cefuroxime sodium injections are administered by IV infusion.

The commercially available frozen cefuroxime sodium injections should not be thawed by warming them in a water bath or by exposure to microwave radiation. A precipitate may form while the commercially available frozen injection is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of cefuroxime sodium frozen injection is not affected.

After thawing at room temperature or under refrigeration, the container should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection container. The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete. Intermittent IV infusions of cefuroxime are generally infused over 15-60 minutes.

Other IV solutions flowing through a common administration tubing or site should be discontinued while cefuroxime is being infused unless the solutions are known to be compatible and the flow rate is adequately controlled. If an aminoglycoside is administered concomitantly with cefuroxime, the drugs should be administered at separate sites.

IM Injection

IM injections of Zinacef® are prepared by adding 3 mL of sterile water for injection to a vial labeled as containing 750 mg of cefuroxime to provide a suspension containing approximately 220 mg/mL. The suspension should be shaken gently prior to administration, and the entire contents of the vial should be withdrawn for each dose. IM injections should be made deeply into a large muscle mass such as the gluteus or lateral aspect of the thigh. The plunger of the syringe should be drawn back before IM injection to ensure that the needle is not in a blood vessel.

Dosage

Dosage of cefuroxime axetil is expressed in terms of cefuroxime. The manufacturer of Ceftin® states that cefuroxime axetil film-coated tablets and oral suspension are not bioequivalent and are not substitutable on a mg/mg basis. (See Pharmacokinetics: Absorption.) Dosage of cefuroxime sodium also is expressed in terms of cefuroxime and is identical for IM or IV administration.

Adult Dosage

For the treatment of uncomplicated skin and skin-structure infections in adults and adolescents 13 years of age or older, the usual oral dosage of cefuroxime given as cefuroxime axetil tablets is 250 or 500 mg twice daily for 10 days.

For the treatment of uncomplicated urinary tract infections (UTIs), the usual oral dosage of cefuroxime given as cefuroxime axetil tablets is 125 or 250 mg twice daily for 7-10 days.

The usual parenteral adult dosage of cefuroxime given as cefuroxime sodium is 750 mg to 1.5 g every 8 hours. Uncomplicated UTIs, skin and skin structure infections, and uncomplicated pneumonia in adults generally respond to a parenteral dosage of 750 mg every 8 hours.

Severe or complicated infections or bone and joint infections in adults generally require 1.5 g every 8 hours and life-threatening infections or infections caused by less susceptible organisms may require 1.5 g every 6 hours. Dosage of parenteral cefuroxime for the treatment of bacterial meningitis in adults should not exceed 3 g every 8 hours.

Respiratory Tract Infections

For the treatment of acute bacterial maxillary sinusitis, the usual oral dosage of cefuroxime given as cefuroxime axetil tablets for adults and adolescents 13 years of age or older is 250 mg twice daily for 10 days. For the treatment of acute bacterial exacerbations of chronic bronchitis and secondary bacterial infections of acute bronchitis, the usual oral dosage of cefuroxime given as cefuroxime axetil tables for adults and adolescents 13 years of age or older is 250 or 500 mg twice daily.

The manufacturer recommends that therapy be continued for 10 days for the treatment of acute bacterial exacerbations of chronic bronchitis or for 5-10 days for the treatment of secondary bacterial infections of acute bronchitis.

While there is evidence that a 5-day regimen of cefuroxime axetil is as effective as a 10-day regimen of the drug for the treatment of secondary bacterial infections of acute bronchitis, efficacy of the shorter regimen for the treatment of acute exacerbations of chronic bronchitis has not been established. If cefuroxime axetil is used for the outpatient treatment of acute community-acquired pneumonia (CAP) in immunocompetent adults, some clinicians recommend an oral dosage of 500 mg of cefuroxime twice daily. For the treatment of uncomplicated pneumonia in adults, the manufacturers recommends a parenteral cefuroxime dosage of 750 mg every 8 hours. In severe or complicated infections, a dosage of 1.5 g every 8 hours is recommended.

Pharyngitis and Tonsillitis

For the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci) in adults and adolescents 13 years of age or older, the usual dosage of cefuroxime given as cefuroxime axetil tablets is 250 mg twice daily for 10 days.

Gonorrhea and Associated Infections

For the parenteral treatment of uncomplicated gonorrhea caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism, the manufacturer of Zinacef® recommends that adults receive a single 1.5-g dose of cefuroxime IM and 1 g of oral probenecid; the dose of cefuroxime should be divided and given at 2 different sites.

For the parenteral treatment of disseminated gonococcal infections, the manufacturers recommend that adults receive 750 mg of cefuroxime IM or IV every 8 hours. For the oral treatment of uncomplicated urethral or endocervical gonorrhea caused by PPNG or nonpenicillinase-producing strains of N. gonorrhoeae or for the oral treatment of uncomplicated rectal gonorrhea in females caused by nonpenicillinase-producing strains of the organism, adults and adolescents 13 years of age or older have received a single 1-g dose of cefuroxime.

Lyme Disease

For the treatment of early Lyme disease manifested as erythema migrans, the manufacturer recommends that adults and adolescents 13 years of age or older receive 500 mg of oral cefuroxime twice daily for 20 days. As an alternative to oral doxycycline or amoxicillin in patients who are allergic to or intolerant of those drugs, the Infectious Diseases Society of America (IDSA) and other clinicians recommend that adults receive 500 mg of oral cefuroxime twice daily for 14-28 days for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree AV heart block.

Perioperative Prophylaxis

For perioperative prophylaxis in clean-contaminated or potentially contaminated surgery (e.g., vaginal hysterectomy), the manufacturers recommend that adults receive 1.5 g of cefuroxime IV just prior to surgery (approximately 30-60 minutes before the initial incision) and, in lengthy operations, 750 mg of the drug IV or IM every 8 hours. For adults undergoing open-heart surgery, the manufacturers recommend that a single 1.5-g dose of cefuroxime be given IV at the time of induction of anesthesia and every 12 hours thereafter for a total dosage of 6 g.

When cefuroxime is used for perioperative prophylaxis in patients undergoing cardiac surgery (e.g., prosthetic valve, coronary artery bypass, other open-heart surgery, pacemaker or defibrillator implant), some clinicians recommend that 1.5 g of cefuroxime be given IV just prior to the procedure; some of these clinicians recommend that an additional dose may be given when the patient is removed from bypass during open-heart surgery.

When cefuroxime is used for perioperative prophylaxis in patients undergoing noncardiac thoracic surgery, some clinicians recommend that 1.5 g of cefuroxime be given IV just prior to the procedure. For most surgical procedures, continuation of prophylaxis for more than 24 hours after surgery appears to be of no additional value and may increase the risk of toxicity and bacterial superinfection. Although the manufacturers and some clinicians suggest that cefuroxime be continued for at least 48 hours in patients undergoing open-heart surgery, other clinicians state that postoperative doses generally are unnecessary.

Pediatric Dosage

The manufacturer of Ceftin® states that cefuroxime axetil film-coated tablets and oral suspension are not bioequivalent and are not substitutable on a mg/mg basis. (See Pharmacokinetics: Absorption.)

The usual IM or IV dosage of cefuroxime for the treatment of most susceptible infections (except bone and joint infections or meningitis) in children 3 months of age or older is 50-100 mg/kg daily given in equally divided doses every 6-8 hours; the manufacturer states that 100 mg/kg should be used for more severe infections. The usual IM or IV dosage of cefuroxime for the treatment of bone and joint infections in children 3 months of age or older is 150 mg/kg daily in 3 divided doses every 8 hours.

For the treatment of bacterial meningitis in children 3 months of age or older, the usual dosage of IV cefuroxime is 200-240 mg/kg daily given in divided doses every 6-8 hours.

Acute Otitis Media

For the treatment of acute otitis media in children 3 months to 12 years of age who can swallow tablets whole, the usual oral dosage of cefuroxime as cefuroxime axetil film-coated tablets is 250 mg twice daily for 10 days.

Alternatively, children 3 months to 12 years of age with acute otitis media can receive cefuroxime as cefuroxime axetil oral suspension in a dosage of 30 mg/kg daily (maximum 1 g daily) given in 2 divided doses for 10 days.Cefuroxime axetil also has been administered in a 5-day regimen for the treatment of acute otitis media in children 3 months to 12 years of age.

Pharyngitis and Tonsillitis

For the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A b-hemolytic streptococci) in children 3 months to 12 years of age who can swallow tablets whole, the usual oral dosage of cefuroxime as cefuroxime axetil film-coated tablets is 125 mg every 12 hours for 10 days.

Alternatively, children 3 months to 12 years of age may receive cefuroxime as cefuroxime axetil oral suspension in a dosage of 20 mg/kg daily (maximum 500 mg daily) in 2 divided doses for 10 days.

Acute Sinusitis

For the treatment of acute bacterial maxillary sinusitis in children 3 months to 12 years of age who can swallow tablets whole, the usual oral dosage of cefuroxime as cefuroxime axetil film-coated tablets is 250 mg twice daily for 10 days.

Alternatively, children 3 months to 12 years of age may receive cefuroxime as cefuroxime axetil oral suspension in a dosage of 30 mg/kg daily (maximum 1 g daily) given in 2 divided doses for 10 days. Impetigo For the treatment of impetigo in children 3 months to 12 years of age, the usual oral dosage of cefuroxime as cefuroxime axetil oral suspension is 30 mg/kg daily (maximum 1 g daily) in 2 divided doses for 10 days.

Lyme Disease

As an alternative to oral doxycycline or amoxicillin for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans in the absence of neurologic involvement or third-degree AV heart block, the AAP, IDSA, and other clinicians recommend that children receive oral cefuroxime in a daily dosage of 30 mg/kg (maximum dose: 500 mg) administered in 2 divided doses for 14-28 days.

Duration of Therapy

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

For the treatment of uncomplicated UTIs, the manufacturer recommends that therapy with cefuroxime axetil tablets be continued for 7-10 days.

For the treatment of uncomplicated skin and skin-structure infections, or acute otitis media caused by susceptible organisms, the manufacturer recommends that therapy with cefuroxime axetil tablets be continued for 10 days. C

hronic urinary tract infections may require several weeks of cefuroxime therapy, and bacteriologic and clinical assessments should be made frequently during therapy and for several months after the drug is discontinued. When cefuroxime is used in the treatment of staphylococcal and other infections involving a collection of pus, surgical drainage should be performed when indicated.

Dosage in Renal Impairment

Modification of usual dosage of cefuroxime is unnecessary in patients with creatinine clearances greater than 20 mL/minute.

However, in patients with creatinine clearances of 20 mL/minute or less, doses and/or frequency of administration of cefuroxime must be modified in response to the degree of renal impairment, severity of the infection, and susceptibility of the causative organism.

The manufacturers and some clinicians recommend that adults with creatinine clearances of 10-20 mL/minute receive 750 mg IM or IV every 12 hours and that adults with creatinine clearances less than 10 mL/minute receive 750 mg IM or IV every 24 hours. In children with impaired renal function, the manufacturers recommend that the frequency of administration of parenteral cefuroxime be modified based on the recommendations for adults with impaired renal function.

Specific recommendations for adjusting oral dosage of cefuroxime axetil in patients with renal impairment currently are not available. In patients undergoing hemodialysis, a supplemental dose of cefuroxime should be given after each dialysis period.

Cautions

Adverse effects reported with cefuroxime axetil and cefuroxime sodium are similar to those reported with other cephalosporins.

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions have been reported in less than 1% of patients receiving cefuroxime axetil or cefuroxime sodium.

These reactions include rash (e.g., morbilliform), fever, pruritus, erythema, urticaria, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, serum sickness-like reactions, angioedema, and anaphylaxis. At least one case of severe bronchospasm has been reported in a patient who received cefuroxime axetil.

Positive direct antiglobulin (Coombs’) test results have also been reported in a few patients receiving oral or parenteral cefuroxime; however, it is not clear whether the mechanism of this reaction is immunologic in nature. If a severe hypersensitivity reaction occurs during cefuroxime therapy, the drug should be discontinued and the patient given appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

There is clinical and laboratory evidence of partial cross-allergenicity among cephalosporins and other b-lactam antibiotics including penicillins and cephamycins; however, the true incidence of cross-allergenicity among these anti-infectives has not been established.

When cefuroxime axetil was used in patients with a history of delayed hypersensitivity reactions to penicillins and no history of hypersensitivity to cephalosporins, a delayed hypersensitivity reaction occurred in about 3% of these patients. The manufacturer states that when cefuroxime sodium was used in patients with a history of hypersensitivity to penicillin, rash reportedly occurred in 4.4-6.% of these patients.

Local Effects

The most frequent adverse reactions to IM or IV cefuroxime sodium are local reactions at the injection site. Mild to moderate pain, which persists for less than 5 minutes, has been reported in up to 95% of patients following IM administration of cefuroxime. Severe pain has been reported occasionally. IM injections of cefuroxime reportedly are less painful when the drug is administered as a suspension rather than a solution and are also less painful when the injection is given into the buttock rather than the thigh.

Thrombophlebitis reportedly occurs in approximately 2% of patients receiving cefuroxime IV.

GI Effects

Nausea and vomiting have been reported in 2.6-6.% and diarrhea or loose stools have been reported in 3.7-10.% of patients receiving oral cefuroxime axetil. A strong, persistent, bitter taste has been reported when cefuroxime axetil was administered as crushed tablets (see Pediatric Precautions). In addition, up to 5% of children receiving the commercially available oral suspension of cefuroxime axetil disliked the taste of the suspension; during clinical trials, discontinuance of therapy because of the taste of the suspension or other problems with administration occurred in 1.4% of patients.

Gagging, epigastric burning, GI bleeding, abdominal pain, flatulence, GI infection, ptyalism, indigestion, mouth ulcers, swollen tongue, anorexia, thirst, dyspepsia, and stomach cramps also have been reported in patients receiving the drug orally.

The frequency of adverse GI effects (particularly diarrhea) may be greater with oral cefuroxime axetil than with oral cefaclor, and nausea appears to be more common when oral cefuroxime axetil is used concomitantly with oral probenecid than when the antibiotic is used alone. In addition, adverse GI effects were reported more frequently with previously available oral formulations of cefuroxime axetil, and, in part, prompted several reformulations of the product.

Adverse GI effects including nausea and diarrhea have been reported in less than 1% of patients receiving IM or IV cefuroxime sodium. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by toxin-producing clostridia resistant to cefuroxime, has been reported rarely following oral or parenteral cefuroxime therapy.

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

Antiperistaltic agents (e.g., opiates, diphenoxylate with atropine) may prolong and/or worsen the condition and should be avoided if C. difficile-associated colitis is suspected. If colitis is moderate to severe or is not relieved by discontinuance of cefuroxime, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable.

Other causes of colitis also should be considered.

Hematologic Effects

Decreased hemoglobin concentration and decreased hematocrit have been reported in about 10% of patients receiving cefuroxime. Transient eosinophilia occurs less frequently, and transient neutropenia, pancytopenia, thrombocytopenia, and leukopenia occur rarely. Thrombocytosis, lymphocytosis, hemolytic anemia, and increased prothrombin time also have been reported.

CNS Effects

Headache, dizziness, somnolence or sleepiness, hyperactivity, irritable behavior, seizures, myoclonic jerks, and generalized hyperexcitability have been reported rarely in patients receiving cefuroxime. A psychotic reaction, consisting of disorientation, fluctuating consciousness, and episodes of restlessness, agitation, and anxiety, occurred in a geriatric patient who received IV cefuroxime sodium; symptoms resolved within 24 hours after the drug was discontinued. Some patients who experienced adverse CNS effects while receiving cefuroxime had preexisting renal impairment.

Hepatic Effects

Transient increases in serum AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and bilirubin concentrations have been reported in less than 5% of patients receiving oral or parenteral cefuroxime. Jaundice has been reported rarely.

Renal and Genitourinary Effects

Acute renal failure and interstitial nephritis have been reported rarely in patients receiving cefuroxime. Although a causal relationship has not been established, transient increases in BUN and/or serum creatinine concentrations and decreased creatinine clearance have been reported in a few patients receiving cefuroxime. Bilateral renal cortical necrosis that appeared to be a hypersensitivity reaction has been reported in at least one patient who received cefuroxime axetil.

Urinary tract infection, kidney pain, urethral pain or bleeding, dysuria, vaginitis, vaginal candidiasis, vulvovaginal pruritus, and vaginal discharge or irritation have been reported in less than 1% of patients receiving oral cefuroxime axetil therapy.

Other Adverse Effects

The manufacturer states that the Jarisch-Herxheimer reaction has occurred in 5.6% of patients receiving the drug for the treatment of Lyme disease. In a clinical study in patients with early Lyme disease, the Jarisch-Herxheimer reaction occurred in 11.% of patients receiving cefuroxime axetil and 11.% of patients receiving doxycycline. These transient reactions generally last only 1-2 days.

Overgrowth with nonsusceptible organisms (e.g., perianal, oral, or vaginal candidiasis; pseudomembranous colitis; superinfection) has occurred in patients receiving cefuroxime sodium or cefuroxime axetil. (See Cautions: GI Effects and also Precautions and Contraindications.) Mild to severe hearing loss has been reported in a few pediatric patients receiving cefuroxime sodium for the treatment of meningitis.

Persistence of positive CSF cultures at 18-36 hours has been observed with cefuroxime sodium injection; however, the clinical relevance of this finding is unknown. Muscle spasm of the neck, muscle cramps or stiffness, chest pain or tightness, shortness of breath, tachycardia, chills, lockjaw-type reaction, viral illness, upper respiratory infection, sinusitis, fever, cough, joint swelling, and arthralgia have been reported in less than 1% of patients receiving oral cefuroxime axetil therapy.

Diaper rash has been reported in 3.4% of pediatric patients receiving cefuroxime axetil as the commercially available oral suspension.

Precautions and Contraindications

Prior to initiation of cefuroxime therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. Cefuroxime axetil and cefuroxime sodium are contraindicated in patients who are hypersensitive to cefuroxime or other cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins.

Use of cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins. Although it has not been definitely proven that allergic reactions to antibiotics are more frequent in atopic individuals, the manufacturers state that cefuroxime should be used with caution in patients with a history of allergy, particularly to drugs.

Prolonged use of cefuroxime axetil or cefuroxime sodium may result in overgrowth of nonsusceptible organisms. Careful observation of the patient during cefuroxime therapy is essential. If suprainfection or superinfection occurs, appropriate therapy should be instituted. Cefuroxime should be used with caution in patients with a history of GI disease, particularly colitis.

Because C. difficile-associated diarrhea and colitis has been reported with the use of cefuroxime and other cephalosporins, it should be considered in the differential diagnosis of patients who develop diarrhea during or after cefuroxime therapy.

The safety and efficacy of cefuroxime axetil therapy in patients with GI malabsorption have not been established. Although cefuroxime sodium only rarely causes adverse renal effects, the manufacturers state that renal function should be monitored during therapy with the drug, especially when maximum dosage is used in seriously ill patients.

Because serum concentrations of cefuroxime are higher and more prolonged in patients with renal impairment than in patients with normal renal function, dose and/or frequency of administration of cefuroxime sodium should be decreased in patients with transient or persistent renal impairment. (See Dosage in Renal Impairment in Dosage and Administration: Dosage.)

Several cephalosporins (including cefuroxime) have been associated with the development of seizures, particularly in patients with renal impairment, in whom dosage of the drug was not reduced.

If seizures associated with cefuroxime develop, the drug should be discontinued and anticonvulsant therapy initiated as clinically indicated. Because some cephalosporins have been associated with a decrease in prothrombin activity, the manufacturer states that prothrombin time (PT) should be monitored when cefuroxime is used in patients with renal or hepatic impairment, in patients with poor nutritional status, in patients receiving a protracted course of anti-infective therapy, or in those previously stabilized on anticoagulant therapy.

Vitamin K should be administered if indicated.

Pediatric Precautions

Safety and efficacy of cefuroxime axetil or cefuroxime sodium in children younger than 3 months of age have not been established. In vitro studies indicate that cefuroxime does not appear to displace bilirubin appreciably from albumin binding sites in neonates.

Cefuroxime Axetil

The manufacturer states that safety and efficacy of cefuroxime axetil for the treatment of acute bacterial maxillary sinusitis in pediatric patients 3 months to 12 years of age have been established based on safety and efficacy of the drug in adults.

In addition, use of cefuroxime axetil in pediatric patients is supported by pharmacokinetic and safety data in adult and pediatric patients, clinical and microbiologic data from adequate and well-controlled studies of the treatment of acute bacterial maxillary sinusitis in adults and acute otitis media with effusion in pediatric patients, and postmarketing surveillance of adverse effects. Cefuroxime axetil tablets and oral suspension generally are well tolerated in children aged 3 months to 12 years.

Cefuroxime axetil has a strong, persistent, bitter taste and complaints caused by the taste were reported in up to 66% of children who received the drug as crushed tablets and vomiting was induced aversively in some of these children. This bitter taste and/or problems with administering the drug required discontinuance of such cefuroxime axetil therapy in 2-28% of children in clinical trials.

Although discontinuance of therapy with the suspension because of its taste or other problems with administration occurred in 1.4% of children receiving the oral suspension, the commercially available oral suspension should be used in children who cannot swallow the tablets whole.

Geriatric Precautions

In clinical studies of cefuroxime axetil, 375 patients were 65 years of age or older and 151 were 75 years of age or older. There were no apparent differences in safety or effectiveness between these individuals and younger adults.

Although the group of patients aged 65 years or older experienced a lower incidence of some adverse effects (e.g., vaginal candidiasis, GI effects) compared with patients 12-64 years of age, no clinically important differences were observed between geriatric and younger patients and there have been no reports of differences in response in either group. In clinical studies of cefuroxime sodium involving over 1900 patients, approximately 47% of the patients were 65 years of age or older and 22% were 75 years of age or older.

Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.

Cefuroxime is substantially excreted by the kidney, and renal elimination of the drug may be decreased and the risk of severe adverse reactions may be increased in patients with impaired renal function.

Limited data indicate that mean serum elimination half-life of cefuroxime is prolonged in geriatric patients (mean age: 83. years) who have a mean creatinine clearance of approximately 35 mL/minute.

Despite this prolonged elimination, the manufacturer states that age-based dosage adjustment does not appear to be necessary. However, because geriatric patients are more likely to have decreased renal function, the manufacturer states dosage should be selected with caution in these patients and monitoring of renal function may be useful.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed with cefuroxime in various in vitro and in vivo test systems, including the mouse lymphoma assay, micronucleus test, and bacterial mutation tests. Cefuroxime produced positive results in the in vitro chromosome aberration assay. Studies have not been performed to date to evaluate the carcinogenic potential of cefuroxime.

Pregnancy, Fertitlity and Lactation

Reproduction studies in mice and rabbits using cefuroxime sodium in dosages up to 6 and 2 times the usual human dosage based on mg/m2, respectively, and reproduction studies in mice and rats using cefuroxime axetil in dosages up to 14 and 9 times, respectively, the usual human dosage based on mg/m2 have not revealed evidence of impaired fertility or harm to the fetus.

There are no adequate and controlled studies to date using cefuroxime in pregnant women, and cefuroxime axetil and cefuroxime sodium should be used during pregnancy only when clearly needed. Cefuroxime axetil has not been studied for use during labor and delivery.

Because cefuroxime is distributed into milk, cefuroxime axetil and cefuroxime sodium should be used with caution in nursing women.

Drug Interactions

Probenecid

Oral probenecid administered shortly before or concomitantly with cefuroxime usually slows the rate of tubular secretion of cefuroxime and produces higher and more prolonged serum concentrations of cefuroxime. This effect is usually used to therapeutic advantage in the treatment of gonorrhea.

Peak serum concentrations of cefuroxime and the half-life of the drug are reportedly increased by up to 30% when probenecid is administered concomitantly; the area under the concentration-time curve (AUC) of cefuroxime is increased by about 50%. Concomitant administration of probenecid also reportedly decreases the apparent volume of distribution of cefuroxime by about 20%.

Aminoglycosides

In vitro studies indicate that the antibacterial activity of cefuroxime and aminoglycosides may be additive or synergistic against some organisms including Enterobacter, Escherichia coli, Klebsiella, Proteus mirabilis, and Serratia marcescens.

Concurrent use of aminoglycosides and certain cephalosporins reportedly may increase the risk of nephrotoxicity during therapy. Although this effect has not been reported to date with cefuroxime, the possibility that nephrotoxicity may be potentiated should be considered if the drug is used concomitantly with an aminoglycoside.

Other Drugs

The manufacturers state that cefuroxime should be used with caution in patients receiving diuretics because concurrent use of these drugs may increase the risk of adverse renal effects.

Laboratory Test Interferences

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have been reported in a few patients receiving cefuroxime axetil or cefuroxime sodium. This reaction may interfere with hematologic studies or transfusion cross-matching procedures.

Tests for Glucose

Like most other cephalosporins, cefuroxime reportedly causes false-positive results in urine glucose determinations using cupric sulfate solution (Benedict’s reagent, Clinitest®); however, glucose oxidase tests (Clinistix®) are unaffected by the drug.

Cefuroxime may cause false-negative results when ferricyanide methods are used to determine blood glucose concentrations.

Tests for Creatinine

Although some cephalosporins reportedly cause falsely elevated serum or urine creatinine values when the Jaffe reaction is used, cefuroxime does not appear to interfere with this laboratory test.

Acute Toxcicity

Limited information is available on the acute toxicity of cefuroxime in humans.

Overdosage of cephalosporins can cause CNS irritation leading to seizures. If acute overdosage of cefuroxime occurs, hemodialysis and/or peritoneal dialysis can be used to enhance elimination of the drug from the body.

Mechanism of Action

Cefuroxime is usually bactericidal in action. Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall. For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06.

Spectrum Based on its spectrum of activity, cefuroxime is classified as a second generation cephalosporin. For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

Like other currently available second generation cephalosporins (e.g., cefaclor, cefamandole, cefprozil), cefuroxime generally is more active in vitro against gram-negative bacteria than first generation cephalosporins but has a narrower spectrum of activity against gram-negative bacteria than third generation cephalosporins.

The spectrum of activity of cefuroxime resembles that of cefamandole and, to a lesser extent, that of cefoxitin. Cefuroxime is more resistant to hydrolysis by b-lactamases than cefamandole and is active against some strains of gram-negative bacteria (e.g., Escherichia coli, Enterobacter, Klebsiella, Neisseria) that are resistant to cefamandole. Cefoxitin is active against several organisms that generally are resistant to cefuroxime (e.g., Serratia marcescens, Proteus vulgaris, Bacteroides fragilis).

In Vitro Susceptibility Testing

Results of in vitro cefuroxime susceptibility tests are not generally affected by inoculum size, culture media, presence of serum, or pH. However, results of susceptibility tests for some gram-negative bacilli (e.g., Morganella morganii, Bacteroides fragilis, Serratia) may be affected by the size of the inoculum.

Different interpretive criteria are used for defining in vitro susceptibility of certain organisms to cefuroxime axetil and cefuroxime sodium, and the appropriate zone diameter or MIC categories should be used when determining whether or not an isolate is susceptible to the parenteral or oral preparation of the drug.

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to cefuroxime, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to cefuroxime, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.

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

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

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to cefuroxime axetil and cefuroxime sodium, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug. In addition, NCCLS currently recommends that non-b-lactamase-producing strains of H. influenzae that are resistant to ampicillin (BLNAR H. influenzae) should be considered resistant to cefuroxime despite the fact that results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to cefuroxime axetil or cefuroxime sodium, a disk containing 30 mcg of cefuroxime should be used. The cephalosporin class disk containing 30 mcg of cephalothin should not be used to test susceptibility to cefuroxime.

When disk-diffusion susceptibility test is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterobacteriaceae with growth inhibition zones of 18 mm or greater are susceptible to parenteral cefuroxime sodium, those with zones of 15-17 have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug. When disk-diffusion susceptibility test is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus with growth inhibition zones of 23 mm or greater are susceptible to oral cefuroxime axetil, those with zones of 15-22 have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug.

Staphylococcus with growth inhibition zones of 18 mm are susceptible to parenteral cefuroxime sodium, those with zones of 15-17 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 20 mm or greater should are susceptible to oral cefuroxime axetil or parenteral cefuroxime sodium, those with zones of 17-19 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drugs.

When disk-diffusion susceptibility testing is performed according the NCCLS standardized procedures using GC agar (with 1% defined growth supplement), N. gonorrhoeae with growth inhibition zones of 31 mm or greater are susceptible to parenteral cefuroxime sodium, those with zones of 26-30 mm have intermediate susceptibility, and those with zones of 25 mm or less are resistant to the drug. Interpretive criteria are not available to determine susceptibility of streptococci (including S. pneumoniae) to cefuroxime using the disk-diffusion procedure, and NCCLS suggests that in vitro susceptibility of these organisms to cefuroxime is best assessed using a dilution procedure.

NCCLS states that S. pneumoniae found to be susceptible to penicillin using an oxacillin disk and the NCCLS standardized procedure for disk susceptibility testing can be considered susceptible to cefuroxime. In addition, b-hemolytic streptococci or viridans streptococci found to be susceptible to penicillin using NCCLS standardized disk procedure may be considered susceptible to cefuroxime.

Dilution Susceptibility Tests

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

When dilution susceptibility tests are performed according to NCCLS standardized procedures, Staphylococcus with MICs of 4 mcg/mL or less are susceptible to oral cefuroxime axetil, those with MICs of 8-16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug. Staphylococcus with MICs of 8 mcg/mL or less are susceptible to parenteral cefuroxime sodium, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICS of 32 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing for Haemophilus is performed according to NCCLS standardized procedures using HTM, Haemophilus with MICs of 4 mcg/mL or less are susceptible to oral cefuroxime axetil or parenteral cefuroxime sodium, those with MICs of 8 mcg/mL have intermediate susceptibility, and those with MICs of 16 mcg/mL or greater are resistant to the drugs.

When dilution susceptibility testing for N. gonorrhoeae is performed according to the NCCLS standardized procedure using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with MICs of 1 mcg/mL or less are susceptible to parenteral cefuroxime sodium, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.

When broth dilution susceptibility testing for S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), S. pneumoniae with MICs of 0.5 mcg/mL or less are susceptible to parenteral cefuroxime sodium, those with MICs of 1 mcg/mL have intermediate susceptibility, and those with MICs of 2 mcg/mL or greater are resistant to the drug. S. pneumoniae with MICs of 1 mcg/mL or less are susceptible to oral cefuroxime axetil, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL are resistant to the drug. NCCLS states that b-hemolytic streptococci or viridans streptococci found to be susceptible to penicillin using the NCCLS standardized broth dilution procedure can be considered susceptible to cefuroxime.

Gram-positive Aerobic Bacteria

In vitro, cefuroxime concentrations of 0.5-1 mcg/mL inhibit most strains of Staphylococcus aureus (including penicillinase-producing and nonpenicillinase-producing strains) and concentrations of 1-2 mcg/mL inhibit most strains of S. epidermidis. Most strains of staphylococci resistant to penicillinase-resistant penicillins also are resistant to cefuroxime. In vitro, a-hemolytic and b-hemolytic streptococci are usually inhibited by cefuroxime concentrations of 0.05-0. mcg/mL and Streptococcus pneumoniae is usually inhibited by concentrations of 0.01-0. mcg/mL. Most strains of enterococci, including E. faecalis (formerly S. faecalis), are generally resistant to cefuroxime. Listeria monocytogenes is also generally resistant to cefuroxime.

Gram-negative Aerobic Bacteria

Cefuroxime is active in vitro against most gram-negative aerobic cocci and many gram-negative aerobic bacilli including Enterobacteriaceae. Pseudomonas aeruginosa is resistant to cefuroxime. Acinetobacter calcoaceticus is also usually resistant to the drug. Generally, cefuroxime is active in vitro against the following Enterobacteriaceae: Citrobacter diversus, C. freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii (formerly Proteus inconstans group B), Salmonella, and Shigella. Although cefuroxime is active in vitro against some strains of Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), and Proteus vulgaris, most strains of these organisms are resistant to the drug. In addition, Enterobacter cloacae, Pseudomonas, Campylobacter spp., Providencia, and most strains of Serratia are usually resistant to cefuroxime.

Most susceptible Enterobacteriaceae are inhibited in vitro by cefuroxime concentrations of 1-12. mcg/mL. In vitro on a weight basis, the activity of cefuroxime against susceptible Enterobacteriaceae is approximately equal to that of cefoxitin but less than that of cefotaxime or ceftizoxime. Cefuroxime may be active in vitro against some strains of E. aerogenes that are resistant to cefoxitin; however, cefotaxime, ceftizoxime, and, to a lesser extent, cefoxitin may be active in vitro against some strains of P. vulgaris and Serratia resistant to cefuroxime.

Cefuroxime is active in vitro against Haemophilus influenzae (including ampicillin-resistant strains) and H. parainfluenzae. Most susceptible strains of H. influenzae are inhibited in vitro by cefuroxime concentrations of 0.1-2 mcg/mL. Cefuroxime is active in vitro against Neisseria gonorrhoeae (including both penicillinase-producing and nonpenicillinase-producing strains) and N. meningitidis.

The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of cefuroxime reported for N. gonorrhoeae (including both penicillinase-producing and nonpenicillinase-producing strains) is 0.1-0. mcg/mL.

Anaerobic Bacteria

Cefuroxime is active in vitro against some anaerobic bacteria including Actinomyces, Eubacterium, Fusobacterium, Lactobacillus, Peptococcus, Peptostreptococcus, Propionibacterium, and Veillonella. Cefuroxime is active in vitro against some strains of Clostridium; however, C. difficile is usually resistant to the drug. Most susceptible anaerobes are inhibited in vitro by cefuroxime concentrations of 0.5-16 mcg/mL. Although cefuroxime concentrations of 16 mcg/mL inhibit some strains of Bacteroides fragilis in vitro, most strains of the organism are resistant to the drug.

Spirochetes

Cefuroxime is active in vitro and in vivo against Borrelia burgdorferi, the causative organism of Lyme disease. In vitro, the MIC of cefuroxime for B. burgdorferi reportedly is 0.13 mcg/mL and the minimum bactericidal concentration (MBC) is 1 mcg/mL.

Resistance

For information on possible mechanisms of bacterial resistance to cephalosporins, see Resistance in the Cephalosporins General Statement 8:12.06. Because cefuroxime contains a methoxyimino group that protects the b-lactam ring from hydrolysis by many penicillinases and cephalosporinases, the drug is more resistant to hydrolysis by b-lactamases than are first generation cephalosporins or cefamandole.

Cefuroxime is generally resistant to hydrolysis by b-lactamases classified as Richmond-Sykes types I, II, III, IV, and V2, 6, 13, 23, 30 and most b-lactamases produced by Neisseria gonorrhoeae, Haemophilus influenzae, and staphylococci.

However, cefuroxime is hydrolyzed by b-lactamases produced by B. fragilis and some type I b-lactamases produced by Serratia, P. vulgaris, and P. rettgeri. Results of one in vitro study indicate that cefuroxime is hydrolyzed more rapidly than cefotaxime by b-lactamases produced by P. vulgaris and B. fragilis. Although cefuroxime is resistant to hydrolysis by b-lactamases produced by Ps. aeruginosa, these organisms are resistant to cefuroxime because the drug cannot penetrate their cell wall.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, cefuroxime was administered orally as the 1-(acetyloxy)ethyl ester (i.e., cefuroxime axetil) and parenterally as the sodium salt; dosages and concentrations of the drug are expressed in terms of cefuroxime. Because cefuroxime axetil is hydrolyzed rapidly (t1/2: 3.5 minutes) in vitro in blood or serum, some clinicians recommend that acetonitrile be added immediately to blood or serum samples intended for pharmacokinetic determinations of the drug in order to prevent further hydrolysis and resultant falsely high concentrations of active drug.

Absorption

Cefuroxime Axetil

Following oral administration of cefuroxime axetil, the drug is absorbed as the 1-(acetyloxy)ethyl ester from the GI tract and rapidly hydrolyzed to cefuroxime by nonspecific esterases in the intestinal mucosa and blood.

Cefuroxime remaining within the intestinal lumen following hydrolysis of the ester is not absorbed appreciably. The drug has little, if any, microbiologic activity until hydrolyzed in vivo to cefuroxime. Bioavailability following oral administration of cefuroxime axetil is variable and depends on the formulation used and presence of food in the GI tract.

Many published studies on the pharmacokinetics of the drug used various formulations that provided poorer bioavailability than the currently available tablets and cannot be used to provide information on the currently available preparation. When tested in healthy adults, the bioavailability of cefuroxime axetil oral suspension was found not to be equivalent to that of cefuroxime axetil tablets. Mean area under the concentration-time curve (AUC) for the oral suspension was 91% of the AUC for the tablets, and the mean peak plasma concentration of cefuroxime following administration of the cefuroxime axetil oral suspension was 71% of that achieved following administration of cefuroxime axetil tablets.

Therefore, cefuroxime axetil oral suspension and tablet formulations are not substitutable on a mg/mg basis. (See Dosage: Pediatric Dosage in Dosage and Administration.) In adults, bioavailability of cefuroxime following oral administration of commercially available cefuroxime axetil tablets averages about 37% when given in the fasting state and 52% when given with or shortly after food. Absorption of the drug is increased when given with milk or infant formula. In one study, the extent but not the rate of absorption was substantially greater when the drug was administered concomitantly with milk compared with applesauce or fasting.

Following oral administration in adults of a single 125-mg, 250-mg, 500-mg, or 1-g dose of commercially available cefuroxime axetil tablets immediately following a meal, peak serum cefuroxime concentrations are attained approximately 2-3 hours after the dose and average 2.1, 4.1, 7, or 13. mcg/mL, respectively; serum concentrations 6 hours after the dose average 0.3, 0.7, 2.2, or 3.4 mcg/mL, respectively.

AUC of the drug in these individuals averaged 6.7, 12.., or 50 mcg-h/mL, respectively. Results of a study in healthy adults indicate that cefuroxime axetil oral suspensions containing 125 mg/5 mL or 250 mg/5 mL are bioequivalent. In healthy adults who received a 250-mg dose of cefuroxime axetil given as a suspension containing 125 mg/5 mL or 250 mg/5 mL with food, peak plasma concentrations of cefuroxime were 2.4 or 2.2 mcg/mL, respectively, and were attained 3 hours after the dose. In pharmacokinetic studies of cefuroxime axetil oral suspension in children, the drug was administered postprandially or with food; no data are available regarding absorption of the suspension in fasting children.

Following oral administration to children 3 months to 12 years of age (mean age: 23 months) of a single 10-, 15-, or 20-mg/kg dose of commercially available cefuroxime axetil oral suspension concomitantly with milk or milk products, peak serum cefuroxime concentrations are attained approximately 3.6, 2.7, or 3.1 hours after the dose, respectively, and average 3.3, 5.1, or 7 mcg/mL, respectively.

Cefuroxime Sodium

Cefuroxime sodium is not appreciably absorbed from the GI tract and must be given parenterally. Following IM administration of a single 500-mg, 750-mg, or 1-g dose of cefuroxime in healthy adults with normal renal function, peak serum concentrations of the drug are attained within 15-60 minutes and range from 20.-25.-34., and 32-40 mcg/mL, respectively.

In one study following IM administration of a single 750-mg dose of cefuroxime in healthy adults, serum concentrations of the drug averaged 32-40 mcg/mL 40 minutes after the dose, 19. mcg/mL 2 hours after the dose, 6.1 mcg/mL 4 hours after the dose, 1.5 mcg/mL 6 hours after the dose, and 0.7 mcg/mL 8 hours after the dose. IM injection of a single 1.5-g dose of the drug reportedly results in peak serum concentrations averaging 46 mcg/mL.

Mean peak serum concentrations of cefuroxime and the areas under the concentration-time curve (AUC) are not substantially different after IM injection of cefuroxime as a suspension or as a solution.

The AUC of cefuroxime is proportional to the dose administered and is similar following IM or IV administration of the drug. In one preliminary study in women, serum concentrations of cefuroxime were lower when IM injections of the drug were given into the gluteus maximus than when the same dose was given into the thigh. In one study in healthy adults with normal renal function, a single 500-mg or 1-g dose of cefuroxime given by IV injection over 3 minutes resulted in serum concentrations of cefuroxime that averaged 66. and 99. mcg/mL, respectively, immediately after the injection; serum concentrations of the drug averaged 2.1 and 3.6 mcg/mL, respectively, 4 hours after the injection.

In another study in healthy adults with normal renal function, IV injection over 2-3 minutes of a single 750-mg dose of cefuroxime resulted in serum concentrations of cefuroxime that averaged 52. mcg/mL 15 minutes after the injection, 24 mcg/mL 1 hour after the injection, 9.7 mcg/mL 2 hours after the injection, 3.5 mcg/mL 4 hours after the injection, and 0.5 mcg/mL 8 hours after the injection. IV infusion over 30 minutes of a single 500- or 750-mg dose of cefuroxime reportedly results in peak serum concentrations of the drug averaging 37.8 and 51. mcg/mL, respectively.

IV infusion over 1 hour of a single 750-mg or 1-g dose of cefuroxime reportedly results in peak serum concentrations of the drug averaging 38 and 64.4 mcg/mL, respectively. In one study in neonates, IM administration of a single cefuroxime dose of 25 mg/kg resulted in serum concentrations of the drug that averaged 45 mcg/mL 30 minutes after the injection, 35 mcg/mL 3 hours after the injection, and 10. mcg/mL 12 hours after the injection. IM administration of a single cefuroxime dose of 10 mg/kg in neonates younger than 3 weeks of age reportedly resulted in serum concentrations of the drug that ranged from 15-25 mcg/mL 30-60 minutes after injection.

Distribution

The apparent volume of distribution of cefuroxime in healthy adults ranges from 9.3-15.8 L/1.73 m2.

Following IM or IV administration of usual dosages of cefuroxime, the drug is widely distributed into body tissues and fluids including the kidneys, heart, gallbladder, liver, prostatic adenoma tissue, uterine and ovarian tissue, aqueous humor, saliva, sputum, bronchial secretions, bone, bile, adipose tissue, wound exudates, peritoneal fluid, ascitic fluid, synovial fluid, pericardial fluid, and pleural fluid.

Following oral administration of cefuroxime axetil in pediatric patients with acute otitis media with effusion or with chronic or recurrent otitis media with effusion, cefuroxime is distributed into middle ear effusions. In a study in pediatric patients 1-4 years of age with acute otitis media with effusion who received a single 15 mg/kg dose of cefuroxime as cefuroxime axetil oral suspension, cefuroxime concentrations in middle ear effusions 2-5 hours after a dose ranged from 0.2-3. mcg/mL; concurrent serum concentrations were 2.8-7.3 mcg/mL.

Cefuroxime is 33-50% bound to serum proteins. Cefuroxime concentrations in CSF are low following IV administration of usual dosages of the drug in patients with uninflamed meninges; however, therapeutic concentrations of cefuroxime may be attained following IV administration of the drug in patients with inflamed meninges. In one study in adults receiving 1-2 g of cefuroxime IV every 8 hours, the maximum CSF concentration of cefuroxime in patients with uninflamed or inflamed meninges was 0.1 or 8.28 mcg/mL, respectively.

In adults with meningitis receiving 1.5 g of cefuroxime every 6 or 8 hours, mean CSF concentrations of the drug attained within 8 hours after dosing are 6 mcg/mL (range: 1.5-13.5) or 5.2 mcg/mL (range: 2.7-8.9), respectively. In one study in children 1-4 years of age with meningitis receiving rapid IV injection of cefuroxime 50 mg/kg every 6 hours, CSF concentrations of the drug after at least 2 days of therapy ranged from 1.1-9.8 mcg/mL in CSF specimens obtained 2 hours after a dose.

In pediatric patients 4 weeks to 6.5 years of age with meningitis receiving 50 mg/kg every 6 hours, mean CSF concentrations of cefuroxime were 6.6 mcg/mL (range: 0.9-17.3). In another study in pediatric patients 7 months to 9 years of age with meningitis receiving 67-77 mg/kg every 8 hours, mean CSF concentrations of cefuroxime were 8.3 mcg/mL (range: less than 2 up to 22.). Cefuroxime readily crosses the placenta.

Amniotic fluid concentrations of cefuroxime reportedly average 17-18.6 mcg/mL 3-5.5 hours after a single 750-mg IM dose of the drug. Cefuroxime is distributed into milk.

Elimination

In adults, the serum or plasma half-life of cefuroxime following oral administration of commercially available cefuroxime axetil tablets or oral suspension ranges from 1.2-1. hours.

In adults with normal renal function, the serum half-life of cefuroxime following IM or IV administration reportedly ranges from 1-2 hours. In adults, approximately 50% of an administered dose of cefuroxime axetil is recovered in the urine within 12 hours. In patients with renal impairment, the serum half-life of the drug is prolonged and generally ranges from 1.9-16. hours depending on the degree of impairment. In one study, the serum half-life of cefuroxime was 1 hour in patients with creatinine clearances of 50-79 mL/minute, 2.55 hours in patients with creatinine clearances of 25-46 mL/minute, 5.1 hours in patients with creatinine clearances of 10-24 mL/minute, and 14.8 hours in patients with creatinine clearances less than 10 mL/minute.

A serum half-life of 15-22 hours has been reported in anuric patients. In neonates and children, the serum half-life of cefuroxime is inversely proportional to age. Following oral administration of cefuroxime axetil oral suspension in children 3 months to 12 years of age, the serum half-life of cefuroxime averages 1.4-1. hours.

The serum half-life of cefuroxime following IM or IV administration is reportedly 5.1-5. hours in neonates 3 days of age or younger, 2-4. hours in neonates 6-14 days of age, and 1-1. hours in neonates 3-4 weeks of age.

The manufacturer of Ceftin® states that the urinary pharmacokinetics of cefuroxime axetil have not been determined in children and that the renal pharmacokinetics of cefuroxime axetil as established in the adult population should not be extrapolated to children.

Following oral administration, cefuroxime axetil is rapidly hydrolyzed to cefuroxime by nonspecific esterases in the intestinal mucosa and blood; the axetil moiety is metabolized to acetaldehyde and acetic acid. Cefuroxime is not metabolized and is excreted unchanged principally in urine by both glomerular filtration and tubular secretion. In adults with normal renal function, 90-100% of a single IM or IV dose of cefuroxime is excreted unchanged in urine within 24 hours; most of the dose is excreted within the first 6 hours following administration.

Following IM administration of a single 750-mg dose of cefuroxime, urinary concentrations of the drug average 1.3 mg/mL in urine collected during the first 8 hours after administration.

Urinary concentrations of cefuroxime average 1.15 or 2.5 mg/mL in urine collected over the first 8 hours following IV administration of a single 750-mg or 1.5-g dose of the drug, respectively.

Concomitant administration of probenecid competitively inhibits renal tubular secretion of cefuroxime and produces higher and more prolonged serum concentrations of the drug. (See Drug Interactions: Probenecid.) Cefuroxime is removed by hemodialysis and by peritoneal dialysis.

Chemistry and Stability

Chemistry

Cefuroxime is a semisynthetic cephalosporin antibiotic. cefuroxime contains a methoxyimino group at position 7 on the b-lactam ring and also contains a carbamate group at position 3 on the ring. The methoxyimino group results in stability against hydrolysis by many b-lactamases and the carbamate group results in metabolic stability. Cefuroxime is commercially available for parenteral administration as the sodium salt.

The drug is commercially available for oral administration as film-coated tablets or as a powder for suspension of cefuroxime axetil, the 1-(acetyloxy)ethyl ester of the drug. Potency of cefuroxime sodium and cefuroxime axetil is expressed in terms of cefuroxime.

Cefuroxime Axetil

Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. Esterification of the carboxyl C-4 group of cefuroxime results in a more lipophilic and readily absorbable (from the GI tract) form of the drug.

Cefuroxime axetil occurs as a white to cream-colored, amorphous powder.

Cefuroxime Sodium

Cefuroxime sodium occurs as a white to off-white powder. The drug has solubilities of about 200 mg/mL in water and 1 mg/mL in alcohol. The drug has a pKa of 2.45. The sodium salt of cefuroxime contains 2.4 mEq of sodium per gram of cefuroxime.

Following reconstitution, cefuroxime sodium solutions are light yellow to amber in color and have a pH of 6-8.5, depending on the concentration of the drug and the diluent used. Reconstitution of cefuroxime sodium sterile powder for injection to provide a final concentration of 208 mg/mL results in the formation of a suspension; dilution to at least 100 mg/mL effects complete dissolution of the drug.

Commercially available frozen cefuroxime sodium injections are light yellow- to amber-colored, nonpyrogenic, sterile solutions of the drug and have osmolalities of approximately 300 mOsm/kg; about 1.4 g of dextrose has been added to the 750-mg injection of cefuroxime sodium to adjust osmolality. Cefuroxime sodium frozen injections also contain anhydrous sodium citrate as buffer and hydrochloric acid and/or sodium hydroxide to adjust pH to 5-7.5.

Stability

Cefuroxime Axetil

Cefuroxime axetil tablets should be stored in tight containers at 15-30°C. The drug should be protected from excessive moisture. When cefuroxime axetil tablets are allowed to disintegrate in apple juice, the drug is stable for 24 hours at room temperature. Commercially available cefuroxime axetil powder for oral suspension should be stored at 2-30°C. Following reconstitution, oral suspensions of cefuroxime axetil containing 125 mg/5 mL or 250 mg/5 mL should be stored at 2-25°C (i.e., in a refrigerator or at room temperature). Any unused oral suspension should be discarded after 10 days.

Cefuroxime Sodium

Commercially available cefuroxime sodium sterile powder for injection should be stored at 15-30°C and protected from light. The commercially available frozen cefuroxime sodium injection should be stored at a temperature not greater than -20°C. Cefuroxime sodium sterile powder and solutions of the drug tend to darken, depending on storage conditions; however, this discoloration does not necessarily indicate a change in potency.

Following reconstitution with sterile water for injection, cefuroxime sodium solutions containing 90-100 mg of cefuroxime per mL or suspensions containing 200-220 mg of the drug per mL are stable for 24 hours at room temperature or 48 hours at 5°C. Following reconstitution of 750-mg or 1.5-g piggyback infusion packs of cefuroxime with sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, solutions containing 7.5-15 mg of cefuroxime per mL are stable for 24 hours at room temperature or 7 days at 5°C.

Following reconstitution of 750-mg or 1.5-g ADD-Vantage® vials of cefuroxime with 5% dextrose injection, 0.9% sodium chloride injection, or 0.45% sodium chloride injection, solutions containing 7.5-15 mg of cefuroxime per mL are stable for 24 hours at room temperature or 7 days under refrigeration; joined ADD-Vantage® vials that have not been activated may be used within a 14-day period.

Cefuroxime sodium is chemically and physically compatible with the following IV solutions: 0.9% sodium chloride; Ringer’s; lactated Ringer’s; 5% dextrose; 5% dextrose and 0.2%, 0.45%, or 0.9% sodium chloride; 10% dextrose; 10% invert sugar; or 1/6 M sodium lactate. Reconstituted solutions of cefuroxime that have been further diluted to a concentration of 1-30 mg/mL with one of the above IV solutions are stable for 24 hours at room temperature or at least 7 days at 5°C. The manufacturer of Zinacef® states that cefuroxime sodium solutions may be frozen; however, Zinacef® solutions in ADD-Vantage® vials should not be frozen.

Following reconstitution of vials labeled as containing 750 mg or 1.5 g of cefuroxime with 8 or 16 mL, respectively, of sterile water for injection, the entire contents from the vials should be immediately withdrawn and added to Viaflex® minibags containing 50 or 100 mL of 0.9% sodium chloride injection or 5% dextrose injection; alternatively, 8 or 16 mL of reconstituted solution can be withdrawn from the 7.5-g pharmacy bulk package and added to any of these minibags.

These extemporaneously prepared solutions are stable for 6 months when frozen at -20°C. After thawing at room temperature, these solutions are stable for 24 hours at room temperature or 7 days at 5°C.

Frozen solutions of cefuroxime should be thawed at room temperature and should not be refrozen. The manufacturer states that the stability of the commercially available frozen cefuroxime sodium injection may vary.

These injections are stable for at least 90 days from the date of shipment when stored at -20°C. Thawed solutions of the commercially available frozen injection are stable for 24 hours at room temperature (25°C) or 28 days when refrigerated at 5°C. The frozen injection may be thawed at room temperature or under refrigeration and, once thawed, should not be refrozen.

The commercially available frozen injection of the drug is provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy® containers).

Solutions in contact with PL 2040 can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Cefuroxime sodium is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).

Specialized references should be consulted for specific compatibility information. Admixtures in 0.9% sodium chloride injection containing cefuroxime sodium and heparin (10 or 50 units/mL) or potassium chloride (10 or 40 mEq/L) are stable for 24 hours at room temperature.

The manufacturer of Zinacef® states that cefuroxime sodium not be diluted with sodium bicarbonate injection. Because of the potential for incompatibility, the manufacturers state that cefuroxime sodium and aminoglycosides should not be admixed. For further information on chemistry, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of cefuroxime, see the Cephalosporins General Statement 8:12.06.

Preparations

Cefuroxime Axetil Oral For Suspension 125 mg (of cefuroxime) per 5 Ceftin®, (with povidone) mL GlaxoSmithKline 250 mg (of cefuroxime) per 5 Ceftin®, (with povidone) mL GlaxoSmithKline Tablets, film- 125 mg (of cefuroxime) Ceftin®, (with parabens and coated propylene glycol) GlaxoSmithKline 250 mg (of cefuroxime) Ceftin®, (with parabens and propylene glycol) GlaxoSmithKline 500 mg (of cefuroxime) Ceftin®, (with parabens and propylene glycol) GlaxoSmithKline Cefuroxime Sodium Parenteral For injection 750 mg (of cefuroxime) Cefuroxime Sodium For Injection, American Pharmaceutical Partners Sandoz Kefurox®, Lilly Zinacef®, GlaxoSmithKline 1.5 g (of cefuroxime) Cefuroxime Sodium For Injection, American Pharmaceutical Products Sandoz Kefurox®, Lilly Zinacef®, GlaxoSmithKline 7.5 g (of cefuroxime) Cefuroxime Sodium For pharmacy bulk package Injection, American Pharmaceutical Products Sandoz Kefurox®, Lilly Zinacef®, GlaxoSmithKline For injection, for 750 mg (of cefuroxime) Kefurox®, IV infusion Lilly Kefurox® ADD-Vantage®, Lilly Zinacef® ADD-Vantage®, GlaxoSmithKline Zinacef® Infusion Pack, GlaxoSmithKline 1.5 g (of cefuroxime) Kefurox®, Lilly Kefurox® ADD-Vantage®, Lilly Zinacef® ADD-Vantage®, GlaxoSmithKline Zinacef® Infusion Pack, GlaxoSmithKline Cefuroxime Sodium in Dextrose Parenteral Injection (frozen) 15 mg (of cefuroxime) per mL Zinacef® in Iso-osmotic , for IV infusion (750 mg) in 2.8% Dextrose Dextrose Injection, (Galaxy® [Baxter]) GlaxoSmithKline Cefuroxime Sodium in Water Parenteral Injection (frozen) 30 mg (of cefuroxime) per mL Zinacef® Iso-osmotic in , for IV infusion (1. g) Sterile Water Injection, (Galaxy® [Baxter])