Cefuroxime for Injection, USP

Cefuroxime has in vitro activity against a wide range of gram-positive and gram-negative organisms, and it is highly stable in the presence of beta-lactamases of certain gram-negative bacteria. The bactericidal action of cefuroxime results from inhibition of cell-wall synthesis.

Cefuroxime is usually active against the following organisms in vitro.

Aerobes, Gram-positive:Staphylococcusaureus; Staphylococcus epidermidis; Streptococcus pneumoniae; and Streptococcus pyogenes (and other streptococci). NOTE: Most strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci and Listeria monocytogenes are resistant to cefuroxime.

Aerobes, Gram-negative:Citrobacter spp.,Enterobacter spp.,Escherichia coli,Haemophilus influenzae (including ampicillin-resistant strains), Haemophilusparainfluenzae, Klebsiella spp. (including Klebsiella pneumoniae), Moraxella (Branhamella) catarrhalis (including ampicillin- and cephalothin-resistant strains), Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase- and non-penicillinase-producing strains), Neisseria meningitidis, Proteusmirabilis, Providencia rettgeri (formerly Proteus rettgeri), Salmonella spp., and Shigella spp.

NOTE: Some strains of Morganella morganii, Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins. Pseudomonas and Campylobacter spp., Legionella spp., Acinetobacter calcoaceticus, and most strains of Serratia spp. and Proteus vulgaris are resistant to most first- and second-generation cephalosporins.

Anaerobes: Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.), gram-positive bacilli (including Clostridium spp.), and gram-negative bacilli (including Bacteroides and Fusobacterium spp.).

NOTE: Clostridium difficile and most strains of Bacteroides fragilis are resistant to cefuroxime.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters give an estimate of antibiotic susceptibility. One such standard procedure¹ that has been recommended for use with disks to test susceptibility of organisms to cefuroxime uses the 30 mcg cefuroxime disk. Interpretation involves the correlation of the diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for cefuroxime.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “Moderately Susceptible” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained. A report of “Intermediate” suggests an equivocable or indeterminate result. A report of “Resistant” indicates that achievable concentrations of the antibiotic are unlikely to be inhibitory and other therapy should be selected.

Reports from the laboratory giving results of the standard single-disk susceptibility test for organisms other than Haemophilus spp. and Neisseria gonorrhoeae with a 30 mcg cefuroxime disk should be interpreted according to the following criteria:

 Results for Haemophilus spp. should be interpreted according to the following criteria:

 Results for Neisseria gonorrhoeae should be interpreted according to the following criteria:

 Organisms should be tested with the cefuroxime disk since cefuroxime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam disks are used. The cefuroxime disk should not be used for testing susceptibility to other cephalosporins.

Standardized procedures require the use of laboratory control organisms. The 30 mcg cefuroxime disk should give the following zone diameters.

1. Testing for organisms other than Haemophilus spp. and Neisseria gonorrhoeae:

 2. Testing for Haemophilus spp.:

 3. Testing for Neisseria gonorrhoeae:

 Dilution Techniques: Use a standardized dilution method¹ (broth, agar, microdilution) or equivalent with cefuroxime powder. The MIC values obtained for bacterial isolates other than Haemophilus spp. and Neisseria gonorrhoeae should be interpreted according to the following criteria:

 MIC values obtained for Haemophilus spp. should be interpreted according to the following criteria:

 MIC values obtained for Neisseria gonorrhoeae should be interpreted according to the following criteria:

 As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard cefuroxime powder should provide the following MIC values.

1. For organisms other than Haemophilus spp. and Neisseria gonorrhoeae:

 2. For Haemophilus spp:

 3. For Neisseria gonorrhoeae:

Although Cefuroxime for Injection, USP rarely produces alterations in kidney function, evaluation of renal status during therapy is recommended, especially in seriously ill patients receiving the maximum doses. Cephalosporins should be given with caution to patients receiving concurrent treatment with potent diuretics as these regimens are suspected of adversely affecting renal function.

The total daily dose of Cefuroxime for Injection, USP should be reduced in patients with transient or persistent renal insufficiency (see DOSAGE AND ADMINISTRATION), because high and prolonged serum antibiotic concentrations can occur in such individuals from usual doses.

As with other antibiotics, prolonged use of Cefuroxime for Injection, USP may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

As with other therapeutic regimens used in the treatment of meningitis, mild-to-moderate hearing loss has been reported in a few pediatric patients treated with cefuroxime. Persistence of positive CSF (cerebrospinal fluid) cultures at 18 to 36 hours has also been noted with cefuroxime injection, as well as with other antibiotic therapies; however, the clinical relevance of this is unknown.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous Vitamin K administered as indicated.

Prescribing Cefuroxime for Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Patients should be counseled that antibacterial drugs, including Cefuroxime for Injection, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefuroxime for Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefuroxime for Injection, USP or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

In common with other antibiotics, cefuroxime may affect the gut flora, leading to lower estrogen reabsorption and reduce efficacy of combined estrogen/progesterone oral contraceptives.

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict’s or Fehling’s solution or with CLINITEST^® tablets) but not with enzyme-based tests for glycosuria. As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving Cefuroxime for Injection, USP.

Cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

Although lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime in the mouse lymphoma assay and a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay, however, negative results were found in an in vivo micronucleus test at doses up to 10 g/kg. Reproduction studies in mice at doses up to 3,200 mg/kg per day (3.1 times the recommended maximum human dose based on mg/m²) have revealed no impairment of fertility.

Reproductive studies revealed no impairment of fertility in animals.

Since cefuroxime is excreted in human milk, caution should be exercised when Cefuroxime for Injection, USP is administered to a nursing woman.

Safety and effectiveness in pediatric patients below 3 months of age have not been established. Accumulation of other members of the cephalosporin class in newborn infants (with resulting prolongation of drug half-life) has been reported.

Of the 1,914 subjects who received cefuroxime in 24 clinical studies of Cefuroxime for Injection, USP, 901 (47%) were 65 and over while 421 (22%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with Cefuroxime for Injection, USP and were reported spontaneously. Data are generally insufficient to allow an estimate of incidence or to establish causation.

Immune System Disorders: Cutaneous vasculitis.

Neurologic:Seizure.

Non-site Specific: Angioedema.

In addition to the adverse reactions listed above that have been observed in patients treated with cefuroxime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:

Adverse Reactions: Vomiting, abdominal pain, colitis, vaginitis including vaginal candidiasis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage.

Several cephalosporins, including Cefuroxime for Injection, USP, have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION). If seizures associated with drug therapy should occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Altered Laboratory Tests: Prolonged prothrombin time, pancytopenia, agranulocytosis.

To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Adults: The usual adult dosage range for Cefuroxime for Injection, USP is 750 mg to 1.5 grams every 8 hours, usually for 5 to 10 days. In uncomplicated urinary tract infections, skin and skin structure infections, disseminated gonococcal infections, and uncomplicated pneumonia, a 750 mg dose every 8 hours is recommended. In severe or complicated infections, a 1.5 gram dose every 8 hours is recommended.

In bone and joint infections, a 1.5 gram dose every 8 hours is recommended. In clinical trials, surgical intervention was performed when indicated as an adjunct to therapy with Cefuroxime for Injection, USP. A course of oral antibiotics was administered when appropriate following the completion of parenteral administration of Cefuroxime for Injection, USP.

In life-threatening infections or infections due to less susceptible organisms, 1.5 grams every 6 hours may be required. In bacterial meningitis, the dosage should not exceed 3 grams every 8 hours. The recommended dosage for uncomplicated gonococcal infection is 1.5 grams given intramuscularly as a single dose at 2 different sites together with 1 gram of oral probenecid. For preventive use for clean-contaminated or potentially contaminated surgical procedures, a 1.5 gram dose administered intravenously just before surgery (approximately one-half to 1 hour before the initial incision) is recommended. Thereafter, give 750 mg intravenously or intramuscularly every 8 hours when the procedure is prolonged.

For preventive use during open heart surgery, a 1.5 gram dose administered intravenously at the induction of anesthesia and every 12 hours thereafter for a total of 6 grams is recommended.

Impaired Renal Function: A reduced dosage must be employed when renal function is impaired. Dosage should be determined by the degree of renal impairment and the susceptibility of the causative organism (see Table 2).

When only serum creatinine is available, the following formula² (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

NOTE: As with antibiotic therapy in general, administration of Cefuroxime for Injection, USP should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended in infections caused by Streptococcus pyogenes in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment for several weeks; and doses smaller than those indicated above should not be used. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

Pediatric Patients Above 3 Months of Age: Administration of 50 to 100 mg/kg per day in equally divided doses every 6 to 8 hours has been successful for most infections susceptible to cefuroxime. The higher dosage of 100 mg/kg per day (not to exceed the maximum adult dosage) should be used for the more severe or serious infections.

In bone and joint infections, 150 mg/kg per day (not to exceed the maximum adult dosage) is recommended in equally divided doses every 8 hours. In clinical trials, a course of oral antibiotics was administered to pediatric patients following the completion of parenteral administration of Cefuroxime for Injection, USP.

In cases of bacterial meningitis, a larger dosage of Cefuroxime for Injection, USP is recommended, 200 to 240 mg/kg per day intravenously in divided doses every 6 to 8 hours.

In pediatric patients with renal insufficiency, the frequency of dosing should be modified consistent with the recommendations for adults.

The directions for preparing Cefuroxime for Injection, USP for both IV and IM use are summarized in Table 3.

For Intramuscular Use: Each 750 mg vial of Cefuroxime for Injection, USP should be constituted with 3 mL of Sterile Water for Injection. Shake gently to disperse and withdraw completely the resulting suspension for injection.

For Intravenous Use: Each 750 mg vial should be constituted with 8.3 mL of Sterile Water for Injection. Withdraw completely the resulting solution for injection.

Each 1.5 gram vial should be constituted with 16 mL of Sterile Water for Injection, and the solution should be completely withdrawn for injection.

Each 750 mg and 1.5 gram infusion bottle should be constituted with 100 mL of Sterile Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or any of the solutions listed under the Intravenous portion of the Compatibility and Stability section.

After constitution, Cefuroxime for Injection, USP may be given intravenously or by deep IM injection into a large muscle mass (such as the gluteus or lateral part of the thigh). Before injecting intramuscularly, aspiration is necessary to avoid inadvertent injection into a blood vessel.

Intravenous Administration: The IV route may be preferable for patients with bacterial septicemia or other severe or life-threatening infections or for patients who may be poor risks because of lowered resistance, particularly if shock is present or impending.

For direct intermittent IV administration, slowly inject the solution into a vein over a period of 3 to 5 minutes or give it through the tubing system by which the patient is also receiving other IV solutions.

For intermittent IV infusion with a Y-type administration set, dosing can be accomplished through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing Cefuroxime for Injection, USP, it is advisable to temporarily discontinue administration of any other solutions at the same site.

For continuous IV infusion, a solution of Cefuroxime for Injection, USP may be added to an IV infusion pack containing one of the following fluids: 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 1/6 M Sodium Lactate Injection.

Solutions of Cefuroxime for Injection, USP, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction.

However, if concurrent therapy with Cefuroxime for Injection, USP and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

Intramuscular: When constituted as directed with Sterile Water for Injection, suspensions of cefuroxime for IM injection maintain satisfactory potency for 24 hours at room temperature and for 48 hours under refrigeration (5°C).

After the periods mentioned above any unused suspensions should be discarded.

Intravenous: When the 750 mg and 1.5 g vials are constituted as directed with Sterile Water for Injection, the solutions Cefuroxime for Injection, USP for IV administration maintain satisfactory potency for 24 hours at room temperature and for 48 hours (750 mg and 1.5 g vials) under refrigeration (5°C). More dilute solutions, such as 750 mg or 1.5 g plus 100 mL of Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, also maintain satisfactory potency for 24 hours at room temperature and for 7 days under refrigeration.

These solutions may be further diluted to concentrations of between 1 and 30 mg/mL in the following solutions and will lose not more than 10% activity for 24 hours at room temperature or for at least 7 days under refrigeration: 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; Ringer’s Injection, USP; Lactated Ringer’s Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 10% Dextrose Injection; and 10% Invert Sugar in Water for Injection.

Unused solutions should be discarded after the time periods mentioned above.

Cefuroxime for Injection, USP has also been found compatible for 24 hours at room temperature when admixed in IV infusion with heparin (10 and 50 U/mL) in 0.9% Sodium Chloride Injection and Potassium Chloride (10 and 40 mEq/L) in 0.9% Sodium Chloride Injection. Sodium Bicarbonate Injection, USP is not recommended for the dilution of Cefuroxime for Injection, USP.

Frozen Stability: Constitute the 750 mg or 1.5 g vial as directed for IV administration in Table 3. Immediately withdraw the total contents of the 750 mg or 1.5 g vial and add to a minibag containing 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection and freeze. Frozen solutions are stable for 6 months when stored at -20°C. Frozen solutions should be thawed at room temperature and not refrozen. Do not force thaw by immersion in water baths or by microwave irradiation. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

As with other cephalosporins, Cefuroxime for Injection, USP powder as well as solutions and suspensions tend to darken, depending on storage conditions, without adversely affecting product potency.