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Merrem IV

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Merrem I.V.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Meropenem is an antibacterial drug.

Pharmacokinetics

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of MERREM I.V. in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of MERREM I.V. in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/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 mcg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of meropenem is approximately 2%.

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

Tissue I.V. Dose (g) Number of Samples Mean [μg/mL or mcg/(g)]1 Range [μg/mL or mcg/(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 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 fluid2 0.5 9 5.5 3.2-8.6
Skin 1 10 5.3 1.3–16.7
Interstitial fluid2 1 5 26.3 20.9–37.4
Colon 1 2 2.6 2.5–2.7
Bile 1 7 14.6 (3 h) 4.0–25.7
Gall bladder 1 1 3.9
Peritoneal fluid 1 9 30.2 7.4–54.6
Lung 1 2 4.8 (2 h) 1.4–8.2
Bronchial mucosa 1 7 4.5 1.3–11.1
Muscle 1 2 6.1 (2 h) 5.3–6.9
Fascia 1 9 8.8 1.5–20
Heart valves 1 7 9.7 6.4–12.1
Myocardium 1 10 15.5 5.2–25.5
CSF (inflamed) 20 mg/kg3 40 mg/kg4 8 5 1.1 (2 h) 3.3 (3 h) 0.2-2.8 0.9-6.5
CSF (uninflamed) 1 4 0.2 (2 h) 0.1–0.3
1at 1 hour unless otherwise noted
2obtained from blister fluid
3in pediatric patients of age 5 months to 8 years
4in pediatric patients of age 1 month to 15 years

Metabolism

There is one metabolite of meropenem that is microbiologically inactive.

Excretion

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour.

Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50 – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations

Renal Impairment

Pharmacokinetic studies with MERREM I.V. in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see OVERDOSAGE].

Hepatic Impairment

A pharmacokinetic study with MERREM I.V. in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Geriatric Patients

A pharmacokinetic study with MERREM I.V. in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

The pharmacokinetics of meropenem 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.

Drug Interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended.

Microbiology

Mechanism of Action

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, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

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 PBPs, 3) increased expression of efflux pump components, and 4) production of antibiotic-destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.

Cross-Resistance

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

Interactions with Other Antibiotics

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

Spectrum of Activity

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

Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus
(methicillin-susceptible isolates only)
Streptococcus agalactiae

Streptococcus pneumoniae
(penicillin-susceptible isolates only)
Streptococcus pyogenes
Viridans group streptococci

Gram-negative bacteria

Escherichia coli
Haemophilus influenzae

Klebsiella pneumoniae

Neisseria meningitidis

Pseudomonas aeruginosa

Proteus mirabilis

Anaerobic bacteria

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 bacteria have exhibited in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoints for meropenem. However, the safety and effectiveness of meropenem in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.

Gram-positive bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Gram-negative bacteria

Aeromonas hydrophila
Campylobacter jejuni

Citrobacter koseri
(formerly diversus)
Citrobacter freundii

Enterobacter cloacae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Pasteurella multocida

Proteus vulgaris

Serratia marcescens

Anaerobic bacteria

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 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 test method. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent using 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. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-mcg of meropenem to test the susceptibility of microorganisms to meropenem. The disk diffusion interpretive criteria are provided in Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to meropenem as MICs can be determined by a standardized test method2,4. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2: Susceptibility Interpretive Criteria for Meropenem

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
S I R S I R
Enterobacteriaceae ≤ 1 2 ≥ 4 ≥ 23 20-22 ≤ 19
Pseudomonas aeruginosa a ≤ 2 4 ≥ 8 ≥ 19 16-18 ≤ 15
Haemophilus influenzae b ≤ 0.5 ≥ 20
Neisseria meningitidis b ≤ 0.25 ≥ 30
Streptococcus pneumoniae c,e ≤ 0.25 0.5 ≥ 1
Streptococcus agalactiae and Streptococcus pyogenesb,d,e ≤ 0.5
Anaerobes f ≤ 4 8 ≥ 16
S = Susceptible, I = Intermediate, R = Resistant
No interpretative criteria have been established for testing enterococci.
Susceptibility of staphylococci to meropenem may be deduced from testing penicillin and either cefoxitin or oxacillin.
aThe interpretive criteria for P. aeruginosa are based upon the dosing of 1g every 8 hours
bThe 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 additional testing.
cFor nonmeningitis isolates of S. pneumoniae a penicillin MIC of ≤ 0.06 mcg/mL or oxacillin zone ≥ 20 mm can predict susceptibility to meropenem. MIC testing should be performed on isolates that do not test as susceptible by either of these methods, and on all meningitis S. pneumoniae isolates.
dViridans group streptococci should be tested for meropenem susceptibility using an MIC method and results should be reported using the interpretive criteria listed for S. agalactiae and S. pyogenes.
eReliable disk diffusion tests for meropenem do not yet exist for testing streptococci
fMIC 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. Broth microdilution is only recommended for testing the B. fragilis group. MIC values for agar or broth microdilution are considered equivalent for that group.

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 controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard meropenem powder should provide the following range of values noted in Table 3.

Table 3: Acceptable Quality Control Ranges for Meropenem

QC Strain Minimum Inhibitory Concentrations (MICs = mcg/mL) Disk Diffusion (Zone diameters in mm)
Staphylococcus aureus ATCC 29213 0.03-0.12
Staphylococcus aureus ATCC 25923 29–37
Streptococcus pneumoniae ATCC 49619 0.06-0.25 28–35
Enterococcus faecalis ATCC 29212 2–8  
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 27–33
Bacteroides fragilis1 ATCC 25285 0.03–0.25  
Bacteroides thetaiotaomicron1 ATCC 29741 0.125-0.5  
Eubacterium lentum1 ATCC 43055 0.125-1  
Clostridium difficile1 ATCC 700057 0.5-4  
1Using the Reference Agar Dilution procedure

Clinical Studies

Complicated Skin and Skin Structure Infections

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 Rate1
Population MERREM I.V. n2/N3 (%) Imipenem-cilastatin n2/N3 (%)
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)
1Percent of satisfactory clinical response at follow-up evaluation.
2n=number of patients with satisfactory response.
3N=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).

MICROORGANISMS1 MERREM I.V. n2/N3 (%)4 Imipenem-cilastatin n2/N3 (%)4
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.
2n=number of patients with satisfactory response.
3N=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%).

Complicated Intra-Abdominal Infections

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 every 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%

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013

4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard -Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012

Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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