Cefobid pharmacy bulk package - not for direct infusion

High serum and bile levels of CEFOBID are attained after a single dose of the drug. Table 1 demonstrates the serum concentrations of CEFOBID in normal volunteers following either a single 15-minute constant rate intravenous infusion of 1, 2, 3 or 4 grams of the drug, or a single intramuscular injection of 1 or 2 grams of the drug.

The mean serum half-life of CEFOBID is approximately 2.0 hours, independent of the route of administration.

In vitro studies with human serum indicate that the degree of CEFOBID reversible protein binding varies with the serum concentration from 93% at 25 mcg/mL of CEFOBID to 90% at 250 mcg/mL and 82% at 500 mcg/mL.

CEFOBID achieves therapeutic concentrations in the following body tissues and fluids:

CEFOBID is excreted mainly in the bile. Maximum bile concentrations are generally obtained between one and three hours following drug administration and exceed concurrent serum concentrations by up to 100 times. Reported biliary concentrations of CEFOBID range from 66 mcg/mL at 30 minutes to as high as 6000 mcg/mL at 3 hours after an intravenous bolus injection of 2 grams.

Following a single intramuscular or intravenous dose, the urinary recovery of CEFOBID over a 12-hour period averages 20-30%. No significant quantity of metabolites has been found in the urine. Urinary concentrations greater than 2200 mcg/mL have been obtained following a 15-minute infusion of a 2 g dose. After an IM injection of 2 g, peak urine concentrations of almost 1000 mcg/mL have been obtained, and therapeutic levels are maintained for 12 hours.

Repeated administration of CEFOBID at 12-hour intervals does not result in accumulation of the drug in normal subjects. Peak serum concentrations, areas under the curve (AUC's), and serum half-lives in patients with severe renal insufficiency are not significantly different from those in normal volunteers. In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients with combined renal and hepatic insufficiencies, CEFOBID may accumulate in the serum.

CEFOBID has been used in pediatrics, but the safety and effectiveness in children have not been established. The half-life of CEFOBID in serum is 6-10 hours in low birth-weight neonates.

Microbiology

CEFOBID is active in vitro against a wide range of aerobic and anaerobic, gram-positive and gram-negative pathogens. The bactericidal action of CEFOBID results from the inhibition of bacterial cell wall synthesis. CEFOBID has a high degree of stability in the presence of beta-lactamases produced by most gram-negative pathogens. CEFOBID is usually active against organisms which are resistant to other beta-lactam antibiotics because of beta-lactamase production. CEFOBID is usually active against the following organisms in vitro and in clinical infections:

Gram-Positive Aerobes:

Staphylococcus aureus , penicillinase and non-penicillinase producing strains

Staphylococcus epidermidis

Streptococcus pneumoniae (formerly Diplococcus pneumoniae )

Streptococcus pyogenes (Group A beta-hemolytic streptococci)

Streptococcus agalactiae (Group B beta-hemolytic streptococci)

Enterococcus ( Streptococcus faecalis, S. faecium and S. durans )

Gram-Negative Aerobes:

Escherichia coli

Klebsiella species (including K. pneumoniae )

Enterobacter species

Citrobacter species

Haemophilus influenzae

Proteus mirabilis

Proteus vulgaris

Morganella morganii (formerly Proteus morganii )

Providencia stuartii

Providencia rettgeri (formerly Proteus rettgeri )

Serratia marcescens

Pseudomonas aeruginosa

Pseudomonas species

Some strains of Acinetobacter calcoaceticus

Neisseria gonorrhoeae

Anaerobic Organisms:

Gram-positive cocci (including Peptococcus and Peptostreptococcus )

Clostridium species

Bacteroides fragilis

Other Bacteroides species

CEFOBID is also active in vitro against a wide variety of other pathogens although the clinical significance is unknown. These organisms include: Salmonella and Shigella species, Serratia liquefaciens , N. meningitidis , Bordetella pertussis , Yersinia enterocolitica , Clostridium difficile , Fusobacterium species, Eubacterium species and beta-lactamase producing strains of H. influenzae and N. gonorrhoeae .

SUSCEPTIBILITY TESTING

Diffusion Technique. For the disk diffusion method of susceptibility testing, a 75 mcg CEFOBID diffusion disk should be used. Organisms should be tested with the CEFOBID 75 mcg disk since CEFOBID has been shown in vitro to be active against organisms which are found to be resistant to other beta-lactam antibiotics.

Tests should be interpreted by the following criteria:

Quantitative procedures that require measurement of zone diameters give the most precise estimate of susceptibility. One such method which has been recommended for use with the CEFOBID 75 mcg disk is the NCCLS approved standard. (Performance Standards for Antimicrobial Disk Susceptibility Tests. Second Information Supplement Vol. 2 No. 2 pp. 49-69. Publisher-National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania.)

A report of "susceptible" indicates that the infecting organism is likely to respond to CEFOBID therapy and a report of "resistant" indicates that the infecting organism is not likely to respond to therapy. A "moderately susceptible" report suggests that the infecting organism will be susceptible to CEFOBID if a higher than usual dosage is used or if the infection is confined to tissues and fluids (e.g., urine or bile) in which high antibiotic levels are attained.

Dilution Techniques. Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) of CEFOBID. Serial twofold dilutions of CEFOBID should be prepared in either broth or agar. Broth should be inoculated to contain 5 × 10 5 organisms/mL and agar "spotted" with 10 4 organisms.

MIC test results should be interpreted in light of serum, tissue, and body fluid concentrations of CEFOBID. Organisms inhibited by CEFOBID at 16 mcg/mL or less are considered susceptible, while organisms with MIC's of 17-63 mcg/mL are moderately susceptible. Organisms inhibited at CEFOBID concentrations of greater than or equal to 64 mcg/mL are considered resistant, although clinical cures have been obtained in some patients infected by such organisms.

CEFOBID is indicated for the treatment of the following infections when caused by susceptible organisms:

Respiratory Tract Infections caused by S. pneumoniae , H. influenzae , S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes * (Group A beta-hemolytic streptococci), P. aeruginosa , Klebsiella pneumoniae , E. coli , Proteus mirabilis , and Enterobacter species.

Peritonitis and Other Intra-abdominal Infections caused by E. coli , P. aeruginosa , * and anaerobic gram-negative bacilli (including Bacteroides fragilis ).

Bacterial Septicemia caused by S. pneumoniae , S. agalactiae , * S. aureus , Pseudomonas aeruginosa , * E. coli , Klebsiella spp., * Klebsiella pneumoniae , * Proteus species * (indole-positive and indole-negative), Clostridium spp. * and anaerobic gram-positive cocci. *

Infections of the Skin and Skin Structures caused by S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes , * and P. aeruginosa .

Pelvic Inflammatory Disease, Endometritis, and Other Infections of the Female Genital Tract caused by N. gonorrhoeae , S. epidermidis ,* S. agalactiae , E. coli , Clostridium spp., * Bacteroides species (including Bacteroides fragilis ), and anaerobic gram-positive cocci.

Cefobid, 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.

Urinary Tract Infections caused by Escherichia coli and Pseudomonas aeruginosa .

Enterococcal Infections:   Although cefoperazone has been shown to be clinically effective in the treatment of infections caused by enterococci in cases of peritonitis and other intra-abdominal infections, infections of the skin and skin structures, pelvic inflammatory disease, endometritis and other infections of the female genital tract, and urinary tract infections, * the majority of clinical isolates of enterococci tested are not susceptible to cefoperazone but fall just at or in the intermediate zone of susceptibility, and are moderately resistant to cefoperazone. However, in vitro susceptibility testing may not correlate directly with in vivo results. Despite this, cefoperazone therapy has resulted in clinical cures of enterococcal infections, chiefly in polymicrobial infections. Cefoperazone should be used in enterococcal infections with care and at doses that achieve satisfactory serum levels of cefoperazone.

Susceptibility Testing

Before instituting treatment with CEFOBID, appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Treatment may be started before results of susceptibility testing are available.

Combination Therapy

Synergy between CEFOBID and aminoglycosides has been demonstrated with many gram-negative bacilli. However, such enhanced activity of these combinations is not predictable. If such therapy is considered, in vitro susceptibility tests should be performed to determine the activity of the drugs in combination, and renal function should be monitored carefully. (See PRECAUTIONS , and DOSAGE AND ADMINISTRATION sections.)

CEFOBID is contraindicated in patients with known allergy to the cephalosporin-class of antibiotics.

BEFORE THERAPY WITH CEFOBID IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN- SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES.

PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH THE USE OF CEPHALOSPORINS (AND OTHER BROAD-SPECTRUM ANTIBIOTICS); THEREFORE, IT IS IMPORTANT TO CONSIDER ITS DIAGNOSIS IN PATIENTS WHO DEVELOP DIARRHEA IN ASSOCIATION WITH ANTIBIOTIC USE.

Treatment with broad-spectrum antibiotics alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis. Cholestyramine and colestipol resins have been shown to bind the toxin in vitro .

Mild cases of colitis may respond to drug discontinuance alone.

Moderate to severe cases should be managed with fluid, electrolyte, and protein supplementation as indicated.

When the colitis is not relieved by drug discontinuance or when it is severe, oral vancomycin is the treatment of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile . Other causes of colitis should also be considered.

In clinical studies the following adverse effects were observed and were considered to be related to CEFOBID therapy or of uncertain etiology:

Hypersensitivity:   As with all cephalosporins, hypersensitivity manifested by skin reactions (1 patient in 45), drug fever (1 in 260), or a change in Coombs' test (1 in 60) has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.

Hematology:   As with other beta-lactam antibiotics, reversible neutropenia may occur with prolonged administration. Slight decreases in neutrophil count (1 patient in 50) have been reported. Decreased hemoglobins (1 in 20) or hematocrits (1 in 20) have been reported, which is consistent with published literature on other cephalosporins. Transient eosinophilia has occurred in 1 patient in 10.

Hepatic:   Of 1285 patients treated with cefoperazone in clinical trials, one patient with a history of liver disease developed significantly elevated liver function enzymes during CEFOBID therapy. Clinical signs and symptoms of nonspecific hepatitis accompanied these increases. After CEFOBID therapy was discontinued, the patient's enzymes returned to pre-treatment levels and the symptomatology resolved. As with other antibiotics that achieve high bile levels, mild transient elevations of liver function enzymes have been observed in 5-10% of the patients receiving CEFOBID therapy. The relevance of these findings, which were not accompanied by overt signs or symptoms of hepatic dysfunction, has not been established.

Gastrointestinal:   Diarrhea or loose stools has been reported in 1 in 30 patients. Most of these experiences have been mild or moderate in severity and self-limiting in nature. In all cases, these symptoms responded to symptomatic therapy or ceased when cefoperazone therapy was stopped. Nausea and vomiting have been reported rarely.

Symptoms of pseudomembranous colitis can appear during or for several weeks subsequent to antibiotic therapy (see WARNINGS ).

Renal Function Tests:   Transient elevations of the BUN (1 in 16) and serum creatinine (1 in 48) have been noted.

Local Reactions:   CEFOBID is well tolerated following intramuscular administration. Occasionally, transient pain (1 in 140) may follow administration by this route. When CEFOBID is administered by intravenous infusion some patients may develop phlebitis (1 in 120) at the infusion site.