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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:
|Tissue or Fluid||N||Imipenem Level μg/mL or μg/g||Range|
|Vitreous Humor||3||3.4 (3.5 hours post dose)||2.88-3.6|
|Aqueous Humor||5||2.99 (2 hours post dose)||2.4-3.9|
|Lung Tissue||8||5.6 (median)||3.5-15.5|
|Peritoneal||12||23.9 S.D.+5.3 (2 hours post dose)||—|
|Bile||2||5.3 (2.25 hours post dose)||4.6-6.0|
|CSF (uninflamed)||5||1.0 (4 hours post dose)||0.26-2.0|
|CSF (inflamed)||7||2.6 (2 hours post dose)||0.5-5.5|
Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.)
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.
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)
(NOTE: Imipenem is inactive in vitro against Stenotrophomonas [formerly Xanthomonas, formerly Pseudomonas] maltophilia and some strains of Burkholderia cepacia.)
Serratia spp., including S. marcescens
Bacteroides spp., including B. fragilis
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.
Group C streptococci
Group G streptococci
Viridans group streptococci
Neisseria gonorrhoeae including penicillinase-producing strains
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.
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 method1,2 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.
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 concentrations2,3. 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.
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
|Pathogen||Minimum Inhibitory Concentrations MIC (μg/mL)||Disk Diffusion Zone Diameter (mm)|
|Enterobacteriaceae||≤ 1.0||2||≥ 4.0||≥ 23||20-22||≤ 19|
|Pseudomonas aeruginosa||≤ 2||4||≥ 8||≥ 19||16-18||≤ 15|
|Acinetobacter spp.||≤ 4||8||≥ 16||≥ 16||14-15||≤ 13|
|Staphylococcus spp.*||≤ 4||8||≥ 16||≥ 16||14-15||≤ 13|
|Haemophilus influenzae and H. parainfluenzae†||≤ 4||-||-||≥ 16||-||-|
|Streptococcus pneumoniae‡||≤ 0.12||0.25-0.5||≥ 1||-||-||-|
|Anaerobes||≤ 4.0||8||≥ 16.0||-||-||-|
|* For oxacillin-susceptible S.
aureus and coagulase negative staphylococci results for carbapenems, including
imipenem, if tested, should be reported according to the results generated
using routine interpretive criteria. For oxacillin-resistant S. aureus and
coagulase negative staphylococci, other beta lactam agents, including
carbapenems, may appear active in vitro but are not effective clinically.
Results for beta lactam agents other than cephalosporins with anti-MRSA
activity should be reported as resistant or should not be reported.
† For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible”. For strains yielding results suggestive of a “non-susceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed.
‡ For non-meningitis S. pneumoniae isolates, penicillin MICs ≤ 0.06 μg/mL (or oxacillin zones ≥ 20 mm) indicate susceptibility to imipenem.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable. 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 which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound at the infection site reaches the concentrations usually achievable, and that other therapy should be selected.
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
|Microorganism||Minimum Inhibitory Concentrations MIC Range (μg/mL)||Disk Diffusion Zone Diameter (mm)|
|Pseudomonas aeruginosa ATCC 27853||1-4||20-28|
|Escherichia coli ATCC 25922||0.06-0.25||26-32|
|Haemophilus influenzae ATCC 49247||-||21-29|
|Haemophilus influenzae ATCC 49766||0.25-1.0||-|
|Staphylococcus aureus ATCC 29213||0.015-0.06||-|
|Enterococcus faecalis ATCC 29212||0.5-2.0||-|
|Streptococcus pneumoniae ATCC 49619||0.03-0.12||-|
|Bacteroides fragilis ATCC 25285||0.03-0.25*||-|
|Bacteroides thetaiotaomicron ATCC 29741||0.25-1.0*||-|
|Eubacterium lentum ATCC 43055||0.25-2.0*||-|
|* Quality control ranges for broth microdilution testing
† Quality control ranges for agar dilution testing
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.
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