Meropenem, 1 g

Pharmacotherapeutic group: Antibiotic, carbapenem

ATX code: J01DH02

Pharmacological action

Antibiotic for parenteral use from the group of carbapenems. It has bactericidal action (inhibits synthesis of the bacterial cell wall), easily penetrates through the cell wall of bacteria, resistant to most beta-lactamases.

In contrast to imipenem, it is practically not degraded in renal tubules by dehydropeptidase-1 (it does not need to be combined with cilastatin, a specific inhibitor of dehydropeptidase-1) and, correspondingly, nephrotoxic breakdown products are not formed; it has high affinity to penicillin-binding proteins.

Bactericidal and bacteriostatic concentrations are almost indistinguishable.

It interacts with receptors – specific penicillin-binding proteins on the surface of cytoplasmic membrane, inhibits synthesis of peptidoglycan layer of cell wall, inhibits transpeptidase, promotes release of autolytic enzymes of cell wall which finally causes its damage and death of bacteria.

The spectrum of antibacterial activity of meropenem includes most clinically relevant Gram-positive and Gram-negative aerobic and anaerobic bacterial strains:

Gram-positive aerobes: Enterococcus faecalis (including vancomycin-resistant strains); Staphylococcus aureus(penicillinase-producing and penicillinase-producing [methicillin-sensitive]): Streptococcus agalactiae; Streptococcus pneumoniae (penicillin-sensitive only); Streptococcus pyogenes; Streptococcus spp. viridans group.

Gram-negative aerobes: Escherichia coli; Haemophilus influenzae (penicillin- and penicillin-insensitive); Klebsiella pneumoniae; Neisseria meningitidis; Pseudomonas aeruginosa; Proteus mirabilis.

Anaerobic bacteria: Bacteroides fragilis; Bacteroides thetaiotaomicron; Peptostreptococcus spp.

Meropenem is effective in vitro against the following microorganisms; however, its clinical efficacy in diseases caused by these pathogens has not been proven:

Gram-positive aerobes: Staphylococcusepidermidis (penicillinase- and penicillinase-producing |methicillin-sensitive]).

Gram-negative aerobes: Acinetobacter spp.Aeromonas hydrophila; Campylobacter jejuni; Citrobac-ter diversus; Citrobacter freundii; Enterobacter cloacae; Haemophilus influenzae (ampicillin-resistant, penicillin-zone-producing strains); Hafnia alvei; Klebsiella oxytoca; Moraxella catarrhalis (penicillinase-producing and penicillinase-producing); Morganella morganii; Pasteurella multocida; Proteus vulgaris; Salmonella spp.; Serratia marcescens; Shigella spp.; Yersinia enterocolitica.

Anaerobic bacteria: Bacteroides distasonis; Bacteroides ovatus; Bacteroides uniformis; Bacteroides chereoluticus; Bacteroides vulgatus; Clostridium difficile; Clostridium perfringens; Eubacterium lentum; Fusobacterium spp.Prevotella bivia; Prevotella intermedia; Prevotella melaninogenica; Porphyromonas asaccharolytica; Propionibacterium acnes.

Pharmacokinetics

When administered v/v in 250 mg for 30 min, C_max – 11 µg/mL, for a dose of 500 mg, 23 µg/mL, and 1 g, 49 µg/mL (there is no absolute pharmacokinetic proportional relationship to the administered dose for C_max and AUC). When the dose is increased from 0.25 to 2 g, clearance decreases from 287 to 205 mL/min. When 500 mg C_max is 52 mcg/mL, 1 g is 112 mcg/mL when administered by IV bolus for 5 min. The binding to plasma proteins is 2%.

It penetrates well into most tissues and body fluids, including cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required for suppression of most bacteria (bactericidal concentrations are established 0.5-1.5 hours after infusion start). It penetrates into breast milk in insignificant amounts.

It is slightly metabolized in the liver with the formation of a single inactive metabolite. T_1/2 – 1 h, in children under 2 years 1.5-2.3 h. There is a linear dependence of pharmacokinetic parameters in the dose range of 10-40 mg/kg in adults and children. It does not cumulate. It is excreted by the kidneys – 70% unchanged within 12 hours. Urinary concentration of meropenem exceeding 10 µg/ml is maintained for 5 hours after administration of 500 mg. In patients with renal insufficiency, clearance correlates with creatinine clearance (CK). In elderly patients, decreased clearance of meropenem correlates with decreased CK associated with age. T_1/2 is 1.5 h. Excreted by hemodialysis.

Indications

Active ingredient

Composition

How to take, the dosage

IV.

In/v bolus in dilution with sterile water for injection 10 ml per 500 mg,15 mg per 1000 mg for at least 5 min.

In/v infusion for 15-30 min diluted to 50-200 ml with compatible infusion fluid.

The dose of the drug and the duration of therapy are established depending on the severity of the infection and the patient’s condition. The following doses are recommended:

In adults:

Meropenem is excreted by hemodialysis. To restore effective plasma concentration at the completion of hemodialysis, a single dose of meropenem recommended for the respective pathology must be administered.

In children:

There is no experience of use in children with impaired renal function.

Interaction

Special Instructions

There is no experience with the use of the drug in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency.

As with other antibiotics, when meropenem is used as monotherapy in critically ill patients with a known or suspected lower respiratory tract infection caused by Pseudomonas aeruginosa, regular sensitivity testing is recommended.

Severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic syndromes (DRESS syndrome), erythema multiforme, acute generalized exanthematous pustulosis have been observed in patients receiving therapy with Meropenem (see section “Side effects”). In case of signs and symptoms indicating the development of these reactions, therapy with meropenem should be immediately discontinued and alternative treatment should be considered.

In rare cases when using Meropenem, as with virtually all antibiotics, the development of pseudomembranous colitis is observed, which may vary in severity from mild to life-threatening forms. It is important to remember about the possibility of development of pseudomembranous colitis when diarrhea occurs against the background of using Meropenem. If pseudomembranous colitis develops, Meropenem should be discontinued. The use of drugs that inhibit intestinal peristalsis is contraindicated.

The occurrence of seizures has been infrequently reported with carbapenems, including Meropenem. Caution should be exercised when using the drug

Meropenem in patients with decreased seizure threshold.

There are clinical and laboratory signs of cross-allergic reactions between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. There are rare reports of hypersensitivity reactions (including fatal outcome) when using Meropenem, as well as other beta-lactam antibiotics (see section “Side effects”). Before starting therapy with Meropenem, the patient should be carefully interviewed, paying special attention to the history of hypersensitivity reactions to beta-lactam antibiotics. Meropenem should be used with caution in patients with a history of hypersensitivity reactions to beta-lactam antibiotics (i.e., penicillins and cephalosporins). If an allergic reaction to meropenem has occurred, the drug should be discontinued and appropriate measures taken.

The use of Meropenem in patients with liver disease should be performed under close monitoring of transaminase activity and bilirubin concentration.

As with other antibiotics, overgrowth of insensitive microorganisms is possible, in connection with which continuous patient monitoring is necessary.

The prevalence of acquired antimicrobial resistance of different pathogens may vary by region and over time, and up-to-date information about the resistance of common pathogens in a particular region is desirable, especially when treating severe infections. If resistance is such that the efficacy of the drug against at least some infections becomes questionable, an expert should be consulted.

The co-administration of Meropenem and valproic acid preparations is not recommended because of the possible decrease in serum valproic acid concentrations.

In some patients concentrations below therapeutic may be achieved (see section “Interaction with other medicinal products”). The use of the drug in infections caused by methicillin-resistant Staphylococcus aureus is not recommended.

There have been no studies of the effect of the drug Meropenem on the ability to drive vehicles and other machinery. Nevertheless, it should be taken into account that headache, paresthesia and seizures may be observed when taking Meropenem.

Contraindications

Hypersensitivity to meropenem or other drugs of the carbapenem group in a history.

Developed hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent with a beta-lactam structure (i.e., penicillins or cephalosporins).

Children under 3 months.

With caution

Concomitant use with potentially nephrotoxic drugs.

Patients with gastrointestinal complaints (diarrhea), especially those with colitis.

Side effects

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

Cardiovascular system: development or worsening of heart failure, cardiac arrest, tachycardia or bradycardia, decreased or increased blood pressure, fainting states, myocardial infarction, pulmonary embolism.

Urinary system disorders: dysuria, edema, renal dysfunction (hypercreatininemia, increased concentration of urea in plasma), hematuria.

Allergic reactions: skin itching, skin rash, urticaria, erythema multiforme, erythema malignant exudative (Stevens-Johnson syndrome), angioedema, anaphylactic shock.

Nervous system disorders: headache, dizziness, paresthesia, insomnia, somnolence, hyperexcitability, agitation, anxiety, depression, impaired consciousness, hallucinations, epileptiform seizures, seizures.

Laboratory measures: eosinophilia, neutropenia, leukopenia; rarely – agranulocytosis, hypokalemia, leukocytosis, reversible thrombocytopenia, decreased partial thromboplastin time.

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

Others: false positive direct or indirect Coombs test, anemia, hypervolemia, dyspnea, vaginal candidiasis.

Overdose

Pregnancy use

Similarities