Meropenem Actions

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Actions of Meropenem in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Meropenem is a carbapenem antibiotic for parenteral use, that is stable to human dehydropeptidase-1(DHP-1). It is structurally similar to imipenem.

Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine β-lactamases and its marked affinity for the penicillin-binding proteins (PBPs) explain the potent bactericidal action of Meropenem against a broad spectrum of aerobic and anaerobic bacteria. Bactericidal concentrations are commonly the same as the minimum inhibitory concentrations (MICs).

Meropenem is stable in susceptibility tests and these tests can be performed using normal routine methods. In vitro tests show that Meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that Meropenem has a post-antibiotic effect.

Meropenem is usually active, in vitro and in clinical infections, against the following strains of bacteria as follows:

Gram-Positive Aerobes: Enterococcus faecalis, Staphylococcus aureus (penicillinase negative and positive), Staphylococci-coagulase negative including Staphylococcus epidermidis, Streptococci including Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus mitis, Streptococcus milleri, Streptococcus sanguis, Streptococcus viridans.

Gram-Negative Aerobes: Acinetobacter anitratus, Citrobacter spp including Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae and other Enterobacter spp, Escherichia coli, Haemophilus influenzae (including β-lactamase positive strains), Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Klebsiella pneumoniae and other Klebsiella spp, Morganella morganii, Proteus mirabilis, Serratia spp.

Anaerobic Bacteria: Bacteroides fragilis, Bacteroides thetaiotaomicron and other Bacteroides spp, Clostridium spp including C. perfringens, Eubacterium lentum, Fusobacterium spp, Mobiluncus curtisii, Peptostreptococcus spp, Peptococcus spp.

Some strains of Pseudomonas aeruginosa are susceptible to Meropenem in vitro and in clinical infections.

Enterococcus faecium, Stenotrophomonas (Xanthomonas) maltophilia and methicillin-resistant Staphylococci have been found to be resistant to Meropenem.

Pharmacokinetics: A 30-min IV infusion of a single dose of Meropenem in normal volunteers resulted in peak plasma levels of approximately 11, 23, 49 and 115 mcg/mL following the 250-mg, 500-mg, 1-g and 2-g doses, respectively.

A 5-min IV bolus injection of Meropenem in normal volunteers resulted in peak plasma levels of approximately 52 and 112 mcg/mL for the 500-mg and 1-g dose, respectively.

Intravenous infusions over 2, 3 and 5 min of a 1 g dose of Meropenem were compared in a 3-way crossover trial. These durations of infusion resulted in peak plasma levels of 110, 91 and 94 mcg/mL, respectively.

After an IV dose of 500 mg, plasma levels of Meropenem declined to values of ≤1 mcg/mL 6 hrs after administration.

When multiple doses are administered at 8-hourly intervals to subjects with normal renal function, accumulation of Meropenem does not occur.

In subjects with normal renal function, Meropenem's elimination t½ is approximately 1 hr.

Plasma protein-binding of Meropenem is approximately 2%.

Approximately 70% of the IV administered dose is recovered as unchanged Meropenem in the urine over 12 hrs, after which little further urinary excretion is detectable. Urinary concentrations of Meropenem in excess of 10 mcg/mL are maintained for up to 5 hrs at the 500-mg dose. No accumulation of Meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hrs or 1 g administered every 6 hrs in volunteers with normal renal function.

The only metabolite of Meropenem is microbiologically inactive.

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

Studies in children have shown that the pharmacokinetics of Meropenem in children is essentially similar to those in adults. The elimination t½ for Meropenem was approximately 1.5 hrs in children <2 years.

The pharmacokinetics is linear over the dose range of 10-40 mg/kg.

Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of Meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment.

Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of Meropenem which correlated with age-associated reduction in creatinine clearance.

Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of Meropenem.

How should I take Meropenem?

Meropenem is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Meropenem is usually given every 8 hours. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Meropenem must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

Do not mix other injectable medications in the same IV bag or tubing used to given your Meropenem injection.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Use Meropenem for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Meropenem will not treat a viral infection such as the common cold or flu.

If you use this medication long-term, you may need frequent medical tests at your doctor's office.

Store unopened vials of Meropenem at cool room temperature away from moisture and heat.

After mixing your medicine, you will need to use it within a certain number of hours. This will depend on the diluent and how you store the mixture (at cool room temperature, or in a refrigerator). Carefully follow the mixing and storage instructions provided with your medicine. Ask your pharmacist if you have questions.

Meropenem administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Meropenem will be administered as an intravenous (into a vein) injection by a healthcare provider.

If you are using Meropenem at home, your healthcare provider will give you detailed instructions regarding preparation, administration, and storage of the medication.

It is important to take Meropenem regularly to get the most benefit.

Take all of the Meropenem that has been prescribed for you, even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated.

Your doctor may want you to have blood tests or other medical evaluations during treatment with Meropenem to monitor progress and side effects.

Meropenem pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.

Mechanism Of Action

Meropenem is an antibacterial drug.

Pharmacokinetics

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of Meropenem I.V. in healthy volunteers, mean peak plasma concentrations of Meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 gram dose. A 5-minute intravenous bolus injection of Meropenem I.V. in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 gram dose.

Following intravenous doses of 500 mg, mean plasma concentrations of Meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of Meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of Meropenem is approximately 2%.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Meropenem I.V., the highest mean concentrations of Meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below.

Table 1: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

Tissue

Intravenous Dose (gram)

Number of Samples Mean [μg/mL ormcg/ (gram)]* Range [μg/mL or mcg/ (gram)]
Endometrium 0.5 7 4.2 1.7-10.2
Myometrium 0.5 15 3.8 0.4-8.1
Ovary 0.5 8 2.8 0.8-4.8
Cervix 0.5 2 7 5.4-8.5
Fallopian tube 0.5 9 1.7 0.3-3.4
Skin 0.5 22 3.3 0.5-12.6
Interstitial fluidt 0.5 9 5.5 3.2-8.6
Skin 1 10 5.3 1.3-16.7
Interstitial fluidt 1 5 26.3 20.9-37.4
Colon 1 2 2.6 2.5-2.7
Bile 1 7 14.6 (3 hours) 4-25.7
Gall bladder 1 1 3.9
Peritoneal fluid 1 9 30.2 7.4-54.6
Lung 1 2 4.8 (2 hours) 1.4-8.2
Bronchial mucosa 1 7 4.5 1.3-11.1
Muscle 1 2 6.1 (2 hours) 5.3-6.9
Fascia 1 9 8.8 1.5-20
Heart valves 1 7 9.7 6.4-12.1
Myocardium 1 10 15.5 5.2-25.5
CSF (inflamed) 20 mg/kg‡ 8 1.1 (2 hours) 0.2-2.8
40 mg/kg§ 5 3.3 (3 hours) 0.9-6.5
CSF (uninflamed) 1 4 0.2 (2 hours) 0.1-0.3
*at 1 hour unless otherwise noted

†obtained from blister fluid

‡in pediatric patients of age 5 months to 8 years

§in pediatric patients of age 1 month to 15 years

Metabolism

There is one metabolite of Meropenem that is microbiologically inactive.

Excretion

In subjects with normal renal function, the elimination half-life of Meropenem is approximately 1 hour.

Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that Meropenem undergoes both filtration and tubular secretion.

Urinary concentrations of Meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations

Renal Impairment

Pharmacokinetic studies with Meropenem I.V. in patients with renal impairment have shown that the plasma clearance of Meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less).

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage.

Hepatic Impairment

A pharmacokinetic study with Meropenem I.V. in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of Meropenem.

Geriatric Patients

A pharmacokinetic study with Meropenem I.V. in elderly patients with renal impairment showed a reduction in plasma clearance of Meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

The pharmacokinetics of Meropenem for injection I.V., in pediatric patients 2 years of age or older, are similar to those in adults. The elimination half-life for Meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years.

The pharmacokinetics of Meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below.

Table 2: Meropenem Pharmacokinetic Parameters in Patients Les s Than 3 Months of Age*

GA less than 32 weeks PNA less than 2 weeks (20mg/kg every 12 hours) GA less than 32 weeks PNA 2 weeks or older (20mg/kg every 8 hours) GA 32 weeks or older PNA less than 2 weeks (20mg/kg every 8 hours) GA 32 weeks or older PNA 2 weeks or older (30mg/kg every 8 hours) Overall
CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119
V (L/kg) 0.489 0.467 0.463 0.451 0.468
AUC0-24 (mcg-h/mL) 448 491 445 444 467
Cmax (mcg/mL) 44.3 46.5 44.9 61 46.9
Cmin (mcg/mL) 5.36 6.65 4.84 2.1 5.65
T½ (h) 3.82 2.68 2.33 1.58 2.68
*Values are derived from a population pharmacokinetic analysis of sparse data

Drug Interactions

Probenecid competes with Meropenem for active tubular secretion and thus inhibits the renal excretion of Meropenem. Following administration of probenecid with Meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with Meropenem is not recommended.

Microbiology

Mechanism Of Action

The bactericidal activity of Meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log reduction in cell counts within 12 hours to 24 hours) are typically 1-2 times the bacteriostatic concentrations of Meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

Mechanism Of Resistance

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.

Cross-Resistance

Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

Interactions With Other Antibacterial Drugs

In vitro tests show Meropenem to act synergistically with aminoglycoside antibacterials against some isolates of Pseudomonas aeruginosa.

Spectrum Of Activity

Meropenem has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described.

Gram-positive Bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

Streptococcus pyogenes

Viridans group streptococci

Gram-negative Bacteria

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Neisseria meningitidis

Pseudomonas aeruginosa

Proteus mirabilis

Anaerobic Bacteria

Bacteroides fragilis

Bacteroides thetaiotaomicron

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria have exhibited in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoints for Meropenem. However, the safety and effectiveness of Meropenem in treating clinical infections due to these bacteria have not been established in adequate and wellcontrolled trials.

Gram-positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Gram-negative Bacteria

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter koseri (formerly diversus)

Citrobacter freundii

Enterobacter cloacae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Pasteurella multocida

Proteus vulgaris

Serratia marcescens

Anaerobic Bacteria

Bacteroides distasonis

Bacteroides ovatus

Bacteroides uniformis

Bacteroides ureolyticus

Bacteroides vulgatus

Clostridium difficile

Clostridium perfringens

Eubacterium lentum

Fusobacterium species

Prevotella bivia

Prevotella intermedia

Prevotella melaninogenica

Porphyromonas asaccharolytica

Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method. Standardized procedures are based on a dilution method (broth or agar) The MIC values obtained should be interpreted according to the criteria provided in Table 3.

Table 3: Susceptibility Interpretive Criteria for Meropenem

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
S I R S I R
Enterobacteriaceae ≤ 1 2 ≥ 4 ≥ 23 20-22 ≤ 19
Pseudomonas aeruginosa* ≤ 2 4 ≥ 8 ≥ 19 16-18 ≤ 15
Haemophilus influenzae ≤ 0.5 ≥ 20
Neisseria meningitidis ≤ 0.25 ≥ 30
Streptococcus pneumoniae‡§ ≤ 0.25 0.5 ≥ 1
Streptococcus agalactiae and Streptococcus pyogenest†¶§ ≤ 0.5
Anaerobes# ≤ 4 8 ≥ 16
S = Susceptible, I = Intermediate, R = Resistant

No interpretative criteria have been established for testing enterococci.

Susceptibility of staphylococci to Meropenem may be deduced from testing penicillin and either cefoxitin or oxacillin.

*The interpretive criteria for P. aeruginosa are based upon the dosing of 1g every 8 hours.

†The current absence of data on resistant isolates precludes defining any category other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.

‡For nonmeningitis isolates of S. pneumoniae a penicillin MIC of ≤ 0.06 mcg/mL or oxacillin zone ≥ 20 mm can predict susceptibility to Meropenem. MIC testing should be performed on isolates that do not test as susceptible by either of these methods, and on all meningitis S. pneumoniae isolates.

§Reliable disk diffusion tests for Meropenem do not yet exist for testing streptococci.


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References

  1. DailyMed. "MEROPENEM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. NCIt. "Meropenem Anhydrous: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
  3. EPA DSStox. "Meropenem: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology

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