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Merrem (Meropenem) - Description and Clinical Pharmacology

 
 



To reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM® I.V. (meropenem for injection) and other antibacterial drugs, MERREM I.V. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

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).

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.

Table 1Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

Tissue

I.V.Dose (g)

Number of Samples

Mean [μg/mL or μg/(g)] 1

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

Interstitial fluid 2

0.5

9

5.5

3.2-8.6

Skin

1.0

10

5.3

1.3-16.7

Interstitial fluid

1.0

5

26.3

20.9-37.4

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

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 3

40 mg/kg 4

8

5

1.1 (2 h)

3.3 (3 h)

0.2-2.8

0.9-6.5

CSF (uninflamed)

1.0

4

0.2 (2 h)

0.1-0.3

1 at 1 hour unless otherwise noted
2 obtained from blister fluid
3 in pediatric patients of age 5 months to 8 years
4 in pediatric patients of age 1 month to 15 years

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

Meropenem is a broad-spectrum carbapenem antibiotic. It is active against Gram-positive and Gram-negative bacteria.

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 β-lactamases of most categories, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant staphylococci (MRSA).

In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Mechanism of Action

Meropenem exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, which leads to cell death.

Resistance

Mechanism of Resistance

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target penicillin binding proteins (PBP), 3) increased expression of efflux pump components, and 4) production of antibiotic-destroying enzymes (carbapenemases, metallo-β-lactamases).

Cross-Resistance

Cross resistance is sometimes observed with isolates resistant to other carbapenems.

Lists of Microorganisms

Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic and facultative Gram-positive microorganisms

Enterococcus faecalis (excluding vancomycin-resistant isolates)

Staphylococcus aureus (β-lactamase and non-β-lactamase producing, methicillin-susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

NOTE: Penicillin-resistant isolates had meropenem MIC90 values of 1 or 2 μg/mL, which is above the 0.12 μg/mL susceptible breakpoint for this species.

Streptococcus pyogenes

Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms

Escherichia coli

Haemophilus influenzae (β-lactamase and non-β-lactamase producing)

Klebsiella pneumoniae

Neisseria meningitidis

Pseudomonas aeruginosa

Proteus mirabilis

Anaerobic microorganisms

Bacteroides fragilis

Bacteroides thetaiotaomicron

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown .

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for meropenem. However, the safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic and facultative Gram-positive microorganisms

Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing, methicillin-susceptible isolates only).

Aerobic and faculative Gram-negative

Microorganisms

Acinetobacter species

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter diversus

Moraxella catarrhalis

(β-lactamase and non-β-lactamase-producing isolates)

Citrobacter freundii

Morganella morganii

Enterobacter cloacae

Pasteurella multocida

Haemophilus influenzae

(ampicillin-resistant, non-β-lactamase-producing isolates[BLNAR isolates])

Proteus vulgaris

Salmonella species

Serratia marcescens

Hafnia alvei

Shigella species

Klebsiella oxytoca

Yersinia enterocolitica

Anaerobic microorganisms

Bacteroides distasonis

Eubacterium lentum

Bacteroides ovatus

Fusobacterium species

Bacteroides uniformis

Prevotella bivia

Bacteroides ureolyticus

Prevotella intermedia

Bacteroides vulgatus

Prevotella melaninogenica

Clostridium difficile

Clostridium perfringens

Porphyromonas asaccharolytica

Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that 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 dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of meropenem powder. The MIC values should be interpreted according to the criteria provided in Table 2.

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 procedure2,3 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. The disk diffusion interpretive criteria are provided in Table 2.

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 isolates (i.e., MICs = 0.12-1.0 μg/mL) from isolates that are penicillin resistant (i.e., MICs ≥ 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.

Anaerobic techniques

For anaerobic bacteria, the susceptibility to meropenem as MICs can be determined by standardized test methods4. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2.Susceptibility Interpretive Criteria for Meropenem

Susceptibility Test Result Interpretive Criteria

Minimum Inhibitory Concentrations (μg/mL)

Disk Diffusion

(zone diameters in mm)

Pathogen

S

I

R 1

S

I

R

Enterobacteriaceae, Acinetobacter spp. and Pseudomonas aeruginosa

≤ 4

8

≥ 16

≥ 16

14-15

≤ 13

Haemophilus influenzae

≤ 0.5

--

--

≥ 20

--

--

Staphylococcus aureus 2

≤ 4

8

≥ 16

≥ 16

14-15

≤ 13

Streptococcus pneumoniae 3

≤ 0.12

--

--

Streptococcus agalactiae and

Streptococcus pyogenes

≤ 0.5

--

--

Anaerobes 4

≤ 4

8

≥ 16

1 The current absence of data on resistant isolates precludes defining any category other than “Susceptible.”If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
2 Staphylococci that are resistant to methicillin/oxacillin must be considered resistant to meropenem.
3 No Disk diffusion (zone diameter) interpretative criteria have been established for testing Streptococcus pneumoniae, Streptococcus agalactiae, and Streptococcus pyogenes. Use Dilution (MICs) techniques results.
4 MIC values using either Brucella blood or Wilkins Chalgren agar (former reference medium) are considered equivalent, based upon published in vitro literature and a multicenter collaborative trial for these antimicrobial agents.

No interpretative criteria have been established for testing enterococci and Neisseria meningitidis.

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen 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 a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard meropenem powder should provide the following range of values noted in Table 3.

Table 3Acceptable Quality Control Ranges for Meropenem

QC Strain

Minimum Inhibitory Concentrations

(MICs = μg/mL)

Disk Diffusion

(Zone diameters in mm)

Staphylococcus aureus

ATCC 29213

0.03-0.12

Staphylococcus aureu

ATCC 25923

29-37

Streptococcus pneumoniae

ATCC 49619

0.06-0.25

28-35

Enterococcus faecalis

ATCC 29212

2.0-8.0

Escherichia coli

ATCC 25922

0.008-0.06

28–34

Haemophilus influenzae

ATCC 49766

0.03-0.12

Haemophilus influenzae

ATCC 49247

20-28

Pseudomonas aeruginosa

ATCC 27853

0.25-1.0

27-33

Bacteroides fragilis 1

ATCC 25285

0.03-0.25

Bacteroides thetaiotaomicron

ATCC 29741

0.125-0.5

Eubacterium lentum

ATCC 43055

0.125-1

1 Using the Reference Agar Dilution procedure.

CLINICAL STUDIES

Skin and Skin Structure

Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty-one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.

The following table provides the results for the overall as well as subgroup comparisons in clinically evaluable population.

Success Rate 1

Population

MERREM I.V.

n 2 /N 3 (%)

Imipenem-cilastatin

n/N (%)

Total

225/261 (86)

238/287 (83)

Diabetes mellitus

83/97 (86)

76/105 (72)

No diabetes mellitus

142/164 (87)

162/182 (89)

<65 years of age

190/218 (87)

205/241 (85)

≥65 years of age

35/43 (81)

33/46 (72)

Men

130/148 (88)

137/172 (80)

Women

95/113 (84)

101/115 (88)

1 Percent of satisfactory clinical response at follow-up evaluation.
2 n=number of patients with satisfactory response.
3 N=number of patients in the clinically evaluable population or respective subgroup within treatment groups.

The following clinical efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).

MICROORGANISMS 1

MERREM I.V.

n 2 /N 3 (%) 4

Imipenem-cilastatin

n/N (%)

Gram-positive aerobes

Staphylococcus aureus, methicillin susceptible

82/88 (93)

84/100 (84)

Streptococcus pyogenes (Group A)

26/29 (90)

28/32 (88)

Streptococcus agalactiae (Group B)

12/17 (71)

16/19 (84)

Enterococcus faecalis

9/12 (75)

14/20 (70)

Streptococcus viridans Group, nos

11/12 (92)

5/6 (83)

Gram-negative aerobes

Escherichia coli

12/15 (80)

15/21 (71)

Pseudomonas aeruginosa

11/15 (73)

13/15 (87)

Proteus mirabilis

11/13 (85)

6/7 (86)

Anaerobes

Bacteroides fragilis

10/11 (91)

9/10 (90)

Peptostreptococcus species

10/13 (77)

14/16 (88)

1 Patients may have more than one pretreatment pathogen.
2 n=number of patients with satisfactory response.
3 N=number of patients in the clinically evaluable population or subgroup within treatment groups
4 %=Percent of satisfactory clinical response at follow-up evaluation.

The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups. (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

Intra-abdominal

One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).

Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the following presumptive microbiologic eradication/clinical cure rates and statistical findings were obtained:

Treatment Arm

No. evaluable/ No. enrolled (%)

Microbiologic Eradication Rate

Clinical Cure Rate

Outcome

meropenem

146/516 (28%)

98/146 (67%)

101/146 (69%)

imipenem

65/220 (30%)

40/65 (62%)

42/65 (65%)

Meropenem equivalent to control

cefotaxime/ metronidazole

26/85 (30%)

22/26 (85%)

22/26 (85%)

Meropenem not equivalent to control

clindamycin/ tobramycin

50/212 (24%)

38/50 (76%)

38/50 (76%)

Meropenem equivalent to control

The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation.

Bacterial Meningitis

Four hundred forty-six patients (397 pediatric patients > 3 months to < 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg q 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.

Patients were defined as clinically not cured if any one of the following three criteria were met:

  1. At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of >60 decibels in one or both ears, or blindness.

  2. During therapy the patient’s clinical status necessitated the addition of other antibiotics.

  3. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.

Using the definition, the following efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.

MICROORGANISMS

MERREM I.V.

COMPARATOR

S. pneumoniae

17/24 (71)

19/30 (63)

H. influenzae (+) 1

8/10 (80)

6/6 (100)

H. influenzae (-/NT) 2

44/59 (75)

44/60 (73)

N. meningitidis

30/35 (86)

35/39 (90)

Total (including others)

102/131 (78)

108/140 (77)

1 (+) β-lactamase-producing
2 (-/NT) non-β-lactamase-producing or not tested

Sequelae were the most common reason patients were assessed as clinically not cured.

Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa).

The adverse events seen were comparable between the two treatment groups both in type and frequency. The meropenem group did have a statistically higher number of patients with transient elevation of liver enzymes. (See ADVERSE REACTIONS). Rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents. In the MERREM I.V. treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

Degree of Hearing Loss

(in one or both ears)

Meropenem

n = 128

Comparator

n = 135

No loss

61%

56%

20-40 decibels

20%

24%

>40-60 decibels

8%

7%

>60 decibels

9%

10%

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