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 μ;g/mL for the 250 mg dose, from 21 to 58 μ;g/mL for the 500 mg dose, and from 41 to 83 μ;g/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 μ;g/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 μ;g/mL for the 250 mg dose, from 31 to 49 μ;g/mL for the 500 mg dose, and from 56 to 88 μ;g/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 μ;g/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/cilastatin 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 faecalisformerly 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 Stenotrophomonas [formerly Xanthomonas, formerly Pseudomonas] maltophilia and some strains of Burkholderia 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 μ;g/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 Test Methods

When available, the clinical microbiology laboratory should provide to the physician the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a broth dilution method^1,2 or equivalent with standardized inoculum concentrations and standardized concentrations of imipenem powder. The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations^2,3. This procedure uses paper disks impregnated with 10-μ;g imipenem to test the susceptibility of microorganisms to imipenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to imipenem as MICs can be determined by standardized test methods.^2,4 The MIC values obtained should be interpreted according to criteria provided in Table 1.

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

Table 1: Susceptibility Interpretive Criteria for Imipenem

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard imipenem powder should provide the following range of values noted in Table 2.²

Table 2: Acceptable Quality Control Ranges for Imipenem

REFERENCES

1.Clinical and Laboratory Standards (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 9th ed. CLSI document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100-S22, 2012.

3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11, 2012.

4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 8th ed. CLSI document M11-A8, 2012.

Last reviewed on RxList: 5/2/2012
This monograph has been modified to include the generic and brand name in many instances.