Primaxin I.V. (Imipenem / Cilastatin Sodium) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

ADULTS

INTRAVENOUS ADMINISTRATION

Intravenous infusion of PRIMAXIN I.V. over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 µg/mL for the 250 mg dose, from 21 to 58 µg/mL for the 500 mg dose, and from 41 to 83 µg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 µg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute intravenous infusion of PRIMAXIN I.V., range from 15 to 25 µg/mL for the 250 mg dose, from 31 to 49 µg/mL for the 500 mg dose, and from 56 to 88 µg/mL for the 1000 mg dose.

The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%. Approximately, 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 µg/mL can be maintained for up to 8 hours with PRIMAXIN I.V. at the 500-mg dose. Approximately, 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of PRIMAXIN I.V.

No accumulation of imipenem/cilastastin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.

Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

After a 1 gram dose of PRIMAXIN I.V., the following average levels of imipenem were measured (usually at 1 hour post-dose except where indicated) in the tissues and fluids listed:

Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.)

MICROBIOLOGY

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B.

Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram-negative bacteria which are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.

Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections treated with the intravenous formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.

Gram-positive aerobes:

Enterococcus faecalis (formerly S. faecalis)

(NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium ].)

Staphylococcus aureus including penicillinase-producing strains

Staphylococcus epidermidis including penicillinase-producing strains

(NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.)

Streptococcus agalactiae (Group B streptococci)

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative aerobes:

Acinetobacter spp.

Citrobacter spp.

Enterobacter spp.

Escherichia coli

Gardnerella vaginalis

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella spp.

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Pseudomonas aeruginosa

(NOTE: Imipenem is inactive in vitro against Xanthomonas (Pseudomonas) maltophilia and some strains of P. cepacia.)

Serratia spp., including S. marcescens

Gram-positive anaerobes:

Bifidobacterium spp.

Clostridium spp.

Eubacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Propionibacterium spp.

Gram-negative anaerobes:

Bacteroides spp., including B. fragilis

Fusobacterium spp.

The following in vitro data are available, but their clinical significance is unknown.

Imipenem exhibits in vitro minimum inhibitory concentrations (MICs) of 4 µg/mL or less against most (>/=90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes:

Bacillus spp.

Listeria monocytogenes

Nocardia spp.

Staphylococcus saprophyticus

Group C streptococci

Group G streptococci

Viridans group streptococci

Gram-negative aerobes:

Aeromonas hydrophila

Alcaligenes spp.

Capnocytophaga spp.

Haemophilus ducreyi

Neisseria gonorrhoeae including penicillinase-producing strains

Pasteurella spp.

Providencia stuartii

Gram-negative anaerobes:

Prevotella bivia

Prevotella disiens

Prevotella melaninogenica

Veillonella spp.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

SUSCEPTIBILITY TESTS:

Measurement of MIC or minimum bactericidal concentration (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)

DILUTION TECHNIQUES:

Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such procedure uses a standardized dilution method¹(broth, agar, or microdilution) or equivalent with imipenem powder.

The MIC values obtained should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard imipenem powder should provide the following MIC values:

DIFFUSION TECHNIQUES:

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² that has been recommended for use with disks to test the susceptibility of microorganisms to imipenem uses the 10-µg imipenem disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for imipenem.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg imipenem disk should be interpreted according to the following criteria:

Interpretation should be as stated above for results using dilution techniques.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 10-µg imipenem disk should provide the following diameters in these laboratory test quality control strains:

ANAEROBIC TECHNIQUES:

For anaerobic bacteria, the susceptibility to imipenem can be determined by the reference agar dilution method or by alternate standardized test methods. ³

The MIC values obtained should be interpreted according to the following criteria:

As with other susceptibility techniques, the use of laboratory control microorganisms is required. Standard imipenem powder should provide the following MIC values:

Reference Agar Dilution Testing:

Broth Microdilution Testing: