Meropenem is an ultra-broad spectrum injectable
antibiotic used to treat a wide variety of infections. It is a
b-lactam and belongs to the subgroup of carbapenem,
similar to imipenem and ertapenem. Meropenem was originally developed by
Dainippon Sumitomo Pharma . It gained US FDA approval in July 1996. It
penetrates well into many tissues and body fluids including the cerebrospinal
fluid, bile, heart valves, lung, and peritoneal fluid. It is active against
Gram-positive and Gram-negative bacteria. Meropenem exerts its action by
penetrating bacterial cells readily and interfering with the synthesis of vital
cell wall components, which leads to cell death. 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
For use as single agent therapy for the treatment of the following infections when caused by susceptible isolates of the designated microorganisms: complicated skin and skin structure infections due to Staphylococcus aureus (b-lactamase and non-b-lactamase producing, methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species; complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. Also for use in the treatment of bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (b-lactamase and non-b-lactamase-producing isolates), and Neisseria meningitidis. Meropenem is frequently given in the treatment of febrile neutropenia. This condition frequently occurs in patients with hematological malignancies and cancer patients receiving anticancer drugs that cause bone marrow suppression.
meropenem I.V. is indicated as single
agent therapy for the treatment of the following infections when caused by
susceptible isolates of the designated microorganisms:
Dosage and Administration
Meropenem must be administered intravenously. It is supplied as a white crystalline powder to be dissolved in 5% monobasic potassium phosphate solution. Dosing must be adjusted for altered kidney function and for haemofiltration .
The recommended dose of meropenem I.V. is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. meropenem I.V. should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.
Use in Adults with Renal Impairment
Dosage should be reduced in patients with creatinine clearance less than 51 mL/min. (see dosing table below).
Recommended meropenem I.V. Dosage Schedule for Adults With Impaired Renal Function (Table 1)
When only serum creatinine is available, the following formula (Cockcroft and Gault equation)5 may be used to estimate creatinine clearance.
Males: Creatinine Clearance (mL/min)=
Weight (kg) x (140 - age)
72 x serum creatinine (mg/dL)
Females: 0.85 x above value
There is inadequate information regarding the use of meropenem I.V. in patients on hemodialysis.
There is no experience with peritoneal dialysis.
Use in Adults With Hepatic Insufficiency
No dosage adjustment is necessary in patients with impaired hepatic function.
Use in Elderly Patients
No dosage adjustment is required for elderly patients with creatinine clearance values above 50 mL/min.
Use in Pediatric Patients
For pediatric patients from 3 months of age and older, the meropenem I.V. dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered meropenem I.V. at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. meropenem I.V. should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.
Recommended meropenem I.V. Dosage Schedule for Pediatrics with Normal Renal Function (Table 2)
There is no experience in pediatric patients with renal impairment.
In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.
Pseudomembranous colitis has been
reported with nearly all antibacterial agents, including meropenem, and may
range in severity from mild to life-threatening. Therefore, it is important to
consider this diagnosis in patients who present with diarrhea subsequent to the
administration of antibacterial agents.
Common adverse effects
Meropenem has an half life of
approximately 1 hour in adults and children 2 years of age and older with normal
renal function. Approximately 1.5 hours in children 3 months to 2 years of age.
The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg.
At the end of a 30-minute intravenous infusion of a single dose of meropenem 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 meropenem 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.
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 meropenem 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 3 below.
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.
There is one metabolite which is microbiologically inactive.
Stability in biological fluids 
In Vitro Permeation of Meropenem across Rat Ileal Segments
The cumulative permeation of meropenem (1 mM) across rat ileal segments almost linearly increased with time both in mucosal-to-serosal and serosal-to-mucosal directions. The S- to-M permeation of meropenem across rat ileal segments was much greater than the M-to-S permeation, and the S-to-M/M-to-S ratio of permeation rate was approximately 4.9 (Table 4). Similarly to meropenem, the permeation of cefotaxime, an orally inactive cephem antibiotic, across rat ileal seg-ments was greatly secretory-oriented and the S-to-M/M-to-S ratio of permeation rate was approximately 5.9.
Table 4. Permeation rates of meropenem, cefotaxime, ceftibuten, and faropenem across rat ileum.
Stability of Meropenem in JP 1st and 2nd Fluids
In the JP 2nd fluid with pH of 6.8, meropenem was stable and only 10% was disappeared after 6 h at 37˚C. However, meropenem was very unstable in the JP 1st fluid with pH of 1.2 and approximately 80% of meropenem disappeared by 30 min after the start of incubation. Although cefotaxime, ceftibuten, and faropenem time-dependently disappeared in the JP 1st fluid, they are rather stable compared with meropenem. The percentage of cefotaxime, ceftibuten, and faropenem remaining in the JP 1st fluid after incubation for 1 h were 65.0%, 94.1%, and 70.2%, respectively.
Stability of Meropenem in Supernatant Fluid Obtained from Mucosal Homogenate of Rat Small Intestine
Only slight decrease (approximately 5%) in meropenem concentration was observed in the absence or pre- sence of the supernatant fluids for 60 min.
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.
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).
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%).
One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared to clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared to 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:
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.
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:
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.
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.
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 meropenem 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.
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.
Other pharmacological effects
CAS number: 119478-56-7
Molecular Formula: C17H25N3O5S
Average mass: 383.462494 Da
Monoisotopic mass: 383.151489 Da
Systematic name: 3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6- (1-hydroxyethyl)-4-methyl-7-oxo- 1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid
Std. InChI: 1S/C17H25N3O5S/c1-7-12-11(8(2)21)16(23)20(12)13(17(24)25)14(7)26-9-5-10(18-6-9)15(22)19(3)4/h7-12,18,21H,5-6H2,1-4H3,(H,24,25)/t7-,8-,9+,10+,11-,12-/m1/s1
Appearance: White to pale yellow crystalline powder.
Solubility: 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.
1. Edwards JR, Turner PJ, Wannop C, Withnell ES, Grindey AJ, Nairn K. "In vitro antibacterial activity of SM-7338, a carbapenem antibiotic with stability to dehydropeptidase I". Antimicrob. Agents Chemother. 33, (2): 215-22, 1989.
2. AHFS DRUG INFORMATION 2006 (2006 ed.). American Society of Health-System Pharmacists. 2006.
3. Bilgrami, I.; Roberts, J. A.; Wallis, S. C.; Thomas, J.; Davis, J.; Fowler, S.; Goldrick, P. B.; Lipman, J. "Meropenem Dosing in Critically Ill Patients with Sepsis Receiving High-Volume Continuous Venovenous Hemofiltration". Antimicrobial Agents and Chemotherapy 54, (7): 2974–2978, 2010.
4. Toshihide Saito, Rinako Sawazaki, Kaori Ujiie, Masako Oda, Hiroshi Saitoh "Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic". Pharmacology & Pharmacy, 3, 201-206, (2012).
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