Meropenem, 1 g

Pharmacotherapeutic group:

An antibiotic, carbapenem

ATX code: J01DH02

Pharmacokinetics

Intravenous administration for 30 minutes of meropenem to healthy volunteers results in a maximum plasma concentration of approximately 11 µg/mL for the 250 mg dose, 23 µg/mL for the 500 mg dose and 49 µg/mL for the 1 g dose.

However, there is no absolute pharmacokinetic proportional relationship to the administered dose with respect to maximum concentration (C m ah ) and area under the pharmacokinetic concentration-time curve ( AUC ). A decrease in plasma clearance from 287 to 205 mL/min was observed for doses from 250 to 2 g.

Intravenous bolus injection of meropenem in healthy volunteers for 5 minutes results in a maximum plasma concentration of approximately 52 µg/mL for the 500 mg dose and 112 µg/mL for the 1 g dose.

6 hours after intravenous administration of 500 mg, plasma concentrations of meropenem decrease to values of 1 µg/ml or lower.

Longer infusion (up to 3 hours) of carbapenems may lead to optimization of their pharmacokinetic and pharmacodynamic parameters. When standard 30-minute ‑infusion in healthy volunteers of two doses of 500 and 2000 mg every 8 hours, the % T >MIC (ratio between the period of time when the drug concentration exceeds the MIC and the dosing interval; MIC=4 µg/ml) values were 30% and 58%, respectively. When the same doses were administered to volunteers by 3-hour infusion every 8 hours, the %T>MIC increased to 43% and 73% for 500 and 2000 mg, respectively. Mean plasma concentrations in healthy volunteers after intravenous bolus administration for 10 minutes of 1000 mg exceeded the MIC of 4 μg/mL for 42% of the dosing interval compared with 59% for a 3-hour infusion of 1000 mg.

Meropenem penetrates well into most tissues and body fluids, including the cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations in excess of those required to suppress most bacteria.

There is no cumulation of the drug when repeated administration of meropenem at 8-hour intervals in patients with normal renal function. In patients with normal renal function the elimination half-life is approximately 1 hour. Binding to plasma proteins is approximately 2%.

About 70% of the intravenous dose of meropenem is excreted unchanged ‑by the kidneys within 12 hours, after which minor renal excretion is determined. Urinary concentrations of meropenem exceeding 10 µg/mL are maintained for hours after administration of a 500 mg dose. No cumulation of meropenem in plasma and urine was observed in volunteers with normal hepatic function when the regimens were administered 500 mg every 8 hours or 1 g every 6 hours.

The only metabolite of meropenem is microbiologically inactive.

Studies in children have shown that the pharmacokinetics of meropenem in children and adults are similar. The half-life of meropenem in children under 2 years of age is approximately 1.5-2.3 hours, with a linear relationship in the dose range of 10-40 mg kg.

Renal Impairment

Pharmacokinetic studies in patients with renal impairment have shown that meropenem clearance correlates with creatinine clearance. Dose adjustment is necessary in these patients.

A study of pharmacokinetics in the elderly showed decreased clearance of meropenem that correlated with age-related decreases in creatinine clearance.

Meropenem is excreted by hemodialysis with a clearance estimated to be 4 times that of meropenem in patients with anuria.

Hepatic impairment

Pharmacokinetics studies in patients with liver disease have shown that these pathological changes have no effect on the pharmacokinetics of meropenem.

Pharmacodynamics

Meropenem is an antibiotic of the carbapenem class, intended for parenteral administration, is relatively resistant to human dehydropeptidase-1 (HDP-1) and does not require additional HDP-1 inhibitor administration. Meropenem has a bactericidal effect due to its effect on the synthesis of the bacterial cell wall. High bactericidal activity of meropenem against a wide range of aerobic and anaerobic bacteria is explained by high ability of meropenem to penetrate through the bacterial cell wall, high level of stability to most beta-lactamases and significant affinity to various penicillin-binding proteins (PBPs).

The minimum bactericidal concentrations (MBCs) are generally the same as the minimum inhibitory concentrations (MICs). For 76% of the bacterial species tested, the MBC/MIR ratio was 2 or less.

In vitro tests show that meropenem acts synergistically with various antibiotics. In both in vitro and in vivo tests, meropenem has been shown to have a postantibiotic effect.

Microorganisms may have one or more of the following mechanisms of resistance to meropenem: disruption of the permeability of the cell wall of Gram-negative bacteria due to impaired porin synthesis; decrease in affinity to target PSBs; activation of efflux mechanisms; production of beta-lactamases that hydrolyze carbapenems.

The only recommended criteria for sensitivity to meropenem are based on the pharmacokinetics of the drug and on correlation of clinical and microbiological data – zone diameter and MIC determined for the corresponding pathogens.

Sensitivity to meropenem should be determined using standard methods. Interpretation of results should be performed according to local guidelines.

The efficacy of the drug against the pathogens listed below has been confirmed by clinical experience and antibiotic therapy guidelines. Pathogens susceptible to meropenem:

Gram-positive aerobes: Enterococcus faecalis1, Staphylococcus aureus (methicillin-sensitive‑)2, genus Staphylococcus ( methicillin-sensitive) including Staphylococcus epidermidis, Streptococcus agalactiae group B , group Streptococcus milleri (S. an ginosus, S. constellatus, S. intermedius ), Streptococcus pneumoniae , Streptococcus pyogenes group A.

Gram-negative aerobes: Citrobacter freudii, Citrobacter koseri, Enterobacter aerogenes. Enterobacter cloacae , Escherichia coli, Haemophilus influenzae , Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis , Proteus mirabilis, Proteus vulgaris, Serratia marcescens.

Gram-positive anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, genus Peptostreptococcus (including P. micros, P. anaerobius, P. magnus).

Gram-negative anaerobes: Bacteroides caccae, Bacteroides fragilis, Prevotella bivia , Prevotella disiens.

Pathogens for which the problem of acquired resistance is relevant:

Gram-positive aerobes: Enterococcu s faecium1.

Gram-negative aerobes: genus Acinetobacter , Burkholderia cepacia , Pseudomonas aeruginosa .

Pathogens with natural resistance:

Gram-negative aerobes: Stenotrophomonas maltophilia , Legionella spp .

Other pathogens: Chlamydophila pneumoniae , Chlamydophila psittaci, Coxiella burnetii. Mycoplasma pneumoniae.

1 – pathogens with intermediate sensitivity.

2 – all methicillin-resistant staphylococci are resistant to meropenem.

Indications

Infectious-inflammatory diseases (monotherapy or in combination with other antimicrobial medicines) caused by pathogens sensitive to meropenem:

Active ingredient

Composition

In 1 vial contains:

Active substances:

1 g meropenem.

Excipients:

Sodium carbonate anhydrous 208 mg.

How to take, the dosage

In/vitro for adults a single dose varies from 500 mg to 2 g, the frequency of administration and duration of treatment are determined individually, depending on the indication and the severity of the disease.

In children with body weight less than 50 kg – 10-12 mg/kg every 8 hours; in children with body weight over 50 kg the same doses intended for adults are used.

I/m adults – 500 mg every 8 hours, elderly patients – 500 mg every 12 hours.

Interaction

Probenecid competes with meropenem for active tubular secretion and thus inhibits renal excretion of meropenem, causing an increase in its half-life and plasma concentrations (concomitant use is not recommended).

The use of Meropenem only by prescription, the instructions are for reference!

Special Instructions

Treatment of patients with liver disease should be carried out under close control of the activity of “hepatic” transaminases and bilirubin concentration. In the course of treatment the development of pathogen resistance is possible; therefore, long-term treatment is carried out under constant control of the spread of resistant strains.

In patients with gastrointestinal diseases, especially with colitis, it is necessary to consider the possibility of pseudomembranous colitis (toxin produced by Clostridium difficile is one of the main causes of colitis associated with antibiotics), the first symptom of which may be development of diarrhea during treatment.

When meropenem is used as monotherapy in critically ill patients with an identified or suspected lower respiratory tract infection caused by Pseudomonas aeruginosa, regular testing for sensitivity of the pathogen to meropenem is recommended.

There is no experience of using the drug in children with neutropenia or primary or secondary immunodeficiency.

Contraindications

Hypersensitivity to meropenem or other beta-lactam antibiotics in the history, children under 3 months of age.

Cautions
Concurrent administration with potentially nephrotoxic drugs.

Persons with gastrointestinal complaints (including colitis).

Side effects

Digestive system disorders: epigastric pain, nausea, vomiting, diarrhea, constipation, anorexia, jaundice, cholestatic hepatitis, hyperbilirubinemia, increased activity of “liver” transaminases, alkaline phosphatase, lactate dehydrogenase; rarely – candidiasis of the oral mucosa, pseudomembranous colitis.

Cardiovascular system disorders:development or exacerbation of heart failure, cardiac arrest, tachy or bradycardia, decreased or increased blood pressure, syncope, myocardial infarction, pulmonary artery branch thromboembolism.

Urinary system disorders:dysuria, edema, renal dysfunction (hypercreatininemia, increased concentration of urea in plasma), hematuria.
Allergic reactions:Itchy skin, skin rash, urticaria, erythema multiforme (Stevens-Johnson syndrome), angioedema, anaphylactic shock.

Nervous system disorders:headache, dizziness, paresthesias, insomnia, drowsiness, increased excitability, agitation, anxiety, depression, impaired consciousness, hallucinations, epileptiform seizures, seizures.

Laboratory findings:eosinophilia, neutropenia, leukopenia, rarely agranulocytosis, hypokalemia, leukocytosis, reversible thrombocytopenia, decreased partial thromboplastin time, anemia.

Local reactions:Inflammation, phlebitis, thrombophlebitis, pain at the injection site.

Others:positive direct or indirect Coombs test, hypervolemia, dyspnea, vaginal candidiasis/

.

Overdose

Possible overdose during treatment, especially in patients with impaired renal function.

Treatment:Symptomatic therapy is carried out.

In normal cases the drug is rapidly eliminated through the kidneys.

In patients with impaired renal function, hemodialysis effectively removes meropenem and its metabolite.

Pregnancy use

Pregnancy

The safety of meropenem in women during pregnancy has not been studied. Animal studies have shown no adverse effects on the developing fetus.

Meropenem should not be used during pregnancy unless the potential benefit to the mother from its use exceeds the possible risk to the fetus. In each case, the drug should be used under close medical supervision.

Breast-feeding period

There is evidence of meropenem excretion with breast milk. Meropenem should not be used during breastfeeding unless the potential benefit to the mother from using the drug exceeds the possible risk to the baby. After assessing the benefit to the mother, the decision should be made to stop breastfeeding or discontinue the drug.

Similarities