Ancef Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefazolin

Ancef Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefazolin

CLINICAL PHARMACOLOGY

After intramuscular administration of ANCEF to normal volunteers, the mean serum concentrations were 37 mcg/mL at 1 hour and 3 mcg/mL at 8 hours following a 500-mg dose, and 64 mcg/mL at 1 hour and 7 mcg/mL at 8 hours following a 1-gram dose.

Studies have shown that following intravenous administration of ANCEF to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1-gram dose.

The serum half-life for ANCEF is approximately 1.8 hours following IV administration and approximately 2.0 hours following IM administration.

In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), ANCEF produced a steady serum level at the third hour of approximately 28 mcg/mL.

Studies in patients hospitalized with infections indicate that ANCEF produces mean peak serum levels approximately equivalent to those seen in normal volunteers.

Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to 5 times; however, in patients with obstructive biliary disease, bile levels of ANCEF are considerably lower than serum levels (< 1.0 mcg/mL).

In synovial fluid, the level of ANCEF becomes comparable to that reached in serum at about 4 hours after drug administration.

Studies of cord blood show prompt transfer of ANCEF across the placenta. ANCEF is present in very low concentrations in the milk of nursing mothers.

ANCEF is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. ANCEF achieves peak urine concentrations of approximately 2,400 mcg/mL and 4,000 mcg/mL respectively following 500-mg and 1-gram intramuscular doses.

In patients undergoing peritoneal dialysis (2 L/hr.), ANCEF produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours’ instillation of a dialyzing solution containing 50 mg/L and 150 mg/L, respectively. Mean peak levels were 29 mcg/mL (range 13 to 44 mcg/mL) with 50 mg/L (3 patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 patients). Intraperitoneal administration of ANCEF is usually well tolerated.

Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, SGOT, SGPT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant changes attributed to ANCEF.

In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. ANCEF is active against the following organisms in vitro and in clinical infections:

Staphylococcus aureus (including penicillinase-producing strains)

Methicillin-resistant staphylococci are uniformly resistant to cefazolin

Group A beta-hemolytic streptococci and other strains of streptococci (many strains of enterococci are resistant)

Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter cloacae, Morganella morganii, and Providencia rettgeri are resistant. Serratia, Pseudomonas, Mima, Herellea species are almost uniformly resistant to cefazolin.

Disk Susceptibility Tests:

Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure¹ has been recommended for use with disks to test susceptibility to cefazolin.

Reports from a laboratory using the standardized single-disk susceptibility test¹ with a 30-mcg cefazolin disk should be interpreted according to the following criteria:

Susceptible organisms produce zones of 18 mm or greater, indicating that the tested organism is likely to respond to therapy.

Organisms of intermediate susceptibility produce zones 15 to 17 mm, indicating that the tested organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained.

Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.

For gram-positive isolates, a zone of 18 mm is indicative of a cefazolin-susceptible organism when tested with either the cephalosporin-class disk (30 mcg cephalothin) or the cefazolin disk (30 mcg cefazolin).

Gram-negative organisms should be tested with the cefazolin disk (using the above criteria), since cefazolin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalothin disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk may be susceptible to cefazolin.

Standardized procedures require use of control organisms. The 30-mcg cefazolin disk should give zone diameter between 23 and 29 mm for E. coli ATCC 25922 and between 29 and 35 mm for S. aureus ATCC 25923.

The cefazolin disk should not be used for testing susceptibility to other cephalosporins.

A bacterial isolate may be considered susceptible if the minimal inhibitory concentration (MIC) for cefazolin is not more than 16 mcg per mL. Organisms are considered resistant if the MIC is equal to or greater than 64 mcg per mL.

The range of MICs for the control strains are as follows:

S. aureus ATCC 25923, 0.25 to 1.0 mcg/mL

E. coli ATCC 25922, 1.0 to 4.0 mcg/mL