CLINICAL PHARMACOLOGY
At the end of a 30-minute intravenous infusion of a single dose of MERREM I.V. in normal volunteers, mean peak plasma concentrations are approximately 23 µg/mL (range 14-26) for the 500 mg dose and 49 µg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of MERREM I.V. in normal volunteers results in mean peak plasma concentrations of approximately 45 µg/mL (range 18-65) for the 500 mg dose and 112 µg/mL (range 83-140) for the 1 g dose.
Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 µg/mL at 6 hours after administration.
In subjects with normal renal function, the elimination half-life of MERREM I.V. is approximately 1 hour. Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 µg/mL are maintained for up to 5 hours after a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function.
Plasma protein binding of meropenem is approximately 2%.
There is one metabolite which is microbiologically inactive.
Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of MERREM I.V., the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below.
Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)
Tissue
|
I.V. Dose (g)
|
Number of
Samples
|
Mean [µg/mL
or µg/(g)] *** |
Range [µg/mL
or µg/(g)] |
Endometrium
|
0.5
|
7
|
4.2
|
1.7-10.2
|
Myometrium
|
0.5
|
15
|
3.8
|
0.4-8.1
|
Ovary
|
0.5
|
8
|
2.8
|
0.8-4.8
|
Cervix
|
0.5
|
2
|
7.0
|
5.4-8.5
|
Fallopian tube
|
0.5
|
9
|
1.7
|
0.3-3.4
|
Skin
|
0.5
|
22
|
3.3
|
0.5-12.6
|
Skin
|
1.0
|
10
|
5.3
|
1.3-16.7
|
Colon
|
1.0
|
2
|
2.6
|
2.5-2.7
|
Bile
|
1.0
|
7
|
14.6 (3 h)
|
4.0-25.7
|
Gall bladder
|
1.0
|
1
|
--
|
3.9
|
Interstitial fluid
|
1.0
|
5
|
26.3
|
20.9-37.4
|
Peritoneal fluid
|
1.0
|
9
|
30.2
|
7.4-54.6
|
Lung
|
1.0
|
2
|
4.8 (2 h)
|
1.4-8.2
|
Bronchial mucosa
|
1.0
|
7
|
4.5
|
1.3-11.1
|
Muscle
|
1.0
|
2
|
6.1 (2 h)
|
5.3-6.9
|
Fascia
|
1.0
|
9
|
8.8
|
1.5-20
|
Heart valves
|
1.0
|
7
|
9.7
|
6.4-12.1
|
Myocardium
|
1.0
|
10
|
15.5
|
5.2-25.5
|
CSF (inflamed)
|
20 mg/kg * |
8
|
1.1 (2 h)
|
0.2-2.8
|
|
40 mg/kg ** |
5
|
3.3 (3 h)
|
0.9-6.5
|
CSF (uninflamed)
|
1.0
|
4
|
0.2 (2 h)
|
0.1-0.3
|
* in pediatric patients of age 5 months to 8 years
|
** in pediatric patients of age 1 month to 15 years
|
*** at 1 hour unless otherwise noted
|
|
The pharmacokinetics of MERREM I.V. in pediatric patients 2 years of age or older are essentially similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg.
Pharmacokinetic studies with MERREM I.V. in patients with renal insufficiency have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment. (See DOSAGE AND ADMINISTRATION - Use in Adults with Renal Impairment.) A pharmacokinetic study with MERREM I.V. in elderly patients with renal insufficiency has shown a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.
Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. (See OVERDOSAGE.)
A pharmacokinetic study with MERREM I.V. in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.
MICROBIOLOGY
The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most gram-positive and gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2, and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.
Meropenem has significant stability to hydrolysis by (beta)-lactamases of most categories, both penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of metallo-(beta)-lactamases. Meropenem should not be used to treat methicillin-resistant staphylococci. Cross resistance is sometimes observed with strains resistant to other carbapenems.
In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.
Meropenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
GRAM-POSITIVE AEROBES
Streptococcus pneumoniae (excluding penicillin-resistant strains)
Viridans group streptococci
NOTE: Penicillin-resistant strains had meropenem MIC90 values of 1 or 2 µg/mL, which is above the 0.12 µg/mL susceptible breakpoint for this species.
GRAM-NEGATIVE AEROBES
Escherichia coli Haemophilus influenzae ((beta)-lactamase and non-(beta)-lactamase producing) Klebsiella pneumoniae Neisseria meningitidis Pseudomonas aeruginosa
ANAEROBES
Bacteroides fragilis Bacteroides thetaiotaomicron Peptostreptococcus species
The following in vitro data are available, but their clinical significance is unknown.
Meropenem exhibits in vitro minimum inhibitory concentrations (MIC's) of 0.12 µg/mL against most (>/= 90%) strains of Streptococcus pneumoniae, 0.5 µg/mL or less against most (>/= 90%) strains of Haemophilus influenzae, and 4 µg/mL or less against most (>/= 90%) strains of the other microorganisms in the following list; however, the safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
GRAM-POSITIVE AEROBES
Staphylococcus aureus ((beta)-lactamase and non-(beta)-lactamase producing) Staphylococcus epidermidis ((beta)-lactamase and non-(beta)-lactamase-producing) NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to meropenem.
GRAM-NEGATIVE AEROBES
Acinetobacter species
Aeromonas hydrophila Campylobacter jejuni Citrobacter diversus Citrobacter freundii Enterobacter cloacae Haemophilus influenzae (ampicillin-resistant, non-(beta)-lactamase-producing strains [BLNAR strains]) Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis ((beta)-lactamase and non-(beta)-lactamase-producing strains) Morganella morganii Pasteurella multocida Proteus mirabilis Proteus vulgaris Salmonella species
Serratia marcescens Shigella species
Yersinia enterocolitica
ANAEROBES
Bacteroides distasonis Bacteroides ovatus Bacteroides uniformis Bacteroides ureolyticus Bacteroides vulgatus Clostridium difficile Clostridium perfringens Eubacterium lentum Fusobacterium species
Prevotella bivia Prevotella intermedia Prevotella melaninogenica Porphyromonas asaccharolytica Propionibacterium acnes
SUSCEPTIBILITY TESTS
DILUTION TECHNIQUES:
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method1(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of meropenem powder. The MIC values should be interpreted according to the following criteria for indicated aerobic organisms other than Haemophilus species and streptococci:
MIC (µg/mL)
|
Interpretation
|
= 4
|
(S) Susceptible
|
8
|
(I) Intermediate
|
>/= 16
|
(R) Resistant
|
|
Haemophilus Test Media (HTM) and the following interpretive criteria should be used when testing Haemophilus species:
MIC (µg/mL)
|
Interpretation
|
= 0.5
|
(S) Susceptible
|
|
The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.
The following criteria should be used when testing streptococci including Streptococcus pneumoniae:
When testing S. pneumoniae:
MIC (µg/mL)
|
Interpretation
|
= 0.12
|
(S) Susceptible
|
|
When testing viridans group streptococci:
MIC (µg/mL)
|
Interpretation
|
= 0.5
|
(S) Susceptible
|
|
The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.
A report of `Susceptible' indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood 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 in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard meropenem powder should provide the following MIC values:
Microorganism
|
ATCC
|
MIC (µg/mL)
|
Enterococcus faecalis |
29212
|
2.0-8.0
|
Escherichia coli |
25922
|
0.008-0.06
|
Haemophilus influenzae |
49766
|
0.03-0.12
|
Pseudomonas aeruginosa |
27853
|
0.25-1.0
|
Streptococcus pneumoniae |
49619
|
0.06-0.25
|
|
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 procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg of meropenem to test the susceptibility of microorganisms to meropenem.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg disk should be interpreted according to the following criteria for indicated aerobic organisms other than Haemophilus species and streptococci:
Zone Diameter (mm)
|
Interpretation
|
>/= 16
|
(S) Susceptible
|
14-15
|
(I) Intermediate
|
= 13
|
(R) Resistant
|
|
Haemophilus Test Media and the following criteria should be used when testing Haemophilus species:
Zone Diameter (mm)
|
Interpretation
|
>/= 20
|
(S) Susceptible
|
|
The current absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.
Streptococcus pneumoniae isolates should be tested using 1-µg/mL oxacillin disk. Isolates with oxacillin zone sizes of >/= 20 mm are susceptible (MIC = 0.06 µg/mL) to penicillin and can be considered susceptible to meropenem for approved indications, and meropenem need not be tested. A meropenem MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of = 19 mm. The disk test does not distinguish penicillin intermediate strains (i.e., MIC's = 0.12-1.0 µg/mL) from strains that are penicillin resistant (i.e., MIC's >/= 2 µg/mL). Viridans group streptococci should be tested for meropenem susceptibility using an MIC method. Reliable disk diffusion tests for meropenem do not yet exist for testing streptococci.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for meropenem.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 10-µg meropenem disk should provide the following zone dia-meters in these laboratory test quality control strains:
Microorganism
|
ATCC
|
Zone Diameter (mm)
|
Escherichia coli |
25922
|
28-34
|
Haemophilus influenzae |
49247
|
20-28
|
Pseudomonas aeruginosa |
27853
|
27-33
|
|
ANAEROBIC TECHNIQUES:
For anaerobic bacteria, susceptibility to meropenem as MIC's can be determined by standardized test methods. 3 The MIC values obtained should be interpreted according to the following criteria:
MIC (µg/mL)
|
Interpretation
|
= 4
|
(S) Susceptible
|
8
|
(I) Intermediate
|
>/= 16
|
(R) Resistant
|
|
Interpretation is identical to that stated above for results using dilution techniques.
As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized meropenem powder should provide the following MIC values:
Microorganism
|
ATCC
|
MIC (µg/mL)
|
Bacteroides fragilis |
25285
|
0.06-0.25
|
Bacteroides thetaiotaomicron |
29741
|
0.125-0.5
|
|
|