Meropenem - instructions for use, dose, side effects, contraindications

Meropenem is an antibiotic of the carbapenem class, intended for parenteral use, relatively resistant to human dehydropeptidase-1 (DHP-1), does not require additional administration of DHP-1 inhibitor.

Meropenem has a bactericidal effect due to the effect on the synthesis of the bacterial cell wall. The high bactericidal activity of meropenem against a wide range of aerobic and anaerobic bacteria is due to the high capacity of meropenem to penetrate the bacterial cell wall, a high level of stability to most β-lactamases, and significant affinity for penicillin-binding proteins (PSBs). The minimum bactericidal concentrations (MBCs) are usually the same as the minimum inhibitory concentrations (MICs). For 76% of the tested bacterial species, the MBC / MIC ratio was 2 or less.

Tests in vitro show that meropenem acts synergistically with various antibiotics. In the tests in vitro and in vivo shown, that meropenem has a post-antibiotic effect.

Microorganisms may possess one or more of the listed mechanisms of resistance to meropenem: a violation of the permeability of the cell wall of Gram-negative bacteria due to a violation of the synthesis of porins; decrease in affinity for the target PSB; activation of efflux mechanisms; production of beta-lactamases, under the action of which hydrolysis of carbapenems takes place.

The only recommended criteria for sensitivity to meropenem are based on the pharmacokinetics of the drug and on the correlation of clinical and microbiological data - the diameter of the zone and MICs, determined for the respective pathogens.

Category of the pathogen	Diameter of the zone (mm)
Sensitive	≥ 14
Intermediate	from 12 to 13
Resistant	≤11

The following table shows the threshold values of MIC of meropenem in the European Union (EU) for various bacterial pathogens in clinical settings:

Pathogens	Sensitivity (mg / l)	Resistance
Enterobacteriaceae	≤2	>8
Pseudomonas	≤2	>8
Acinetobacter	≤2	>8
Streptococcus groups A, B, C, G	≤2	>2
Streptococcus pneumoniae¹	≤2	>2
Other streptococci	2	2
Enterococcus⁵	-	-
Staphylococcus²	Depends on the availability of sensitivity to methicillin
Haemophilus influenzae¹ Moraxella catarrhalis	≤2	>2
Neisseria meningitidis^2,3	≤0,25	>0,25
Gram-positive anaerobes	≤2	>8
Gram-negative anaerobes	≤2	>8
Nonspecific thresholds⁴	≤2	>8

¹ Sensitivity threshold for Streptococcus pneumonia and Haemophilus influenzae, with meningitis - 0.25 mg / l.

² Strains for which the MICs are above the sensitivity threshold are rare or not currently detectable. If such a strain is detected, the MIC test is repeated, when the result is confirmed, the strain is sent to a reference laboratory, and the strain is considered resistant until a confirmed clinical effect is obtained with respect to it.

³ Values used only for meningitis.

⁴ For all other pathogens, according to pharmacokinetic and pharmacodynamic data, without taking into account the specific distribution of MIC specific pathogens.

⁵ The sensitivity test is not recommended, since this agent is not an optimal target for meropenem.

The sensitivity to meropenem should be determined using standard methods. Interpretation of results should be carried out in accordance with local guidelines.

The effectiveness of the drug against the pathogens listed below is confirmed by clinical experience and guidelines for antibiotic therapy.

Pathogens sensitive 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. anginosus, S. constellatus, S. intermedins), 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, clan Peptostreptococcus (including P. micros, P. anaerobicus, 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:

Enterococcus 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.

Pharmacokinetics:

The maximum concentration of meropenem when administered intravenously over 30 min in blood plasma is approximately 11 μg / ml for a dose of 250 mg, 23 μg / ml for a dose of 500 mg and 49 μg / ml for a dose of 1 g.

However, with respect to the maximum concentration (C_mOh) and the area under the pharmacokinetic curve "concentration-time" (AUC) there is no absolute pharmacokinetic proportional dependence on the administered dose. There was a decrease in plasma clearance from 287 to 205 ml / min for doses from 250 mg to 2 g.

With an intravenous bolus injection of meropenem for 5 minutes, the maximum plasma concentration in the plasma is approximately 52 μg / ml for a dose of 500 mg and 112 μg / ml for a dose of 1 g.

After 6 hours after intravenous administration of 500 mg, the concentration of meropenem in the blood plasma is reduced to 1 μg / ml and below.

With repeated administration of meropenem with an interval of 8 hours, patients with normal renal function of cumulation of the drugobserved. 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 in the urine unchanged for 12 hours, after which a slight excretion in the urine is determined. Concentrations of meropenem in urine exceeding 10 μg / ml are maintained for 5 hours after the administration of a dose of 500 mg. With regimens of 500 mg every 8 hours or 1 g every 6 hours, there was no cumulation of meropenem in blood plasma and in urine in patients with normal liver function.

The only metabolite of meropenem is microbiologically inactive.

Meropenem penetrates well into most tissues and body fluids, into breast milk, into the cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required for the suppression of most bacteria.

Pharmacokinetics in special clinical cases

The pharmacokinetics in children and adults are similar. The half-life of meropenem in children under 2 years is approximately 1.5-2.3 hours, a linear dependence of pharmacokinetic parameters is observed in the dose range of 10-40 mg / kg.

Renal insufficiency

In patients with renal insufficiency, the clearance of meropenem correlates with the creatinine clearance. Such patients need dose adjustment.

Meropenem is excreted in hemodialysis with a clearance of about 4 times the clearance of meropenem in patients with anuria.

Liver failure

Studies of pharmacokinetics in patients with liver disease have shown that these pathological changes do not affect the pharmacokinetics of meropenem.

Elderly people

In elderly people, a decrease in the clearance of meropenem was found, which correlates with the age-related decrease in creatinine clearance.

Indications:

A drug Meropenem is indicated for treatment in children older than 3 months and adults of the following infectious-inflammatory diseases caused by one or more meropenem-sensitive pathogens:

- pneumonia, including nosocomial pneumonia;

- urinary tract infection;

- infection of the abdominal cavity;

- Infectious-inflammatory diseases of the pelvic organs, such as endometritis;

- infection of the skin and its structures;

- meningitis;

- septicemia.

Empirical therapy of adult patients with a presumed infection with symptoms of febrile neutropenia in monotherapy or in combination with antiviral or antifungal agents.

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

Contraindications:

Hypersensitivity to meropenem, other drugs of the carbapenem group, hypersensitivity to excipients, severe hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent having a beta-lactam structure (ie to penicillins or cephalosporins), as well as other beta- lactam antibiotics; Children's age is up to 3 months.

Carefully:

Simultaneous use with potentially nephrotoxic drugs; in patients with gastrointestinal complaints (diarrhea), especially those suffering from colitis.

Pregnancy and lactation:

Pregnancy

Data on the safety and efficacy of meropenem in women during pregnancy are not available. Meropenem can be used during pregnancy, only in those cases where the potential benefit from its use in the mother justifies the possible risk to the fetus.

Breastfeeding period

Meropenem is excreted in breast milk. Meropenem should not be administered during lactation, except when the potential advantage of using it justifies the possible risk to the child.

If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Dosing and Administration:

Intravenously.

Adults

The dose and duration of therapy should be determined depending on the type and severity of the infection and the condition of the patient.

The following daily doses are recommended:

In the treatment of pneumonia, urinary tract infections, gynecological infections, skin and soft tissue infections - 500 mg intravenously every 8 hours.

In the treatment of hospital pneumonia, peritonitis, suspected bacterial infection in patients with symptoms of neutropenia, as well as with septicemia - 1 g intravenously every 8 hours.

In the treatment of meningitis, the recommended dose is 2 g every 8 hours.

The safety of the use of a dose of 2 g in the form of a bolus injection has not been sufficiently studied.

Dosage in adult patients with impaired renal function

In patients with a creatinine clearance less than 51 mL / min, the recommended dose should be reduced as follows:

Creatinine clearance (ml / min)	Dose (based on a unit dose of 500 mg, 1 g, 2 g)	Frequency of administration
26-50	one dose unit	every 12 hours
10-25	0.5 unit dose	every 12 hours
< 10	0.5 unit dose	every 24 hours

Meropenem is excreted in hemodialysis and hemofiltration. If prolonged drug treatment is required Meropenem, it is recommended that a dose unit (based on the type and severity of the infection) be administered at the end of the hemodialysis procedure to restore an effective concentration in the blood plasma.

There is no experience of using meropenem in patients on peritoneal dialysis.

Liver failure

Patients with hepatic insufficiency do not need a dose adjustment (see section "Special instructions").

Elderly patients

In elderly patients with normal renal function or creatinine clearance greater than 50 mL / min, dose adjustment is not required.

Children

For children aged 3 months to 12 years, the recommended dose for intravenous administration is 10-20 mg / kg every 8 hours, depending on the type and severity of the infection, the sensitivity of the pathogen and the patient's condition.

In children with a body weight of more than 50 kg, doses recommended for adults should be used. With meningitis, the recommended dose is 40 mg / kg every 8 hours.

The safety of administering a dose of 40 mg / kg in the form of a bolus injection has not been adequately studied. There is no experience of using the drug in children with impaired liver and kidney function.

Method of administration

A drug Meropenem for intravenous administration may be administered as an intravenous bolus injection for at least 5 minutes, or as an intravenous infusion for 15-30 minutes; appropriate infusion liquids should be used for dilution.

To prepare a solution for intravenous bolus injections, the drug Meropenem should be dissolved with sterile water for injection (5 ml per 250 mg of meropenem) with a solution concentration of 50 mg / ml.

To prepare a solution for intravenous infusion, the drug Meropenem should be dissolved 0.9% solution of sodium chloride for infusion or 5% solution of dextrose (glucose) for infusion, with the concentration of the solution should be from 1 to 20 mg / ml. The prepared solution should be injected immediately after preparation.

A drug Meropenem should not be mixed or added to other drugs.

When the drug is diluted Meropenem a standard antiseptic regimen should be observed.

Side effects:

In general, the drug is well tolerated. In rare cases, side effects led to the abolition of therapy. Serious adverse reactions are rare.

The incidence of adverse reactions is given in accordance with the following classification: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000); the frequency is unknown (it is not possible to estimate the incidence from the available data).

Violations from the blood and lymphatic system: often - thrombocytosis; infrequently - eosinophilia, thrombocytopenia; rarely - leukopenia, neutropenia, agranulocytosis; very rarely - hemolytic anemia.

Impaired nervous system: infrequently - headache, paresthesia, fainting *, hallucinations *, depression *, anxiety *, increased excitability *, insomnia *; rarely convulsions.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, increased activity of hepatic transaminases, alkaline phosphatase, lactate dehydrogenase, serum bilirubin concentration; infrequently - constipation *, cholestatic hepatitis *; very rarely - pseudomembranous colitis.

Disturbances from the skin and subcutaneous tissues: infrequently - a rash, hives, itchy skin; very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Immune system disorders: very rarely - angioedema, manifestations of anaphylaxis.

Disorders from the cardiovascular system: infrequently - cardiac insufficiency *, cardiac arrest *, tachycardia *, bradycardia *, myocardial infarction *, decreased or increased blood pressure *, thromboembolism of the branches of the pulmonary artery *.

Disorders from the kidneys and urinary tract: infrequently, an increase in the concentration of creatinine in the blood, an increase in the concentration of urea in the blood.

Disturbances from the respiratory system: infrequently - dyspnea *.

Other: often - local reactions (inflammation, thrombophlebitis, pain at the injection site); rarely - vaginal candidiasis, candidiasis of the oral mucosa.

There have been reports of positive direct or indirect Coombs tests, as well as cases of partial thromboplastin time reduction.

* - the cause-and-effect relationship with taking the drug Meropenem not installed.

Overdose:

Symptoms: dizziness, headaches, paresthesia.

Treatment: symptomatic, with renal failure is effective hemodialysis.

Interaction:

Probenecid competes with meropenem for active tubular secretion, inhibiting renal excretion and causing an increase in the half-life and concentration of meropenem in plasma. Since the effectiveness and duration of the drug Meropenem, administered without probenecid, are adequate, the joint administration of probenecid with the drug Meropenem Not recommended.

The possible effect of meropenem on the 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 protein binding is not expected.

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

The use of meropenem during the administration of other drugs was not accompanied by the development of unfavorable pharmacological interactions.

Studies to study the interaction of meropenem with other drugs (with the exception of probenecid) were not conducted.

Repeatedly reported cases of increased anticoagulant effect in the joint administration of indirect anticoagulants (eg, warfarin) and antibacterial drugs. The risk of enhancing the anticoagulant effect may depend on the nature of the infection, the age and general condition of the patient, so it is difficult to assess the effect of the antibacterial drug on increasing the international normalized ratio (INR). During joint administration of an antibacterial drug and an indirect anticoagulant, and for some time after its termination, frequent monitoring of INR is recommended.

Special instructions:

When using the drug Meropenem as a monotherapy, as with the use of other antibiotics, in patients,in a critical condition with an identified lower respiratory tract infection caused by Pseudomonas aeruginosa or if it is suspected, it is recommended that the sensitivity test be performed on a regular basis.

In rare cases, when the drug is used Meropenem, as with almost all antibiotics, there is a development of pseudomembranous colitis that can vary in severity from lungs to life-threatening forms. In the case of diarrhea on the background of drug administration Meropenem it is necessary to remember the possibility of developing pseudomembranous colitis. When pseudomembranous colitis develops, the drug should be discontinued Meropenem. Caution should be given to the drug Meropenem patients with gastrointestinal diseases, especially those suffering from colitis. Contraindicated use of drugs that inhibit intestinal peristalsis.

Against the background of the use of carbapenems, incl. Meropenem, infrequently reported on the occurrence of seizures. Care should be taken when using the drug Meropenem in patients with a reduced threshold of convulsive readiness.

There is evidence of the development 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 outcome) when using the drug Meropenem, as well as other beta-lactam antibiotics. Before starting therapy with the drug, the patient should be thoroughly questioned, paying special attention to the history of hypersensitivity reactions to beta-lactam antibiotics. A drug Meropenem should be used with caution, especially in patients with a history of such events. If there was an allergic reaction to meropenem, it is necessary to stop the introduction of the drug and take appropriate measures.

Application of the drug Meropenem in patients with liver disease should be carried out under careful control of the activity of transaminases and bilirubin.

As with the use of other antibiotics, an increased growth of resistant 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,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 the resistance is such that the effectiveness of the drug against at least some infections becomes questionable, you should consult an expert.

Application of the drug Meropenem for infections caused by methicillin-resistant staphylococcus is not recommended.

No experience with the drug Meropenem in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency.

There is no experience of using the drug in children with impaired liver and kidney function.

Effect on the ability to drive transp. cf. and fur:

Taking into account side effects of the drug, care must be taken when driving vehicles and working with mechanisms that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Powder for solution for intravenous administration, 0.5 g and 1 g.

Packaging:

For 0.5 g or 1 g of active substance in bottles of transparent glass (type II) with a capacity of 30 ml, hermetically sealed with rubber stoppers,Compressed by caps of aluminum or combined type "FLIPP OFF".

Each label is labeled.

Each bottle, together with the instructions for use, is placed in a pack of cardboard. For 100 bottles, together with an equal number of instructions for use, put in a pallet of cardboard, pasted with a shrink film (for hospital).

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003989

Date of registration:01.12.2016

Expiration Date:01.12.2021

The owner of the registration certificate:HIMFARM, JSC HIMFARM, JSC Kazakhstan

Manufacturer: & nbsp

HIMFARM, JSC Kazakhstan

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp13.01.2017

Illustrated instructions

Instructions

Meropenem (Meropenem)