CLINICAL PHARMACOLOGY
Following intramuscular administrations of 500 or 750 mg doses of imipenem-cilastatin sodium in a 1:1 ratio with 1% lidocaine, peak plasma levels of imipenem antimicrobial activity occur within 2 hours and average 10 and 12 μg/mL, respectively. For cilastatin, peak plasma levels average 24 and 33 μg/mL, respectively, and occur within 1 hour. When compared to intravenous administration of imipenem-cilastatin sodium, imipenem is approximately 75% bioavailable following intramuscular administration while cilastatin is approximately 95% bioavailable. The absorption of imipenem from the IM injection site continues for 6 to 8 hours while that for cilastatin is essentially complete within 4 hours. This prolonged absorption of imipenem following the administration of the intramuscular formulation of imipenem-cilastatin sodium results in an effective plasma half-life of imipenem of approximately 2 to 3 hours and plasma levels of the antibiotic which remain above 2 μg/mL for at least 6 or 8 hours, following a 500 mg or 750 mg dose, respectively. This plasma profile for imipenem permits IM administration of the intramuscular formulation of imipenem-cilastatin sodium every 12 hours with no accumulation of cilastatin and only slight accumulation of imipenem.
A comparison of plasma levels of imipenem after a single dose of 500 mg or 750 mg of imipenem-cilastatin sodium (intravenous formulation) administered intravenously or of imipenem-cilastatin sodium (intramuscular formulation) diluted with 1% lidocaine and administered intramuscularly is as follows:
PLASMA CONCENTRATIONS OF IMIPENEM (μg/mL) |
500 MG
|
750 MG
|
|
TIME
25 min
1 hr
2 hr
4 hr
6 hr
12 hr
|
I.V.
45.1
21.6
10.0
2.6
0.6
ND
|
I.M.
6.0
9.4
9.9
5.6
2.5
0.5
|
I.V.
57.0
28.1
12.0
3.4
1.1
ND
|
I.M.
6.7
10.0
11.4
7.3
3.8
0.8
|
Imipenem urine levels remain above 10 μg/mL for the 12-hour dosing interval following the administration of 500 mg or 750 mg doses of the intramuscular formulation of imipenem-cilastatin sodium. Total urinary excretion of imipenem averages 50% while that for cilastatin averages 75% following either dose of the intramuscular formulation of imipenem-cilastatin sodium.
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, increased levels of imipenem are achieved in the urine. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.
In a clinical study in which a 500-mg dose of the intramuscular formulation of imipenem-cilastatin sodium was administered to healthy subjects, the average peak level of imipenem in interstitial fluid (skin blister fluid) was approximately 5.0 μg/mL within 3.5 hours after administration.
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, including 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 many 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 intramuscular formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.
Gram-positive aerobes:
Staphylococcus aureus including penicillinase-producing strains
(NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.)
Group D streptococcus including Enterococcus faecalis (formerly S. faecalis)
(NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium ].)
Streptococcus pneumoniae
Streptococcus pyogenes (Group A streptococci)
Streptococcus viridans group
Gram-negative aerobes:
Acinetobacter spp., including A. calcoaceticus
Citrobacter spp.
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Pseudomonas aeruginosa
(NOTE: Imipenem is inactive in vitro against Xanthomonas (Pseudomonas ) maltophilia and P. cepacia.)
Gram-positive anaerobes:
Peptostreptococcus spp.
Gram-negative anaerobes:
Bacteroides spp., including
Bacteroides distasonis
Bacteroides intermedius
(formerly B. melaninogenicus intermedius)
Bacteroides fragilis
Bacteroides thetaiotaomicron
Fusobacterium spp.
Imipenem exhibits in vitro minimal 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.
Group C streptococci
Group G streptococci
Gram-negative aerobes:
Aeromonas hydrophila
Alcaligenes spp.
Capnocytophaga spp.
Enterobacter agglomerans
Haemophilus ducreyi
Klebsiella oxytoca
Neisseria gonorrhoeae including penicillinase-producing strains
Pasteurella spp.
Proteus mirabilis
Providencia stuartii
Gram-positive anaerobes:
Clostridium perfringens
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:
Dilution Techniques:
Use a standardized dilution method (1) (broth, agar, microdilution) or equivalent with imipenem powder. The MIC values obtained should be interpreted according to the following criteria:
|
MIC (μg/mL)
|
Interpretation
|
|
≤4
8
≥16
|
Susceptible
Moderately Susceptible
Resistant
|
A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “moderately susceptible” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained. A report of “resistant” indicates that achievable concentrations are unlikely to be inhibitory and other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control organisms. Standard imipenem powder should provide the following MIC values:
|
Organism
|
MIC (μg/mL)
|
|
E. coli ATCC 25922
S. aureus ATCC 29213
E. faecalis ATCC 29212
P. aeruginosa ATCC 27853
|
0.06-0.25
0.015-0.06
0.5-2.0
1.0-4.0
|
Diffusion techniques:
Quantitative methods that require measurement of zone diameters give the most precise estimate of antibiotic susceptibility. One such standard procedure (2), which has been recommended for use with disks to test susceptibility of organisms to imipenem, uses the 10-μg imipenem disk. Interpretation involves the correlation of the diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for imipenem.
Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-μg imipenem disk should be interpreted according to the following criteria:
|
Zone Diameter (mm)
|
Interpretation
|
|
≥16
14-15
≤13
|
Susceptible
Moderately Susceptible
Resistant
|
Standardized procedures require the use of laboratory control organisms. The 10-μg imipenem disk should give the following zone diameters:
|
Organism
|
Zone Diameter (mm)
|
|
E. coli ATCC 25922
P. aeruginosa ATCC 27853
|
26-32
20-28
|
For anaerobic bacteria, the MIC of imipenem can be determined by agar or broth dilution (including microdilution) techniques (3).
The MIC values obtained should be interpreted according to the following criteria:
|
MIC (μg/mL)
|
Interpretation
|
|
≤4
8
≥16
|
Susceptible
Moderately Susceptible
Resistant
|
|
