Cefizox® (ceftizoxime for injection, USP) is a sterile, semisynthetic, broad-spectrum, betalactamase resistant cephalosporin antibiotic for parenteral (IV, IM) administration. It is the sodium salt of [6R-[6a,7B(Z)]]-7-[(2,3-dihydro-2-imino-4-thiazolyl) (methoxyimino)acetyl]amino]- 8-oxo-5-thia-i-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its sodium content is approximately 60 mg (2.6 mEq) per gram of ceftizoxime activity.

It has the following molecular formula: C₁₃H₁₂N₅NaO₅S₂ and its molecular weight is 405.38.

Ceftizoxime for injection, USP is a white to pale yellow crystalline powder. Cefizox is supplied in vials equivalent to 500 mg, 1 gram or 2 grams of ceftizoxime, and in Piggyback Vials for IV admixture equivalent to 1 gram or 2 grams of ceftizoxime.

Last updated on RxList: 12/8/2004

Cefizox (ceftizoxime for injection, USP) is indicated in the treatment of infections due to susceptible strains of the microorganisms listed below.

Lower Respiratory Tract Infections caused by Klebsiella spp.; Proteus mirabills; Escherichia coli; Haemophilus influenzae including ampicillin-resistant strains; Staphylococcus aureus (penicillinase- and nonpenicillinase-producing); Serratia spp.; Enterobacter spp.; Bacteroides spp.; and Streptococcus spp. including S. pneumoniae, but excluding enterococci.

Urinary Tract Infections caused by Staphylococcus aureus (penicillinase- and nonpenicillinase- producing); Escherichia coli; Pseudomonas spp. including P. aeruginosa; Proteus mirabilis; P. vulgaris; Providencia rettgeri (formerly Proteus rettgeri) and Morganella morganii (formerly Proteus morganil); Klebsiella spp.; Serratia spp. including S. marcescens; and Enterobacter spp.

Gonorrhea including uncomplicated cervical and urethral gonorrhea caused by Neisseria gonorrhoeae.

Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae, Escherichia coli or Streptococcus agalactiae. NOTE: Ceftizoxime, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.

Intra-Abdominal Infections caused by Escherichia coli; Staphylococcus epidermidis; Streptococcus spp. (excluding enterococci); Enterobacter spp.; Klebsiella spp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp.

Septicemia caused by Streptococcus spp. including S. pneumoniae (but excluding enterococci); Staphylococcus aureus (penicillinase-and nonpenicillinase-producing); Escherichia coli; Bacteroides spp. including B. fragilis; Klebsiella spp.; and Serratia spp.

Skin and Skin Structure Infections caused by Staphylococcus aureus (penicillinase- and nonpenicillinase-producing); Staphylococcus epidermidis; Escherichia coli; Klebsiella spp.; Streptococcus spp. including Streptococcus pyogenes (but excluding enterococci); Proteus mirabills; Serratia spp.; Enterobacterspp.; Bacteroides spp. including B. fragilis; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp.

Bone and Joint Infections caused by Staphylococcus aureus (penicillinase- and nonpenicillinase-producing); Streptococcus spp. (excluding enterococci); Proteus mirabills; Bacteroides spp.; and anaerobic cocci, including Peptococcus spp. and Peptostreptococcus spp.

Meningitis caused by Haemophilus influenzae. Cefizox has also been used successfully in the treatment of a limited number of pediatric and adult cases of meningitis caused by Streptococcus pneumoniae.

Cefizox has been effective in the treatment of seriously ill, compromised patients, including those who were debilitated, immunosuppressed, or neutropenic.

Infections caused by aerobic gram-negative and by mixtures of organisms resistant to other cephalosporins, aminoglycosides, or penicillins have responded to treatment with Cefizox.

Because of the serious nature of some urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt.

Susceptibility studies on specimens obtained prior to therapy should be used to determine the response of causative organisms to Cefizox. Therapy with Cefizox may be initiated pending results of the studies; however, treatment should be adjusted according to study findings. In serious infections, Cefizox has been used concomitantly with aminoglycosides (see PRECAUTIONS). Before using Cefizox concomitantly with other antibiotics, the prescribing information for those agents should be reviewed for contraindications, warnings, precautions, and adverse reactions. Renal function should be carefully monitored.  

The usual adult dosage is 1 or 2 grams of Cefizox (ceftizoxime for injection, USP) every 8 to 12 hours. Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organisms.
 

Because of the serious nature of urinary tract infections due to P. aeruginosa and because many strains of Pseudomonas species are only moderately susceptible to Cefizox, higher dosage is recommended. Other therapy should be instituted if the response is not prompt.

A single, 1 gram IM dose is the usual dose for treatment of uncomplicated gonorrhea.

The IV route may be preferable for patients with bacterial septicemia, localized parenchymal abscesses (such as intra-abdominal abscess), peritonitis, or other severe or life-threatening infections.

In those with normal renal function, the IV dosage for such infections is 2 to 12 grams of Cefizox (ceftizoxime for injection, USP) daily. In conditions such as bacterial septicemia, 6 to 12 grams/day may be given initially by the IV route for several days, and the dosage may then be gradually reduced according to clinical response and laboratory findings.
 

Dosage maybe increased to atotal daily dose of 200 mg/kg (not to exceed the maximum adult dose for serious infection).

Impaired Renal Function

Modification of Cefizox dosage is necessary in patients with impaired renal function. Following an initial loading dose of 500 mg-1 gram IM or IV, the maintenance dosing schedule shown below should be followed. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organisms.

When only the serum creatinine level is available, creatinine clearance may be calculated from the following formula. The serum creatinine level should represent current renal function at the steady state.

Males:
 

Females: Females are 0.85 of the calculated clearance values for males.

In patients undergoing hemodialysis, no additional supplemental dosing is required following hemodialysis; however, dosing should be timed so that the patient receives the dose (according to the table below) at the end of the dialysis.
 

Preparation of Parenteral Solution

Reconstitution:

IM Administration: Reconstitute with Sterile Water for Injection. SHAKE WELL.
 

IV Administration: Reconstitute with Sterile Water for Injection. SHAKE WELL.
 

These solutions of Cefizox are stable 24 hours at room temperature or 96 hours if refrigerated (5°C).

Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, then the drug solution should be discarded. Reconstituted solutions may range from yellow to amber without changes in potency.

Piggyback Vials: Reconstitute with 50 to 100 mL of Sodium Chloride Injection or any other IV solution listed below. SHAKE WELL.

Administer with primary IV fluids, as a single dose. These Piggyback vial solutions of Cefizox are stable 24 hours at room ternperature or 96 hours if refrigerated (5°C).

A solution of 1 gram Cefizox in 13 mL Sterile Water for Injection is isotonic.

IM Injection:

Inject well within the body of a relatively large muscle. Aspiration is necessary to avoid inadvertent injection into a blood vessel. When administering 2 gram IM doses, the dose should be divided and given in different large muscle masses.

IV Administration:

Direct (bolus) injection, slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below). Intermittent or continuous infusion, dilute reconstituted Cefizox in 50 to 100 mL of one of the following solutions:

• Sodium Chloride Injection
• 5% or 10% Dextrose Injection
• 5% Dextrose and 0.9%, 0.45%, or 0.2% Sodium Chloride Injection
• Ringer†s Injection
• Lactated Ringer†s Injection
• Invert Sugar 10% in Sterile Water for Injection
• 5% Sodium Bicarbonate in Sterile Water for Injection
• 5% Dextrose in Lactated Ringer†s Injection (only when reconstituted with 4% Sodium Bicarbonate Injection)

In these fluids, Cefizox is stable 24 hours at room temperature or 96 hours if refrigerated (5°C).

Cefizox® (ceftizoxime for injection, USP)

NDC 0469-7250-01 Product No. 725001 Equivalent to 500 mg ceftizoxime in 10 mL, single-dose, flip-top vials, individually packaged

NDC 0469-7251-01 Product No. 725101 Equivalent to 1 gram ceftizoxime in 20 mL, single-dose, flip-top vials, individually packaged

NDC 0469-7252-01 Product No. 725201 Equivalent to 1 gram ceftizoxime in 100 mL, single-dose, Piggyback, flip-top vials, packaged in tens

NDC 0469-7253-02 Product No. 725302 Equivalent to 2 grams ceftizoxime in 20 mL, single-dose, flip-top vials, individually packaged

NDC 0469-7254-02 Product No. 725402 Equivalent to 2 grams ceftizoxime in 100 mL, single-dose, Piggyback, flip-top vials, packaged in tens

Unreconstituted Cefizox should be protected from excessive light, and stored at controlled room temperature (59°-86°F)in the original package until used.

Rx only

REFERENCES

1. National Committee for Clinical Laboratory Standards, Approved Standard. Performance Standards for Antimicrobial Disk Susceptibility Test, 4th Edition, Vol 10 (7): M2-A4. Villanova, PA, April 1990.

2. National Committee for Clinical Laboratory Standards, Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 2nd Edition, Vol 10 (8): M7-A2. Villanova, PA, April 1990.

Last updated on RxList: 12/8/2004

Cefizox® (ceftizoxime for injection, USP) is generally well tolerated.

The most frequent adverse reactions (greater than 1 % but less than 5%) are:
Hypersensitivity: Rash, pruritus, fever.
Hepatic: Transient elevation in AST (SGOT), ALT (SGPT), and alkaline phosphatase.
Hematologic: Transienteosinophilia, thrombocytosis. Some individuals have developed a positive Coombs test.
Local†Injection site: Burning, cellulitis, phlebitis with IV administration, pain, induration, tenderness, paresthesia.

The less frequent adverse reactions (less than 1%) are:
Hypersensitivity: Numbness and anaphylaxis have been reported rarely.
Hepatic: Elevation of bilirubin has been reported rarely.
Renal: Transient elevations of BUN and creatinine have been occasionally observed with Cefizox.
Hematologic: Anemia, including hemolytic anemia with occasional fatal outcome, leukopenia, neutropenia, and thrombocytopenia have been reported rarely.
Urogenital: Vaginitis has occurred rarely.
Gastrointestinal: Diarrhea; nausea and vomiting have been reported occasionally.
Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment (see WARNINGS).

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

Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, serum-sickness like reaction, toxic nephropathy, aplastic anemia, hemorrhage, prolonged prothrombin. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. (See DOSAGE ANDADMINISTRATION.) If seizures associated with drug therapy occur, the drug should be discontinued.

Anticonvulsant therapy can be given if clinically indicated.
 

Although the occurrence has not been reported with Cefizox, nephrotoxicity has been reported following concomitant administration of other cephalosporins and aminoglycosides.

Last updated on RxList: 12/8/2004

BEFORE THERAPYWITH CEFIZOX IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFJZOX, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS HYPERSENSITIVITY AMONG BETA- LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFIZOX OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTA MINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftizoxime, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to theadministration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that atoxin produced by Clostridium difficile is a primary cause of † antibiotic-associated † colitis.

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

General

As with all broad-spectrum antibiotics, Cefizox (ceftizoxime for injection, USP) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Although Cefizox has not been shown to produce an alteration in renal function, renal status should be evaluated, especially in seriously ill patients receiving
maximum dose therapy. As with any antibiotic, prolonged use may result in overgrowth of nonsusceptible organisms. Careful observation is essential; appropriate
measures should be taken if superinfection occurs.

Drug Interactions

Althoughthe occurrence has not been reported with Cefizox, nephrotoxicity has been reported following concomitant administration of other cephalosporins and
aminoglycosides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of ceftizoxime have not been conducted.
In an in vitro bacterial cell assay (i.e., Ames test), there was no evidence of mutagenicity at ceftizoxime concentrations of 0.001-0.5 mcg/plate. Ceftizoxime did not produce increases in micronuclei in the in vivo mouse micronucleus test when given to animals at doses up to 7500 mg/kg, approximately six times greater than the maximum human daily dose on a mg/M 2 basis.
Ceftizoxime had no effect on fertility when administered subcutaneously to rats at daily doses of up to 1000 mg/kg/day, approximately two times the maximum human daily dose on a mg/M2 basis.
Ceftizoxime produced no histological changes in the sexual organs of male and female dogs when given intravenously for thirteen weeks at a dose of 1000 mg/kg/day, approximately five times greater than the maximum human daily dose on a mg/M2 basis.

Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to Cefizox. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human effects, this drug should be used
during pregnancy only if clearly needed.

Labor and Delivery

Safety of Cefizox use during labor and delivery has not been established.

Nursing Mothers

Cefizox is excreted in human milk in low concentrations. Caution should be exercised when Cefizox is administered to a nursing woman.

Pediatric Use

Safety and efficacy in pediatric patients from birth to six months of age have not been established. In pediatric patients six months of age and older, treatment with Cefizox has been associated with transient elevated levels of eosinophils, AST (SGOT), ALT (SGPT), and CPK (creatine phosphokinase). The CPKelevation may be related to IM administration.

The potential for the toxic effect in pediatric patients from chemicalsthat may leachfrom the single-dose IV preparation in plastic has not been determined.

Last updated on RxList: 12/8/2004

No information provided.

Cefizox (ceftizoxime for injection, USP) is contraindicated in patients who have known allergy to the drug.

Last updated on RxList: 12/8/2004

The table below demonstrates the serum levels and duration of Cefizox (ceftizoxime for injection, USP) following IM administration of 500 mg and 1 gram doses, respectively, to normal volunteers.
 

Following IV administration of 1,2, and 3 gram doses of Cefizox to normal volunteers, the following serum levels were obtained.
 

A serum half-life of approximately 1.7 hours was observed after IV or IM administration.

Cefizox is 30% protein bound.

Cefizox is not metabolized, and is excreted virtually unchanged by the kidneys in 24 hours. This provides a high urinary concentration.

Concentrations greater than 6000 mcg/mL have been achieved in the urine by 2 hours after a 1 gram dose of Cefizox intravenously. Probenecid slows tubular secretion and produces even higher serum levels, increasing the duration of measurable serum concentrations. Cefizox achieves therapeutic levels in various bodyfluids, e.g., cerebrospinal fluid (in patients with inflamed meninges), bile, surgical wound fluid, pleural fluid, aqueous humor, ascitic fluid, peritoneal fluid, prostatic fluid and saliva, and in the following bodytissues: heart, gallbladder, bone, biliary, peritoneal, prostatic, and uterine.

In clinical experience to date, no disulfiram-like reactions have been reported with Cefizox.

Microbiology

The bactericidal action of Cefizox (ceftizoxime for injection, USP) results from inhibition of cell-wall synthesis. Cefizox is highly resistant to a broad spectrum of beta-lactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic gram-positive and gram-negative organisms. Cefizox is active against a wide range of gram-positive and gram-negative organisms, and is usually active against the following organisms in vitro and in clinical situations (see NDICATIONS AND USAGE).

Gram-Positive Aerobes

Staphylococcus aureus (including penicillinase- and nonpenicillinase-producing strains) NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins, including ceftizoxi me.
Staphylococcus epidermidis (including penicillinase- and nonpenicillinase-producing strains)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

NOTE: Ceftizoxime is usually inactive against most strains of Enterococcus faecalis (formerly S. faecalis).

Acinetobacter spp.
Enterobacter spp.
Escherichia coli
Haemophilus influenzae (including ampicillin-resistant strains)
Klebsiella pneumoniae
Morganella morganii (formerly Proteus morganii)
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri (formerly Proteus rettgeri)
Pseudomonas aeruginosa
Serratia marcescens

Anaerobes

Bacteroides spp.
Peptococcus spp.
Peptostreptococcus spp.

Ceftizoxime is usually active against the following organisms in vitro, but the clinical significance of these data is unknown.

Gram-Positive Aerobes

Cotynebacterium diphtheriae

Gram-Negative Aerobes

Aeromonas hydrophila
Citrobacter spp.
Moraxella spp.
Neisseria meningitidis
Pasteurella multocida
Providencia stuartii
Salmonella spp.
Shigella spp.
Yersinia enterocolitica

Anaerobes

Actinomyces spp.
Bifidobacterium spp.
Clostridium spp.
NOTE: Most strains of Clostridium difficile are resistant.
Eubacterium spp.
Fusobacterium spp.
Propionibacterium spp.
Veillonella spp.

Susceptibility Testing

Diffusion Techniques: Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure1 has been recommended for use with disks to test susceptibility of organisms to ceftizoxime. Interpretation involves the correlation of the diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for ceftizoxime.

Organisms should be tested with the ceftizoxime disk, since ceftizoxime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam disks are used.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30 mcg ceftizoxime disk should be interpreted according to the following criteria (with the exception of Pseudomonas aeruginosa).
 

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 tissue and fluids (e.g., urine) in which high antibiotic levels are attained. A report of †Resistant† indicates that achievable concentrations of the antibiotic are unlikely to be inhibitory and other therapy should be selected.

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

Susceptibility Testing for Pseudomonas in Urinary Tract Infections: Most strains of Pseudomonasaeruginosa are moderately susceptible to ceftizoxime. Ceftizoxime achieves high levels in the urine (greater than 6000 mcg/mL at 2 hours with 1 gram IV) and therefore, the following zone sizes should be used when testing ceftizoxime for treatment of urinary tract infections caused by Pseudomonas aeruginosa.

Susceptible organisms produce zones of 20 mm or greater, indicating that the test organism is likely to respond to therapy.

Organisms that producezones of 11 to 19 mm are expected to be susceptible when the infection is confined to the urinary tract (in which high antibiotic levels are attained).

Resistant organisms produce zones of 10 mm or less, indicating that other therapy should be selected.

Dilution Techniques: When using the NCCLS agar dilution or broth dilution (including microdilution) method 2 or equivalent, the following MIC data should be used for interpretation.
 

As with standard disk diffusion methods, dilution procedures require the use of laboratory control organisms. Standard ceftizoxime powder should give MIC values in the following ranges.
 

Last updated on RxList: 12/8/2004

See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.

Last updated on RxList: 12/8/2004