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Merrem I.V. (Meropenem) - Description and Clinical Pharmacology

 
 



DESCRIPTION

MERREM® I.V. (meropenem for injection) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It is (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio] -6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S·3H2O with a molecular weight of 437.52. Its structural formula is:

MERREM I.V. is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When constituted as instructed (see DOSAGE AND ADMINISTRATION; PREPARATION OF SOLUTION), each 1 g MERREM I.V. vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg MERREM I.V. vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq).

MERREM I.V. in the ADD-Vantage **/* vial is intended for intravenous use only after dilution with the appropriate volume of diluent solution in the Abbott ADD-Vantage® diluent container. (See DOSAGE AND ADMINISTRATION; PREPARATION OF SOLUTION.) MERREM I.V. in the ADD-Vantage vial is available in two strengths. Each 1 g ADD-Vantage vial of MERREM I.V. will deliver 90.2 mg of sodium as sodium carbonate (3.92 mEq), and each 500 mg ADD-Vantage vial will deliver 45.1 mg of sodium as sodium carbonate (1.96 mEq).

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
(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
(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
(S) Susceptible

When testing viridans group streptococci:

MIC (µg/mL) Interpretation
(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
(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 S. pneumoniae with oxacillin zone sizes of /= 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
(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

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