Mandol Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefamandole

Mandol Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefamandole

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY

After intramuscular administration of a 500-mg dose of cefamandole to normal volunteers, the mean peak serum concentration was 13 µg/mL. After a 1-g dose, the mean peak concentration was 25 µg/mL. These peaks occurred at 30 to 120 minutes. Following intravenous doses of 1, 2, and 3 g, serum concentrations were 139, 240, and 533 mcg/mL respectively at 10 minutes. These concentrations declined to 0.8, 2.2, and 2.9 mcg/mL at 4 hours. Intravenous administration of 4-g doses every 6 hours produced no evidence of accumulation in the serum. The half-life after an intravenous dose is 32 minutes; after intramuscular administration, the half-life is 60 minutes.

Sixty-five percent to 85% of cefamandole is excreted by the kidneys over an 8-hour period, resulting in high urinary concentrations. Following intramuscular doses of 500 mg and 1 g, urinary concentrations averaged 254 and 1,357 mcg/mL respectively. Intravenous doses of 1 and 2 g produced urinary levels averaging 750 and 1,380 mcg/mL respectively. Probenecid slows tubular excretion and doubles the peak serum level and the duration of measurable serum concentrations.

The antibiotic reaches therapeutic levels in pleural and joint fluids and in bile and bone.

Microbiology The bactericidal action of cefamandole results from inhibition of cell-wall synthesis. Cephalosporins have in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefamandole is usually active against the following organisms in vitro and in clinical infections:

Gram-positive

Staphylococcus aureus, including penicillinase- and non-penicillinase-producing strains

Staphylococcus epidermidis

(beta)-hemolytic and other streptococci (Most strains of enterococci, eg, Enterococcus faecalis [formerly Streptococcus faecalis ], are resistant.)

Streptococcus pneumoniae

Gram-negative

Escherichia coli

Klebsiella spp.

Enterobacter spp. (Initially susceptible organisms occasionally may become resistant during therapy.)

Haemophilus influenzae

Proteus mirabilis

Providencia rettgeri (formerly Proteus rettgeri )

Morganella morganii (formerly Proteus morganii )

Proteus vulgaris (Some strains of P. vulgaris have been shown by in vitro tests to be resistant to cefamandole and certain other cephalosporins.)

Anaerobic organisms

Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.)

Gram-positive bacilli (including Clostridium spp.)

Gram-negative bacilli (including Bacteroides and Fusobacterium spp.). Most strains of Bacteroides fragilis are resistant.

Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea   spp.), and most Serratia strains are resistant to cefamandole and certain other cephalosporins. Cefamandole is resistant to degradation by (beta)-lactamases from certain members of the Enterobacteriaceae.

Susceptibility Tests  Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure ¹ has been recommended for use with disks to test susceptibility to cefamandole. Interpretation involves correlation of the diameters obtained in the disk test with minimal inhibitory concentration (MIC) values for cefamandole.

Reports from the laboratory giving results of the standardized single-disk susceptibility test ¹ using a 30-mcg cefamandole 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 of 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 (eg, 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, the test may be performed with either the cephalosporin-class disk (30 mcg cephalothin) or the cefamandole disk (30 mcg cefamandole), and a zone of 18 mm is indicative of a cefamandole-susceptible organism.

Gram-negative organisms should be tested with the cefamandole disk (using the above criteria), since cefamandole has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalosporin-class disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk are not necessarily of intermediate susceptibility or resistant to cefamandole.

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

A bacterial isolate may be considered susceptible if the MIC value for cefamandole ² is not more than 16 mcg/mL. Organisms are considered resistant if the MIC is greater than 32 mcg/mL.