Meronym, 1 g 10 pcs

Pharmacology

Mechanism of action

Meropenem is a broad-spectrum carbapenem antibiotic for parenteral use, resistant to the action of beta-lactamases. The bactericidal activity of meropenem is due to inhibition of bacterial cell wall synthesis.

Meropenem rapidly penetrates the cell wall of most Gram-positive and Gram-negative bacteria and interacts with penicillin-binding proteins (PBP). It has the highest affinity to PBP 2 of Escherichia coli , PBP 2 and 3 of Pseudomonas aeruginosa and 1, 2 and 4 of Staphylococcus aureus.

Meropenem is stable in the presence of most serine beta-lactamases (penicillinase and cephalosporinase) produced by Gram-positive and Gram-negative bacteria.

Microbiology

The in vitro sensitivity of a specific isolate to meropenem must be determined by standard methods. Interpretation of in vitro test results should be made in accordance with existing recommendations for infectious diseases and clinical microbiology. Meropenem has been shown to be active against the microorganisms listed below for the clinical infections listed in the “Indications” field.

Aerobic and facultative gram-positive microorganisms: Staphylococcus aureus (only methicillin sensitive strains), Staphylococcus epidermidis (only methicillin sensitive strains), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans.

Aerobic and facultative gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including strains producing beta-lactamase), Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

Gram-positive anaerobes: Peptostreptococcus species, Clostridium perfringens.

Gram-negative anaerobes: Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Prevotella bivia.

Published literature on medical microbiology describes the in vitro sensitivity to meropenem of many other bacterial species. However, the clinical relevance of in vitro results must be confirmed by local experts in infectious diseases and clinical microbiology and appropriate clinical guidelines. The clinical safety and efficacy of meropenem have not been established for the treatment of infections caused by the following microorganisms.

Aerobic and facultative gram-positive microorganisms: Streptococcus anginosus.

Aerobic and facultative gram-negative microorganisms: Enterobacter aerogenes.

The minimum bactericidal concentration (MBC) and minimum inhibitory concentration (MIC) values were little affected by changes in inoculum concentration between 104 and 108 CFU/mL or by performing studies in pH-adjusted broth in the 5-7 range or in test medium supplemented with 50% human serum. At pH 8, only P.aeruginosa was observed to increase MPC and MBK.

Postantibiotic effects of meropenem for ≥0.5 h after antibiotic administration were obtained in 87% of all strains tested, including strains of Enterobacteriaceae, Gram-positive aerobic bacteria, B.fragilis and in vivo in mice with neutropenia infected with P.aeruginosa.

In vitro tests show that meropenem acts synergistically with aminoglycoside antibiotics against certain isolates of Pseudomonas aeruginosa and Enterobacteriaceae. Meropenem and vancomycin act synergistically against some enterococci and coagulase-positive and coagulase-negative strains of staphylococci, including those resistant to methicillin. These in vitro tests show no antagonistic effect of meropenem with aminoglycosides or vancomycin against Gram-negative and Gram-positive aerobes, respectively.

Resistance

Meropenem is active against many bacteria resistant to other antibiotics. Meropenem has been active against bacteria with known resistance mechanisms such as S.aureus, S.epidermidis, N.gonorrhoeae or M.catarrhalis that produce beta-lactamase, H.influenzae that are resistant to ampicillin or produce beta-lactamase, and S.pneumoniae that are resistant to penicillin. Meropenem has high activity against strains of Staphylococcus aureus, Enterobacteriaceae and P.aeruginosa expressing plasmid or chromosome-encoded beta-lactamases. It is unaffected when tested against Enterobacteriaceae strains containing transferable (plasmid-mediated) beta-lactamases that hydrolyze ceftazidime, cefotaxime and other third generation cephalosporins.

The sequential passaging with meropenem did not result in resistant S.aureus strains. In contrast, 10 consecutive passages with meropenem increased IPC values for each K.pneumoniae, E.cloacae or S.marcescens strain; two further studies failed to select enterobacteriaceae with increased IPC values by point mutation.

Bacterial resistance to meropenem can be caused by one or more of the following factors: reduced outer membrane permeability of Gram-negative bacteria (due to reduced porin production), reduced affinity for target PBP, increased expression of efflux pump components, and production of beta-lactamases that can hydrolyze carbapenems.

Sensitivity

If possible, the clinical microbiology laboratory should provide the physician with in vitro sensitivity test results for the antimicrobial drugs used in community health facilities in the form of periodic reports describing the sensitivity profile for nosocomial and out-of-hospital pathogens. These reports should assist the physician in selecting the most effective antimicrobial agent.

Dilution Methods. Quantitative methods are used to determine the IPC of antimicrobial drugs. The obtained MAC values allow to estimate the sensitivity of bacteria to antimicrobial drugs. MPC must be determined using a standardized procedure based on the dilution method (broth or agar) or equivalent with standardized concentrations of inoculum and standardized concentrations of meropenem powder.

Diffusion methods. Quantitative methods that require measurement of zone diameters provide reproducible estimates of the sensitivity of bacteria to antimicrobial drugs. One such standardized procedure requires the use of standardized concentrations of inoculum. This procedure uses paper disks impregnated with 10 µg of meropenem to test the sensitivity of microorganisms to meropenem.

The anaerobic methods. For anaerobic bacteria, sensitivity to meropenem, expressed as MPC values, must be determined by standardized test methods.

Pharmacokinetics

The pharmacokinetics of meropenem are typical of parenteral beta-lactam antibiotics, which bind only slightly to plasma proteins and are primarily excreted by the kidneys.

Meropenem exhibits biexponential pharmacokinetics after IV administration in healthy adult volunteers with normal renal function. There is a rapid distribution phase followed by a terminal excretion phase with a T1/2 of approximately 1 h.

The serum AUC of meropenem is increased approximately 5.5-fold in the dose range from 500 mg to 2 g. No marked changes in pharmacokinetic parameters are observed. However, when administering higher doses, a decrease in renal clearance is observed, probably due to overloading of tubular clearance. These changes in kinetic parameters are not clinically relevant in healthy adults.

There were no significant changes in pharmacokinetics when meropenem was administered for 5 minutes compared with a 30-minute infusion. The plasma Cmax of meropenem increased 2-fold after bolus administration, but plasma concentrations were similar at both rates of administration 1 h after administration.

Distribution

At completion of a 30-minute IV infusion of a single dose of meropenem in healthy male volunteers, the mean plasma Cmax is approximately 23 µg/mL for the 500 mg dose, 49 µg/mL for the 1 g dose, and 115 µg/mL for the 2 g dose.

When meropenem was administered by IV bolus injection for 5 min to healthy male volunteers, the mean plasma Cmax was approximately 52 µg/mL for the 500 mg dose and 112 µg/mL for the 1 g dose.

Meropenem is distributed in body tissues at concentrations sufficient to treat the most common focal infections.

However, there are difficulties in penetrating the cerebrospinal fluid or intraocular fluid in the absence of inflammation in these areas. In children and adults with bacterial meningitis, the concentration of meropenem in the cerebrospinal fluid after IV administration of the recommended doses exceeds the concentration needed to suppress susceptible bacteria.

Metabolism and excretion

Meropenem is excreted primarily by renal excretion combined with CP and active tubular secretion.

At a dose of 500 mg, the mean plasma level of meropenem decreases to 1 µg/mL or less than 6 hours after administration.

In vitro studies show that meropenem is resistant to human renal dehydropeptidase. This conclusion is supported by the urinary excretion of meropenem, which is usually 60 to 70% of the administered dose. Thus, there is no need to coadminister a dehydropeptidase inhibitor-1 with meropenem.

The binding of meropenem to plasma proteins is low, approximately 2%. Therefore, the renal filtration rate should approach the SCF. However, renal clearance values are usually higher than the measured or calculated GFR, the difference being due to active tubular secretion of meropenem.

The hydrolysis of the beta-lactam bond can occur either chemically in solution or biologically by enzymes. The decrease in extrarenal clearance of meropenem that occurs as renal function decreases suggests that the kidney may be the site of metabolism. The trend toward decreased extrarenal clearance of meropenem observed with concomitant use of meropenem with probenecid suggests that the proximal renal tubule may be involved in meropenem metabolism.

The only identified metabolite of meropenem is ICI 213689, which is formed by hydrolysis of the beta-lactam bond and is bacteriologically inactive. In healthy subjects, the apparent T1/2 of ICI 213689 was longer than that of meropenem by approximately 2.3 h (range 1.8-2.8 h). The AUC for ICI 213689 was approximately 10% of the AUC for meropenem, showing that exposure to the circulating metabolite is small in subjects with normal renal function.

The administration of probenecid with meropenem did not change the urinary T1/2 of ICI 213689. Exposure to ICI 213689 does not appear to be altered by repeat administration of meropenem, and there are no significant changes in ICI 213689 excretion after repeat administration of meropenem in subjects with normal renal function.

In patients with normal renal function, the T1/2 of meropenem is approximately 1 h. Urinary concentrations of meropenem greater than 10 µg/mL are maintained for at least 5 h at the 500 mg dose. Metabolism and excretion of meropenem were studied by administering 14C-labeled meropenem. The radioactive substance was excreted very rapidly, with 95.4% of the dose excreted in the urine 8 h after administration. This rapid excretion is consistent with the observed absence of accumulation with multiple dosing. Overall, 99% of the dose was excreted with the urine and another 2.1% with the feces.

Multiple administration of meropenem to healthy volunteers caused an increase, decrease or no change in the fecal flora, depending on the organism. The changes were minor and reversible after discontinuation of meropenem. Meropenem is present in bile in concentrations up to 25 µg/mL. This excretion with bile of a small fraction of the dose as an active antibiotic may explain both the minor disruption of the fecal flora and the detection of radioactivity in the feces.

Particular populations

Children (≥3 months). The pharmacokinetics of meropenem in infants and children over 2 years of age are generally similar to those in adults, except that the T1/2 is approximately doubled, to 1.75 h, in the younger age group (3-5 months). The T1/2 of meropenem was approximately 1.5 h in children aged 3 months to 2 years. Pharmacokinetics for children are linear at doses of 10, 20, and 40 mg/kg, and plasma Cmax and AUC values are similar to those observed in healthy adult volunteers after administration of doses of 500 mg, 1 g, and 2 g, respectively.

The increase in T1/2 and Vd of meropenem in young adults is consistent with decreased renal function and increased extracellular fluid volume in infants of this age. The dosing interval of 8 h is considered acceptable even in the 3 to 5 month age group.

Elderly age (≥65 years). Changes in the pharmacokinetics of meropenem and ICI 213689 have been observed in the elderly, reflecting age-related decline in renal function. Dose reduction may be required depending on renal function.

Hepatic impairment. A study in patients with alcoholic cirrhosis showed no effect of liver disease on the pharmacokinetics of meropenem.

Kidney function impairment. Meropenem is excreted primarily by the kidneys, and changes in renal function alter the pharmacokinetics of meropenem.

Pharmacokinetic studies of meropenem in patients with renal impairment have shown that plasma clearance of meropenem correlates with Cl creatinine. Dose adjustment is required in patients with impaired renal function. A pharmacokinetic study of meropenem in elderly patients with renal impairment has shown that decreased plasma clearance of meropenem correlates with age-related decreases in Cl creatinine.

The decrease in meropenem clearance correlates well with creatinine Cl and is consistent across studies. Even in patients with impaired renal function, there are no changes in the pharmacokinetics of meropenem due to repeated administration when it is dosed appropriately. The metabolite accumulates at repeated doses; the clinical significance of this observation is unknown. Physiological decreases in renal function due to age and impaired renal function due to disease have similar effects on meropenem clearance.

In chronic toxicity studies, groups of 24 male and 24 female rats of the Alpk:APfSD (Wistar derived) line were administered meropenem at doses of 60, 240 and 1000 mg/kg/day for 6 months. Decreases in ovarian mass and increases in adrenal, cecum and spleen mass and ALT activity were observed at all doses.

Decreased AST levels were observed at the 1000 mg/kg/day dose. These changes were related either to changes in immune activity or to the microbial status of the animals due to the antibiotic activity of meropenem and tissue damage and inflammation resulting from repeated IV administration over a six-month period. Groups of 3 or 4 beagle dogs were given meropenem at doses of 1, 20, 60, 240, or 500 mg/kg/day for 6 months. Increases in liver weight and serum ALP activity occurred at doses greater than 20 mg/kg/day, but no pathological changes or functional abnormalities were observed.

In reproductive toxicity studies, 4 groups of 22 male and 22 female Alpk:APfSD rat lines were administered meropenem by IV at doses of 0, 240, 500, or 1000 mg/kg/day. Males were exposed for 11 weeks before and throughout mating. Females were exposed for 2 weeks before mating and until the eighth day of gestation. No effect on mating, pregnancy or fetal viability was detected.

Pregnant animals receiving a dose of 300 mg/kg for 2 consecutive days showed normal weight gain with no evidence of abnormal vaginal cytology or bleeding. There was no effect on the fecundity of the rats. One dead fetus was found in a total of 55 cases, indicating that meropenem had no abortive effect. Administration of meropenem in males for 4 days resulted in no significant changes in seminal vesicle mass at autopsy on day 5.

Teratological studies have shown no evidence of embryotoxicity or teratogenicity and no effect on the functional ability of F1 generation animals, no signs of toxicity to the mother, embryos. Meropenem has been shown to penetrate the placenta.

Mutagenicity

There was no evidence of mutagenic potential in tests for reverse mutation and frequency of induced mutations in S.typhimurium and E.coli, for gene mutations in cultured mammalian cells, in vitro cytogenetic tests and micronucleus test in mice. All in vitro studies were performed with and without the metabolic activation system (S-9). All doses were the maximum possible based on preliminary studies, except for the micronucleus test, which was performed to a dose that was lethal in acute toxicity studies (up to 2500 mg/kg w/v).

Indications

Treatment of infections caused by susceptible strains of the indicated microorganisms:

– Outpatient lower respiratory tract pneumonia caused by Staphylococcus aureus (methicillin-sensitive strains only), Streptococcus pneumoniae, Escherichia coli and Haemophilus influenzae (including beta-lactamase-producing strains);

– Hospital-acquired pneumonia caused by Staphylococcus aureus (methicillin-sensitive strains only), Escherichia coli, Haemophilus influenzae (non-beta-lactamase-producing strains), Klebsiella pneumoniae and Pseudomonas aeruginosa;

– complicated urinary tract infections caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens;

– complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Clostridium perfringens and Peptostreptococcus species;

– gynecologic infections caused by Staphylococcus aureus (only methicillin-sensitive strains), Staphylococcus epidermidis (only methicillin-sensitive strains), Escherichia coli, Prevotella bivia and Peptostreptococcus species;

– pelvic inflammatory diseases caused by Staphylococcus epidermidis (methicillin-sensitive strains only), Streptococcus agalactiae, Escherichia coli and Prevotella bivia (meropenem has no activity against Chlamydia trachomatis; if this pathogen is expected, additional antimicrobial drugs are required);

– uncomplicated skin and subcutaneous tissue infections caused by Staphylococcus aureus (methicillin-sensitive strains only), Streptococcus agalactiae, Streptococcus pyogenes and Escherichia coli;

– complicated skin and subcutaneous tissue infections, except for infected burns, caused by Staphylococcus aureus (methicillin-sensitive strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Peptostreptococcus species and Bacteroides fragilis;

Bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase-producing strains) and Neisseria meningitidis (there are limited data on the effectiveness of meropenem in adults for the treatment of bacterial meningitis. Support for indications for meningitis in adults is largely provided by data for pediatric patients);

Bacterial septicemia caused by Escherichia coli.

Active ingredient

Composition

One bottle contains:

Active substance:

meropenem trihydrate 1.14 g, which corresponds to the content of meropenem 1 g;

Ancillary substances:

Sodium carbonate (anhydrous) – 208 mg.

How to take, the dosage

Interaction

There have been no specific studies other than studies of the interaction between meropenem and probenecid and valproic acid.

Probenecid. Probenecid competes with meropenem for active tubular secretion and thus inhibits renal excretion of meropenem, resulting in increased T1/2 and plasma concentrations of meropenem. Co-administration of probenecid and meropenem is not required and is not recommended.

Valproic acid. Valproic acid has been reported to decrease blood levels by 60-100% in approximately 2 days when used concomitantly with carbapenems. Because of the rapid progression and high degree of decrease in valproic acid levels, the use of meropenem in patients taking valproic acid is not well controlled and should be avoided (see “Precautions”).

The use of meropenem may result in a positive direct and indirect Coombs test.

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 sensitivity testing is recommended when using meropenem in monotherapy in critically ill patients with or suspected of having a lower respiratory tract infection caused by Pseudomonas aeruginosa.

In rare cases when using Meronem®, as with almost 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 pseudomembranous colitis if diarrhea occurs against the background of Meronem® use.

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 Meronem®, as well as other beta-lactam antibiotics (see section “Side effects”). Before initiating therapy with meropenem, the patient should be carefully interviewed, paying special attention to the history of hypersensitivity reactions to beta-lactam antibiotics. Meronem® should be used with caution in patients with a history of such events. If an allergic reaction to meropenem has occurred, the drug should be discontinued and appropriate measures taken.

The use of Meronem® in patients with liver disease should be performed under close monitoring of transaminase activity and bilirubin concentrations.

As with other antibiotics, overgrowth of insensitive microorganisms is possible; therefore, continuous monitoring of the patient is necessary.

The prevalence of acquired antibiotic resistance of different pathogens may vary by region and time, and up-to-date information on 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 Meronem® and valproic acid preparations is not recommended.

The use of the drug in infections caused by methicillin-resistant Staphylococcus aureus is not recommended.

Impact on the ability to drive and operate machinery. No studies have been conducted on the effect of Meronem® on the ability to drive a car and other machinery. Nevertheless, it should be taken into account that headache, paresthesia and seizures may occur when taking Meronem®.

Contraindications

Side effects

Blood system: frequently – thrombocytosis; infrequently – eosinophilia, thrombocytopenia; rarely – leukopenia, neutropenia, agranulocytosis; very rarely – hemolytic anemia.

Nervous system: infrequent – headache, paresthesia, syncope, hallucinations, depression, anxiety, increased excitability, insomnia; rarely – seizures.

Gastrointestinal tract: frequently – nausea, vomiting, diarrhea, increased liver transaminase activity, ALP, LDH, and concentration of bilirubin in serum; infrequently – constipation, cholestatic hepatitis; very rarely – pseudomembranous colitis.

The skin and subcutaneous tissue: infrequent – rash, urticaria, itching, very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Immune system: very rarely – angioedema, manifestations of anaphylaxis.

CRC: infrequent – heart failure, cardiac arrest, tachycardia, bradycardia, myocardial infarction, decreased or increased BP, pulmonary artery branch thromboembolism.

Kidney and urinary tract: infrequent – increased blood creatinine concentration, increased blood urea concentration.

Respiratory tract: infrequent – dyspnea.

Others: frequent – local reactions (inflammation, thrombophlebitis, pain at the injection site); rarely – vaginal candidiasis and oral candidiasis.

Overdose

Symptoms: Deliberate overdose of meropenem is unlikely, whereas accidental overdose is more likely, especially in patients with reduced renal function. The maximum dose of meropenem administered during the clinical trials was 2 g w/v every 8 h in adult patients with normal renal function and 40 mg/kg every 8 h in pediatric patients with normal renal function. No adverse pharmacological effects were observed with meropenem at these dosages.

Small post-registration experience shows that if side effects occur with overdose, their profile generally follows the side effect profile described in the side effect section.

Treatment: If an overdose occurs, the use of meropenem should be stopped and general supportive therapy should be given until the drug is eliminated from the body by the kidneys.

Meropenem and its metabolite are easily dialyzed and are effectively removed by hemodialysis, but there is no reliable information on the feasibility of using hemodialysis to treat overdose.

In intravenous administration, the LD50 of meropenem for mice and rats is greater than 2500 mg/kg and approximately 2000 mg/kg for dogs.

Pregnancy use

Pregnancy

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

Meronem® 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.

Lactation

Meropenem is detectable in animal breast milk at very low concentrations. 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 discontinue breastfeeding or discontinue Meronem®.