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Meropenem (Merrem I.V.)

Meropenem is a synthetic carbapenem antibiotic. Unlike imipenem, meropenem has a methyl group at position 1 of the 5-membered ring, which confers stability against hydrolysis by dehydropeptidase 1 (DHP 1) present on the brush border of proximal renal tubular cells and therefore does not require concomitant administration with a DHP-1 inhibitor such as cilastatin.

Meropenem has a broad spectrum of activity that resembles the microbiologic activity of imipenem; however, meropenem generally is more active in vitro against Enterobacteriaceae and less active against gram-positive bacteria.

Meropenem appears to be more susceptible to hydrolysis by metallo-b-lactamases.

The drug generally is inactive against methicillin-resistant staphylococci. Like imipenem, meropenem also is highly resistant to hydrolysis by a variety of b-lactamases.

Meropenem is commercially available as the trihydrate; potency is calculated on the anhydrous basis. Each gram of meropenem provides 3.92 mEq (90. mg) of sodium as sodium carbonate. SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.

Uses

Meropenam is used for the treatment of intra-abdominal infections and meningitis caused by susceptible organisms.The drug also is used for the treatment of respiratory tract infections caused by susceptible organisms and for empiric anti-infective therapy in febrile neutropenic patients.

Prior to initiation of meropenem therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. However, meropenem therapy can be initiated empirically pending completion of susceptibility testing, with continuance or alteration (e.g., substitution of an appropriate alternative anti-infective) determined by the results of the culture and susceptibility tests.

Intra-abdominal Infections

IV meropenem is used for the treatment of intra-abdominal infections caused by susceptible organisms. The drug may be used as monotherapy for the treatment of intra-abdominal infections, including complicated appendicitis and peritonitis caused by susceptible viridans streptococci, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and/or Peptostreptococcus.

Meropenem (Merrem I.V.)

Because meropenem has a broad spectrum of antibacterial activity, the drug may be used empirically to treat intra-abdominal infections before identification of the causative organism. In clinical studies in patients with intra-abdominal infections, meropenem monotherapy was similar in efficacy to a 2-drug regimen of tobramycin and clindamycin or monotherapy with imipenem and cilastatin sodium.

At follow-up 7 or more days after empiric anti-infective therapy was completed, clinical cure was achieved in 69, 76, or 65% of evaluable patients treated with meropenem, tobramycin combined with clindamycin, or imipenem and cilastatin, respectively, and the respective rate of microbiologic eradication was 67, 76, or 62%.

Meropenem monotherapy was less effective than a 2-drug regimen of cefotaxime and metronidazole for empiric treatment of complicated intra-abdominal infections. Clinical cure was achieved in 69 or 85% of evaluable patients treated with meropenem or cefotaxime combined with metronidazole, respectively, and the respective rate of microbiologic eradication was 67 or 85%.

The difference in efficacy between treatments resulted possibly from uneven assignment of patients with more severe infection to the group that received meropenem.

Meningitis

IV meropenem is used for the treatment of bacterial meningitis caused by susceptible Streptococcus pneumoniae, Haemophilus influenzae (including b-lactamase-producing strains), or Neisseria meningitidis in children 3 months of age and older. In addition, concurrent bacteremia associated with bacterial meningitis has been eliminated during therapy with meropenem.

Meropenem can be used as monotherapy for the treatment of meningitis; however, efficacy of meropenem monotherapy for the treatment of meningitis caused by penicillin-resistant S. pneumoniae has not been established. In clinical studies that included children who were at least 3 months of age but younger than 17 years old, clinical cure of bacterial meningitis was achieved in 71 or 63% of evaluable patients treated with meropenem or a comparative anti-infective (e.g., cefotaxime, ceftriaxone) administered at usual dosages, respectively, and in whom the causative organism was S. pneumoniae; in 80 or 100% of evaluable patients who received either therapy, respectively, and in whom the causative organism was b-lactamase-producing H. influenzae; in 75 or 73% of evaluable patients who received either therapy, respectively, and in whom the causative organism was H. influenzae that either did not produce b-lactamase or were not tested for such; and in 86 or 90% of evaluable patients who received either therapy, respectively, and in whom the causative organism was N. meningitidis.

Overall, with inclusion of the results with other causative organisms, clinical cure was achieved in 78 or 77% of patients who received either therapy, respectively.

Clinical cure was not achieved if moderate to severe motor, behavior, or development deficits, hearing loss exceeding 60 decibels in either or both ears, or blindness was present at follow-up 5-7 weeks after completion of therapy; if other anti-infectives were added to either therapy; or if a large subdural effusion that required surgical drainage, a cerebral abscess, or bacteriologic relapse developed during therapy or after its completion.

Clinical cure was not considered to have been achieved most commonly because sequelae developed. Bacteriologic cure was not achieved with meropenem in some patients because of relapse or continual growth of Ps. aeruginosa; comparative treatment did not result in bacteriologic cure in some patients because of relapse or the development of cerebral abscess.

Seizures and other adverse CNS effects have been reported during meropenem therapy, occurring most commonly in patients with underlying CNS disorders (e.g., brain lesion, seizure history), bacterial meningitis, or compromised renal function. During initial clinical studies in patients with infections outside the CNS, seizures (whether drug related or not) occurred in 0.7% of meropenem-treated patients; all patients developing seizures during meropenem therapy had preexisting contributing factors such as concomitant therapy with a drug with seizure potential, seizure history, or underlying CNS abnormality.

Respiratory Tract Infections

Meropenem has been used in the treatment of respiratory tract infections, including community-acquired pneumonia (CAP) and nosocomial pneumonia.

Community-acquired Pneumonia

Although meropenem generally is active against S. pneumoniae (including drug-resistant S. pneumoniae), the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) state that the drug is not usually considered a drug of first choice for the empiric treatment of CAP. The ATS suggests that use of meropenem in the treatment of CAP be reserved for patients at risk for Ps. aeruginosa infections.

Factors that increase the risk of Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an intensive care unit (ICU), structural lung disease (bronchiectasis, cystic fibrosis), corticosteroid therapy (prednisone dosage exceeding 10 mg daily), broad-spectrum anti-infective therapy given for longer than 7 days within the past month, and malnutrition. In CAP patients with risk factors for Ps. aeruginosa, the ATS recommends use of an empiric regimen that includes 2 antipseudomonal agents and also provides coverage for drug-resistant S. pneumoniae and Legionella.

These experts suggest that this can be accomplished with a regimen that includes an IV antipseudomonal b-lactam anti-infective (e.g., cefepime, piperacillin and tazobactam, imipenem, meropenem) in conjunction with an IV antipseudomonal fluoroquinolone (e.g., ciprofloxacin) or a regimen that includes one of these IV antipseudomonal b-lactam anti-infectives, an IV aminoglycoside, and either an IV macrolide (e.g., azithromycin) or an IV nonpseudomonal quinolone. If anaerobic bacteria have been identified or are suspected in patients with pulmonary infections, the IDSA recommends use of clindamycin, a b-lactam/b-lactamase inhibitor combination, imipenem, or meropenem.

Empiric Therapy in Febrile Neutropenic Patients

Meropenem is used alone or in conjunction with other anti-infectives for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients. Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present.

The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding usual pathogens in these patients and data regarding their in vitro susceptibility to available anti-infective agents.

The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen. No empiric regimen has been identified that would be appropriate for all patients.

Regimens that have been recommended for empiric therapy in febrile neutropenic patients with presumed bacterial infections include monotherapy with a third or fourth generation cephalosporin (i.e., ceftazidime, cefepime) or a carbapenem (e.g., imipenem and cilastatin sodium, meropenem); combination therapy consisting of a b-lactam antibiotic (e.g., ceftazidime, ceftriaxone), a carbapenem (e.g., imipenem, meropenem), an extended-spectrum penicillin (e.g., mezlocillin, piperacillin, ticarcillin), or a fixed combination of an extended-spectrum penicillin and a b-lactamase inhibitor (e.g., piperacillin sodium and tazobactam sodium, ticarcillin disodium and clavulanate potassium) given in conjunction with an aminoglycoside (e.g., amikacin, gentamicin, tobramycin); or combination therapy consisting of 2 b-lactam antibiotics (e.g., ceftazidime given with piperacillin).

The IDSA recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate) should only be considered in selected adults at low risk for complications who have no focus of bacterial infection and no signs or symptoms of systemic infection other than fever.

At health-care facilities where gram-positive bacteria are common causes of serious infection and use of vancomycin in the initial empiric regimen is considered necessary, the IDSA recommends 2- or 3-drug combination therapy that includes vancomycin and either cefepime, ceftazidime, imipenem, or meropenem given with or without an aminoglycoside; vancomycin should be discontinued 24-48 hours later if a susceptible gram-positive bacterial infection is not identified.

At health-care facilities where vancomycin is not indicated in the initial empiric regimen, the IDSA recommends monotherapy with a third or fourth generation cephalosporin (ceftazidime, cefepime) or a carbapenem (imipenem, meropenem) for uncomplicated cases; however, for complicated cases or if anti-infective resistance is a problem, combination therapy consisting of an aminoglycoside (amikacin, gentamicin, tobramycin) given in conjunction with an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), an antipseudomonal cephalosporin (cefepime, ceftazidime), or a carbapenem (imipenem, meropenem) is recommended.

Regardless of the initial regimen selected, patients should be reassessed after 3-5 days of treatment and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient.

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.

Dosage and Administration

Reconstitution and Administration

Meropenem is administered by IV injection or infusion.

Meropenem (Merrem I.V.)

For direct intermittent IV injection, 10 or 20 mL of sterile water for injection should be added to a vial labeled as containing 500 mg or 1 g, respectively, of meropenem to provide a solution containing approximately 50 mg of meropenem per mL. The vial should be shaken until dissolution occurs and then allowed to stand until the solution is clear. The appropriate dose of reconstituted solution may then be injected over a 3- to 5-minute period.

For intermittent IV infusion, piggyback vials containing 500 mg or 1 g of meropenem should be reconstituted with a compatible IV solution (e.g., 0.9% sodium chloride, 5% dextrose) to provide solutions containing approximately 2.5-50 mg/mL of the drug.

Alternatively, the contents of vials containing 500 mg or 1 g of meropenem may be initially reconstituted, as for direct intermittent IV injection, and then the resultant solution of drug added to a container of compatible IV solution for further dilution. ADD-Vantage® vials containing meropenem should be reconstituted according to the manufacturer’s directions with the diluent provided. The ADD-Vantage® system should not be used in series connections.

Meropenem generally should be infused IV over 15-30 minutes.

Meropenem solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Meropenem is commercially available as the trihydrate; potency and dosage of the drug are expressed on the anhydrous basis. To minimize the risk of seizures, close adherence to recommended meropenem dosage regimens is urged, especially in patients with factors known to predispose to seizure activity; dosage adjustment is recommended for patients with advanced age and/or renal impairment.

Anticonvulsant therapy should be continued in patients with existing seizure disorders. If focal tremors, myoclonus, or seizures develop during meropenem therapy, neurologic evaluation should be performed, anticonvulsant therapy initiated, and dosage of meropenem reassessed to determine whether it should be reduced or the anti-infective discontinued.

Adult Dosage

The usual adult dosage of meropenem is 1 g every 8 hours; dosage should not exceed 2 g (e.g., for meningitis) every 8 hours. The manufacturer states that dosage adjustment is not necessary for geriatric patients with creatinine clearances exceeding 50 mL/minute. For geriatric patients with poorer renal function, dosage should be adjusted according to the guidelines for other renally impaired adults. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Dosage

The manufacturer recommends that children 3 months of age and older weighing 50 kg or less receive meropenem in a dosage of 20-40 mg/kg every 8 hours depending on the type of infection. The maximum pediatric dosage is 2 g every 8 hours. For the treatment of intra-abdominal infections in pediatric patients, the recommended dosage is 20 mg/kg every 8 hours; children weighing more than 50 kg should receive 1 g every 8 hours. For the treatment of meningitis in pediatric patients, the recommended dosage is 40 mg/kg every 8 hours; children weighing more than 50 kg should receive 2 g every 8 hours.

Meropenem (Merrem I.V.)

Dosage in Renal and Hepatic Impairment

Dosage of meropenem should be modified according to the degree of renal impairment for adults with creatinine clearances of 50 mL/minute or less.

The manufacturer states that adults with a creatinine clearance of 26-50 mL/minute can receive the usual dose (i.e., 1 g) every 12 hours, those with a creatinine clearance of 10-25 mL/minute can receive half the usual dose every 12 hours, and those with a creatinine clearance of less than 10 mL/minute can receive half the usual dose every 24 hours. If a measured creatinine clearance is unavailable, the patient’s creatinine clearance (Ccr) can be estimated using the following formulas: The manufacturer states that information on the use of meropenem in hemodialysis patients is inadequate and that the effect of peritoneal dialysis on the drug is unknown.

The manufacturer also states that there is a lack of experience with use of the meropenem in pediatric patients with renal impairment. The manufacturer states that patients with hepatic impairment do not require adjustment of meropenem dosage.

Preparations

Meropenem (Trihydrate) Parenteral For injection, for 500 mg (of anhydrous Merrem® I.V., (with sodium IV use only meropenem) carbonate) AstraZeneca Merrem® I.V. ADD-Vantage®, (with sodium carbonate) AstraZeneca 1 g (of anhydrous meropenem) Merrem® I.V., (with sodium carbonate) AstraZeneca Merrem® I.V. ADD-Vantage®, (with sodium carbonate) AstraZeneca

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