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

Meropenem is indicated for the treatment in children (over 3 months) and adults of the following infectious and inflammatory diseases caused by one or more pathogens sensitive to meropenem:

– pneumonia, including nosocomial pneumonia;
– urinary system infections;
– abdominal infections;
– infectious and inflammatory diseases of the pelvic organs, such as endometritis;
– infections of the skin and its structures;
– meningitis;
– septicemia.

Empirical treatment of adult patients with suspected infection and symptoms of febrile neutropenia, either alone or in combination with antiviral or antifungal drugs.

The effectiveness of Meropenem has been proven both in monotherapy and in combination with other antimicrobial agents in the treatment of polymicrobial infections.

The use of intravenous meropenem was effective for the treatment of cystic fibrosis and chronic lower respiratory tract infections, both in monotherapy and in combination with other antibacterial drugs. Eradication of microorganisms has not always been confirmed.

Pharmacological effect

Pharmacotherapeutic group: Antibiotic, carbapenem

ATX code: J01DH02

Pharmacological action

Antibiotic for parenteral use from the carabapenem group. It has a bactericidal effect (inhibits the synthesis of the bacterial cell wall), easily penetrates the bacterial cell wall, and is resistant to the action of most beta-lactamases.

Unlike imipenem, it is practically not destroyed in the renal tubules by dehydropeptidase-1 (does not need to be combined with cilastatin, a specific inhibitor of dehydropeptidase-1) and, accordingly, no nephrotoxic breakdown products are formed, and has a high affinity for penicillin-binding proteins.

Bactericidal and bacteriostatic concentrations are practically the same.

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

The spectrum of antibacterial activity of meropenem includes the majority of clinically significant gram-positive and gram-negative aerobic and anaerobic strains of bacteria:

Gram-positive aerobes: Enterococcus faecalis (including vancomycin-resistant strains); Staphylococcus aureus (penicillinase-non-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 influenza (penicillinase-non-producing and penicillinase-producing); 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 effectiveness against diseases caused by these pathogens has not been proven:

Gram-positive aerobes: Staphylococcus epidermidis (penicillinase-non-producing and penicillinase-producing | methicillin-sensitive]).

Gram-negative aerobes: Acinetobacter spp.; Aeromonas hydrophila; Campylobacter jejuni; Citrobacter diversus; Citrobacter freundii; Enterobacter cloacae; Haemophilus influenzae (ampicillin-resistant, penicillinzone-non-producing strains); Hafnia alvei; Klebsiella oxytoca; Moraxella catarrhalis (penicillinase-non-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 ureolyticus; Bacteroides vulgatus; Clostridium difficile; Clostridium perfringens; Eubacterium lentum; Fusobacterium spp.; Prevotella bivia; Prevotella intermedia; Prevotella melaninogenica; Porphyromonas asaccharolytica; Propionibacterium acnes.

Pharmacokinetics

With intravenous administration of 250 mg over 30 minutes, Cmax is 11 mcg/ml, for a dose of 500 mg – 23 mcg/ml, 1 g – 49 mcg/ml (there is no absolute pharmacokinetic proportional dependence on the administered dose for Cmax and AUC). When the dose is increased from 0.25 to 2 g, clearance decreases from 287 to 205 ml/min. With intravenous bolus administration of 500 mg Cmax – 52 mcg/ml, 1 g – 112 mcg/ml. Communication with plasma proteins – 2%.

Penetrates well into most tissues and body fluids, incl. into the cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required to suppress most bacteria (bactericidal concentrations are created 0.5-1.5 hours after the start of the infusion). Passes into breast milk in small quantities.

It undergoes minor metabolism in the liver to form a single inactive metabolite. T1/2 – 1 hour, in children under 2 years of age 1.5-2.3 hours. In the dose range of 10-40 mg/kg in adults and children, a linear dependence of the pharmacokinetic parameters is observed. Does not cumulate. Excreted by the kidneys – 70% unchanged within 12 hours. The concentration of meropenem in the urine exceeding 10 mcg/ml is maintained for 5 hours after administration of 500 mg. In patients with renal failure, clearance correlates with creatinine clearance (CC). In elderly patients, decreased clearance of meropenem correlates with age-related decreases in creatinine clearance. T1/2 – 1.5 hours. Excreted during hemodialysis.

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, regular susceptibility testing is recommended when meropenem is used as monotherapy in critically ill patients with known or suspected lower respiratory tract infection due to Pseudomonas aeruginosa.

Severe cutaneous 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, were observed in patients receiving therapy with Meropenem (see section “Side effects”). If signs and symptoms indicating the development of these reactions occur, meropenem therapy should be discontinued immediately and alternative treatment should be considered.

In rare cases, when using the drug Meropenem, as with the use of almost all antibiotics, the development of pseudomembranous colitis is observed, which can vary in severity from mild to life-threatening forms. It is important to remember the possibility of developing pseudomembranous colitis if diarrhea occurs while using the drug Meropenem. If pseudomembranous colitis develops, Meropenem should be discontinued. The use of drugs that inhibit intestinal motility is contraindicated.

Convulsions have been reported infrequently with the use of carbapenems, including meropenem. Caution should be exercised when using the drug

Meropenem in patients with a reduced 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 cases of hypersensitivity reactions (including fatal ones) when using the drug Meropenem, as well as other beta-lactam antibiotics (see section “Side effects”). Before initiating meropenem therapy, the patient should be carefully interviewed, paying particular attention to any 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 occurs, it is necessary to stop administering the drug and take appropriate measures.

The use of Meropenem in patients with liver disease should be carried out under careful monitoring of transaminase activity and bilirubin concentration.

As with other antibiotics, overgrowth of non-susceptible microorganisms is possible, and therefore constant monitoring of the patient is necessary.

The prevalence of acquired antibiotic resistance of various pathogens may vary depending on the region and over time, and it is desirable to have up-to-date information on the resistance of common pathogens in a particular region, especially when treating severe infections. If resistance is such that the effectiveness of the drug against at least some infections becomes doubtful, an expert should be consulted.

Co-administration of Meropenem and valproic acid preparations is not recommended due to a possible decrease in the concentration of valproic acid in the blood serum.

In some patients, subtherapeutic concentrations may be achieved (see section “Interaction with other drugs”). The use of the drug for infections caused by methicillin-resistant staphylococcus is not recommended.

Impact on the ability to drive vehicles and machinery

There have been no studies of the effect of Meropenem on the ability to drive a car or use other equipment. However, it should be taken into account that headache, paresthesia and convulsions may occur when taking Meropenem.

Active ingredient

Meropenem

Composition

One bottle contains:

Active ingredient:

Meropenem trihydrate – 1140.0 mg (in terms of anhydrous meropenem) – 1000.0 mg,

Excipient: Sodium carbonate anhydrous – 208.00 mg.

Pregnancy

Pregnancy

The safety of Meropenem in women during pregnancy has not been studied. Animal studies have not shown any adverse effects on the developing fetus.

Meropenem should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. In each case, the drug must be used under the strict supervision of a physician.

Breastfeeding period

Data have been obtained on the excretion of meropenem in breast milk. Meropenem should not be used during breastfeeding unless the potential benefit to the mother from the drug outweighs the possible risk to the baby. Having assessed the benefit for the mother, a decision should be made to stop breastfeeding or discontinue the drug Meropenem.

Contraindications

History of hypersensitivity to meropenem or other drugs of the carbapenem group.

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

Children under 3 months.

With caution

Concomitant use with potentially nephrotoxic drugs.

Patients with complaints from the gastrointestinal tract (diarrhea), especially those suffering from colitis.

Side Effects

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

From the cardiovascular system: development or worsening of heart failure, cardiac arrest, tachy- or bradycardia, decrease or increase in blood pressure, fainting, myocardial infarction, thromboembolism of the branches of the pulmonary artery.

From the urinary system: dysuria, edema, impaired renal function (hypercreatininemia, increased concentration of urea in plasma), hematuria.

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

From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, increased excitability, agitation, anxiety, depression, impaired consciousness, hallucinations, epileptiform seizures, convulsions.

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

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

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

Interaction

Probenecid competes with meropenem for active tubular secretion, inhibiting renal excretion and causing an increase in the half-life and plasma concentration of meropenem. Because the efficacy and duration of action of Meropenem administered without probenecid are adequate, coadministration of probenecid with Meropenem is not recommended.

The possible effect of Meropenem on the degree of binding of other drugs to plasma proteins or metabolism has not been studied. The binding of Meropenem to plasma proteins is low (about 2%), therefore, interaction with other drugs based on the mechanism of displacement from plasma proteins is not expected.

Co-administration of carbapenems and valproic acid preparations led to a decrease in the concentration of valproic acid in the blood plasma by 60-100% after 2 days of therapy. Due to the rapid and significant decrease in the concentration of valproic acid, co-administration of Meropenem and valproic acid preparations is not recommended.

The use of Meropenem while taking other drugs was not accompanied by the development of adverse pharmacological interactions. No studies have been conducted to study the interaction of meropenem with other drugs (with the exception of probenecid).

Cases of increased anticoagulant effect have been repeatedly reported when indirect anticoagulants (for example, warfarin) and antibacterial drugs are taken together. The risk of increased anticoagulant effect may depend on the nature of the infection, age and general condition of the patient, so it is difficult to assess the effect of an antibacterial drug on increasing the international normalized ratio (INR).

Frequent INR monitoring is recommended during co-administration of an antibacterial drug and an indirect anticoagulant and for some time after its cessation.

Overdose

Accidental overdose during treatment is possible, especially in patients with impaired renal function.

Treatment in case of overdose should be symptomatic. Normally, the drug is rapidly eliminated through the kidneys. In patients with impaired renal function, hemodialysis effectively removes meropenem and its metabolite.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Shelf life

2 years. Do not use after the expiration date stated on the package.

Manufacturer

Kraspharma PJSC, Russia