Local adverse events that were reported with Meropenem were as follows: Systemic adverse events that were reported with Meropenem occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). This inactivates the PBPs, leading to a weakened cell wall, which eventually ruptures because of osmotic pressure forces . Over time, however, problems such as resistance development and selection of resistant organisms have become apparent. Meropenem for injection (I.V.) In contrast to other beta-lactams, it is highly resistant to degradation by β-lactamases or cephalosporinases. The safety and effectiveness of Meropenem have been established for pediatric patients 3 months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections. Table 8: Clinical Efficacy Rate by Pathogen for Clinically Evaluable Population, Staphylococcus aureus, methicillin susceptible. DrugBank Meropenem Anhydrous is the anhydrous form of meropenem, a broad-spectrum carbapenem with antibacterial properties, synthetic Meropenem inhibits cell wall synthesis in gram-positive and gram-negative bacteria. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. The largest dose of Meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours. No information is available on the effects of Meropenem on the breast-fed child or on milk production. What is the mechanisms of action of carbapenems? (See dosing Table below.). The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. There is one metabolite of Meropenem that is microbiologically inactive. Meropenem has been reported to be excreted in human milk. 2. Doripenem, like other β-lactam antibiotics, reacts with penicillin-binding proteins (PBPs) to form stable acyl-enzymes. , Meropenem is administered intravenously as a white crystalline powder to be dissolved in 5% monobasic potassium phosphate solution. The IDSA recommends meropenem as a treatment option for documented meningitis and for empiric therapy in combination with vancomycin after a penetrating trauma or postneurosurgery; meropenem may also be used in combination with vancomycin as empiric therapy for CSF shunt infections when gram negative bacilli are present on gram stain. The carbapenem class of antibiotics have in common a carbon atom substituted for sulfur at position 1 and an unsaturated bond between C2 and C3 of the familiar penicillin nucleus (Figure 1).  It is in the carbapenem family of medications. Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; Meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Meropenem for injection should not be mixed with or physically added to solutions containing other drugs. Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection Vials. When treating complicated skin and skin structure infections caused by P.aeruginosa, a dose of 1 gram every 8 hours is recommended. Cross-resistance is sometimes observed with isolates resistant to other carbapenems. The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University..  For ß-lactams, including meropenem, prolonged intravenous administration is associated with lower mortality than bolus intravenous infusion in persons with whose infections are severe, or caused by bacteria that are less sensitive to meropenem, such as Pseudomonas aeruginosa.. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. Clostridium perfringens 12.4 Microbiology. Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. There is no experience in pediatric patients with renal impairment. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Alert patients receiving Meropenem on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Streptococcus agalactiae The Meropenem group had a statistically higher number of patients with transient elevation of liver enzymes. The pharmacokinetics of Meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below. Monitoring the renal function is vital because carbapenems should be dose adjusted. Streptococcus pyogenes Tell your doctor about the allergy and what signs you had. Medically reviewed by Drugs.com. 4F., No. Mechanism of action of meropenem. Enterococcus faecalis (vancomycin-susceptible isolates only) 1. The concomitant use of Meropenem and valproic acid or divalproex sodium is generally not recommended. Deaths in 5 patients were assessed as possibly related to Meropenem; 36 (1.2%) patients had Meropenem discontinued because of adverse events. Gram-positive bacteria There are numerous reports of seizure activity associated with imipenem-cilastatin, with seizure rates ranging from 3-33%. Probenecid competes with Meropenem for active tubular secretion, resulting in increased plasma concentrations of Meropenem. At the end of a 30-minute intravenous infusion of a single dose of Meropenem for injection in healthy volunteers, mean peak plasma concentrations of Meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 gram dose. Prevotella melaninogenica Chemistry and Mechanism of Action Meropenem. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the Meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). If administration of Meropenem is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)]. Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less [see Dosage and Administration (2.2)]. A 2014 study looked at cross-reaction between carbapenems and … Bactericidal concentrations (defined as a 3 log 10 reduction in cell counts within 12 hours to 24 hours) are typically 1to 2 times the bacteriostatic concentrations of Meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.  Use in pregnancy appears to be safe. The plasma protein binding of Meropenem is approximately 2%. There was no evidence of mutagenic potential found in any of these tests. Seizures and other adverse CNS experiences have been reported during treatment with Meropenem. Genetic toxicity studies were performed with Meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test.  Meropenem has a reduced potential for seizures in comparison with imipenem. If superinfection does occur during therapy, appropriate measures should be taken. Meropenem is an injectable carbapenem antibiotic. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Mechanism of Action. 3. Penetrates well into most body fluids and tissues; CSF concentrations approximate those in plasma. Mechanism of Action: Cause rapid bacterial cell death by covalently binding to penicillin-binding proteins (PBPs) involved in the biosynthesis of mucopeptides in bacterial cell walls. Gram-positive bacteria Meropenem prevents bacteria from forming the walls that surround them. It penetrates the bacterial cell wall with its high levels of stability in all serine beta-lactamases and marked affinity for … It is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxilic acid trihydrate. Use of Meropenem in pediatric patients less than 3 months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from a pediatric pharmacokinetic and safety study [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Repeated evaluation of the patient is essential. During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem (500 mg or 1 gram every 8 hours). The recommended dose of Meropenem for injection is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the Meropenem for injection dose is based on gestational age (GA) and postnatal age (PNA).  Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax. This is not a list of all drugs or health problems that interact with meropenem. Escherichia coli It inhibits bacterial cell wall synthesis like other β-lactam antibiotics. If an allergic reaction to Meropenem occurs, discontinue the drug immediately. The clinical efficacy rates by pathogen are provided in Table 8. Peak tissue time: 1 hr after infusion. Co-administration of probenecid with Meropenem is not recommended. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. Fecal elimination represents only approximately 2% of the dose. Case reports in the literature have shown that co-administration of carbapenems, including Meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison). Prescribing Meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2), Use In Specific Populations (8.6)]. Table 6: Meropenem Pharmacokinetic Parameters in Patients Less Than 3 Months of Age1, Values are derived from a population pharmacokinetic analysis of sparse data. Inhibits cell-wall synthesis by binding to penicillin-binding proteins; resistant to most beta-lactamases. The trial was conducted in the United States, South Africa, Canada, and Brazil. Of the total number of subjects in clinical studies of Meropenem, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Peptostreptococcus species. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)]. Distribution. Adverse events with an incidence of greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia. Administration of a carbapenem (imipenem, meropenem, and perhaps ertapenem) alone or with other antibiotics was associated with a significantly lower ... Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects View in Chinese … the beta-lactam ring. The most common adverse events occurring in greater than 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Imipenem and meropenem are useful in cases in which P. aeruginosa is a suspected pathogen. It inhibits bacterial cell wall synthesis like other β-lactam antibiotics. Single dose clear glass vials of Meropenem for injection containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile Meropenem powder. Case reports in the literature have shown that co-administration of carbapenems, including Meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. It is similar to impenem and cilastin . The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (Meropenem, 2.5% and imipenem-cilastatin, 2.7%). Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If you are allergic to meropenem; any part of meropenem; or any other drugs, foods, or substances. Additional systemic adverse events that were reported with Meropenem and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency: Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%). Pediatric Patients 3 Months of Age and Older, Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function, Complicated skin and skin structure Infections. In individuals with normal renal function, rapid renal elimination takes place. Meropenem for injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, and Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae. Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with Meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. Several cases of severe hypokalemia have been reported. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. See dosing Table 3 below. It is active against Gram-positive and Gram-negative bacteria. Doripenem has high affinity for PBP2 and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli . ... Meropenem and doripenem are thought to be the more potent in vitro agents against gram negative organisms. Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Carcinogenesis studies have not been performed. Skin and Subcutaneous Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis.  The World Health Organization classifies meropenem as critically important for human medicine.. Proteus mirabilis The following are discussed in greater detail in other sections of labeling: Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Enterobacter cloacae Pasteurella multocida However, the efficacy of Meropenem in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical trials. β-Lactams were among the first antimicrobial agents available for the therapy of infectious diseases. Bacteroides vulgatus Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem. Urinary concentrations of Meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose. Continue anti-convulsant therapy in patients with known seizure disorders. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Available for Android and iOS devices. One controlled clinical study of complicated intra-abdominal infection was performed in the United States where Meropenem was compared with clindamycin/tobramycin. Mechanism of Action: Meropenem is a structural analog of impipenem that is resistant to cleavage by renal dehydropeptidase I. The success rates for the clinically evaluable population are provided in Table 7. Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosing must be adjusted for altered kidney function and for haemofiltration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Meropenem and any potential adverse effects on the breast-fed child from Meropenem or from the underlying maternal conditions. Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Staphylococcus aureus (methicillin-susceptible isolates only) The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). Serratia marcescens, Bacteroides ovatus , Common side effects include nausea, diarrhea, constipation, headache, rash, and pain at the site of injection. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. The easiest way to lookup drug information, identify pills, check interactions and set up your own personal medication records. In a peri-postnatal study in rats described in the published literature 2, intravenous Meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. In general, resistance arises due to mutations in penicillin-binding proteins, production of metallo-β-lactamases, or resistance to diffusion across the bacterial outer membrane.  Meropenem is frequently given in the treatment of febrile neutropenia. The adverse reactions seen in these patients that were reported and their rates of occurrence are as follows: Adverse Laboratory Changes in Pediatric Patients: Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. The study included 510 patients randomized to Meropenem and 527 patients randomized to imipenem-cilastatin. There is inadequate information regarding the use of Meropenem for injection in patients on hemodialysis or peritoneal dialysis. The pH of freshly constituted solutions is between 7.3 and 8.3. At this dosage, no adverse pharmacological effects or increased safety risks have been observed. Before initiating therapy with Meropenem, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. Approximately 70% (50% - 75%) of the dose is excreted unchanged within 12 hours. Imipenem was the first carbapenem antibiotic selected for development more than two dec… Bacteroides ureolyticus Propionibacterium acnes. Hafnia alvei, Klebsiella oxytoca Adverse laboratory changes that were reported and occurring in greater than 0.2% of the patients were as follows: Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactose dehydrogenase (LDH), and bilirubin, Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia, Renal: increased creatinine and increased blood urea nitrogen (BUN), Complicated Skin and Skin Structure Infections. Bloodstream Infections. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the Meropenem arm and 83% (238/287) in imipenem-cilastatin arm. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Citrobacter koseri During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). If you are taking probenecid. Bacteroides thetaiotaomicron Meropenem is bactericidal except against Listeria monocytogenes, where it is bacteriostatic. It works against extended-spectrum β-lactamases, but may be more susceptible to metallo-β-lactamases. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In contrast, imipenem has greater affinity to PBP1a and PBP1b in P. ae… Freshly prepared solutions of Meropenem for injection should be used. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem, and may range in severity from mild diarrhea to fatal colitis. 12 & 16, Chuangye Rd., Xinshi Dist., Tainan City 74144, Taiwan for C. difficile produces toxins A and B which contribute to the development of CDAD. Blood and Lymphatic System Disorders: agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. The most common adverse effects are diarrhea (4.8%), nausea and vomiting (3.6%), injection-site inflammation (2.4%), headache (2.3%), rash (1.9%) and thrombophlebitis (0.9%). The following Table shows the degree of hearing loss between the Meropenem-treated patients and the comparator-treated patients. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Meropenem against isolates of similar genus or organism group.
2020 meropenem mechanism of action