β-lactam; cell wall synthesis
Meropenem trihydrate (SM 7338) is a broad-spectrum carbapenem antibiotic. Its primary mechanism of action is the inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs).

Meropenem functions by binding to and deactivating penicillin-binding proteins (PBPs), thereby inhibiting the synthesis of bacterial cell walls. Meropenem is intrinsically stable against dehydropeptidase-1 (DHP-1) degradation. While Meropenem exhibits broad-spectrum in vitro activity against a variety of Gram-positive, Gram-negative, and anaerobic bacteria, it is ineffective against methicillin-resistant Staphylococcus aureus, Enterococcus faecium, and Stenotrophomonas maltophilia[2].

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Meropenem trihydrate (SM 7338) exhibits in vitro antibacterial activity against Neisseria gonorrhoeae, Haemophilus influenzae, and Haemophilus ducreyi [1].
For N. gonorrhoeae: MIC₉₀ values were 0.03 mg/L for β-lactamase-producing (PPNG) strains, 0.015 mg/L for non-PPNG strains from Winnipeg, and 0.015 mg/L for non-PPNG strains from Kenya [1].
For H. influenzae (n=119): MIC₅₀ was 0.03 mg/L and MIC₉₀ was 0.06 mg/L [1].
For H. ducreyi (n=110): MIC₅₀ was 0.06 mg/L and MIC₉₀ was 0.12 mg/L [1].
Meropenem showed greater in vitro activity than imipenem against all three pathogens [1].
β-lactamase production did not significantly reduce susceptibility to meropenem [1].
The minimum bactericidal concentration (MBC) to MIC ratio for ten H. influenzae strains was ≤ 2, indicating no tolerance to the drug [1].
Meropenem exhibits broad-spectrum in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, including methicillin-susceptible S. aureus, penicillin-intermediate and -resistant S. pneumoniae, and many Enterobacteriaceae [2]
It lacks activity against Enterococcus faecium, methicillin-resistant S. aureus (MRSA), and Stenotrophomonas maltophilia [2]
Compared to imipenem, it shows slightly lower activity against Gram-positive bacteria but greater activity against Gram-negative bacteria, including P. aeruginosa [2]
MIC90 values for common pathogens are generally ≤1 mg/L for susceptible Gram-positive aerobes and ≤2 mg/L for Gram-negative anaerobes [2]
Against P. aeruginosa, meropenem shows MIC90 values of 0.5–16 mg/L, with doripenem showing slightly greater activity [2]

The incidence of pancreatic infection is significantly reduced by treatment with meropenem (60 mg/kg; intraperitoneal injection; once; SD rats)[3].

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There was no difference in serum amylase levels between AP induced groups (P > 0.05). Pancreatic histology scores were significantly low in rats treated with deferoxamine (group 4), and combination regimen (group 5) (P < 0.001). Meropenem significantly reduced the incidence of pancreatic infection. Although combination of deferoxamine with meropenem showed better effects than meropenem alone in terms of pancreatic infection, the difference did not reach to statistical significance.
Conclusions: Meropenem treatment reduces secondary pancreatic infections in acute pancreatitis. Treatment with deferoxamine and meropenem combination may be more beneficial than single therapies in reducing the severity of pancreatitis. Further studies investigating the effects of this combination on survival are needed[Pancreas. 2003 Oct;27(3):247-52.].

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Meropenem has been shown to be effective in treating complicated intra-abdominal infections, skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia, complicated urinary tract infections, meningitis, and febrile neutropenia in clinical trials [2]
In a trial comparing meropenem with clindamycin plus tobramycin for intra-abdominal infections, clinical cure rates were 92% vs. 86% [2]
In cystic fibrosis patients with acute pulmonary exacerbations, meropenem plus tobramycin showed a 62% satisfactory response vs. 44% for ceftazidime plus tobramycin [2]

Meropenem, a new carbapenem, was compared with imipenem and seven other broad-spectrum antimicrobial agents against approximately 1000 clinical isolates. Meropenem was two- to four-fold more active than imipenem against Gram-negative organisms and its spectrum of antimicrobial activity was wider than those of all other drugs tested. However, imipenem was more potent than meropenem against the staphylococci, Streptococcus spp. and enterococci. Many rarely isolated organisms were more susceptible to the carbapenems than to other comparison compounds. All anaerobic bacteria were inhibited by meropenem at less than or equal to 8 mg/l and 50% of strains were inhibited by 0.25 mg/l. Meropenem MICs were not significantly influenced by high inocula and the drug was generally bactericidal. Strains producing various beta-lactamases remained susceptible to meropenem but some isolates producing high levels of chromosomally-mediated enzymes showed an inoculum effect only at 10(7) cfu/ml. Meropenem demonstrated antagonism with several other beta-lactams against strains producing Type I cephalosporinases. Susceptibility tests performed on agar and in broth produced very similar meropenem results. Imipenem and meropenem shared a high degree of cross-susceptibility as measured by dilution test methods. Disc diffusion (10-micrograms disc) regression-line correlations with meropenem MICs are reported with two possible sets of interpretive criteria, using meropenem breakpoints of less than or equal to 2 and less than or equal to 4 mg/l[5].

Meropenem, a new parenteral carbapenem demonstrated increased activity as compared to imipenem against 336 strains of Neisseria gonorrhoeae, 119 strains of Haemophilus influenzae, and 110 strains of H. ducreyi. Neither carbapenem was affected by the beta-lactamase activity of the organisms tested. Ceftriaxone and ciprofloxacin demonstrated activity superior to that of both carbapenems while the activity of ceftazidime was similar to that of meropenem[1].

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Meropenem is a parenteral carbapenem antibiotic which has excellent bactericidal activity in vitro against almost all clinically significant aerobes and anaerobes. Its high activity is explained by ease of entry into bacteria combined with good affinity for essential penicillin binding proteins, including those associated with cell lysis. Breadth of spectrum is due, in part, to stability to all serine-based beta-lactamases, including those which hydrolyse third-generation cephalosporins. Meropenem has an antibacterial spectrum which is broadly similar to that of imipenem but, whilst slightly less active against staphylococci and enterococci, it is more active against Pseudomonas aeruginosa, all Enterobacteriaceae and Haemophilus influenzae. Amongst common human pathogens, only methicillin-resistant staphylococci and Enterococcus faecium are uniformly resistant to meropenem. The meropenem MICs for penicillin-resistant Streptococcus pneumoniae are higher than for penicillin-susceptible strains but the organisms remain susceptible. Clinical susceptibility in vitro to meropenem is defined by MICs of < or = 4 mg/L, intermediate susceptibility by MICs of 8 mg/L and MICs of > or = 16 mg/L define resistance; equivalent figures for zones of growth inhibition are > or = 14 (susceptible), 12-13 (intermediate) and < or = 11 (resistant) mm. Studies in guinea pig models of systemic infection and infections localised to the lungs, urinary tract and the central nervous system, some of which used immunocompromised animals, confirm the potential of meropenem demonstrated in vitro. These factors, combined with the human plasma, tissue or urinary concentrations of meropenem which exceed modal MICs for the pathogens isolated in clinical trials for most or all of the recommended 8 h dosing interval, predict that meropenem should be efficacious in the treatment of infections at many body sites [4].

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The agar dilution method was used to determine Minimum Inhibitory Concentrations (MICs). Two-fold serial dilutions of meropenem and comparator antibiotics were prepared and incorporated into molten chocolate agar supplemented with specific growth factors. Bacterial suspensions were standardized to a density of approximately 10⁸ CFU/mL and further diluted to deliver a final inoculum of 10³ CFU/spot for N. gonorrhoeae and 10⁴ CFU/spot for Haemophilus spp. onto the agar surface. Plates were incubated, and the MIC was defined as the lowest concentration of antibiotic that inhibited visible growth [1].
The Minimum Bactericidal Concentration (MBC) was determined for ten H. influenzae strains using a broth macrodilution method. Antibiotic dilutions in supplemented Mueller-Hinton broth were inoculated with a bacterial suspension to achieve a final concentration of approximately 5 x 10⁵ CFU/mL. Tubes were incubated, and the MIC was recorded as the lowest concentration preventing visible growth. Tubes showing no growth were vortexed and incubated for an additional 4 hours. Subsequently, 0.1 mL samples from these tubes were plated onto chocolate agar. The MBC was defined as the lowest drug concentration that killed ≥ 99.9% of the original inoculum [1].

Animal Model: Acute necrotizing pancreatitis was induced in male Sprague-Dawley rats weighing 250–350 g.
Dosage: 60 mg/kg
Administration: Intraperitoneal injection; once
Result: The incidence of pancreatic infection was significantly decreased.

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One hundred male Sprague-Dawley rats were randomly divided into 5 groups. All rats underwent laparotomy with cannulation of biliopancreatic duct. Group 1 received intraductal saline injection. Acute necrotizing pancreatitis was induced in group 2, 3, 4, and 5 by intraductal injection of 3% taurocholate. Group 1 (sham operated) and group 2 were injected with saline of 0.3 mL/kg intraperitoneally (i.p). Group 3 was injected with meropenem 60 mg/kg/d i.p, group 4 with deferoxamine 80 mg/kg/d s.c and group 5 with combination of these 2 agents at the same doses. While meropenem was started 2 hours later, all treatments were started immediately after the induction of pancreatitis. All rats were killed at the 48th hour of the treatment and blood and tissue samples were collected for amylase determinations, pathologic examinations, and culture.[3]

Absorption, Distribution, and Excretion
Excretion Route
Following intravenous injection, approximately 70% of the dose is excreted unchanged in the urine within 12 hours, after which almost no further urinary excretion is detected.
Following intravenous injection, approximately 70% of the dose is excreted unchanged in the urine within 12 hours, after which almost no further urinary excretion is detected. Following a 500 mg dose, urinary meropenem concentrations can remain above 10 μg/mL for up to 5 hours.
Meropenem is distributed in most body tissues and fluids, including the bronchial mucosa, lungs, bile, gynecological tissues (endometrium, myometrium, ovaries, cervix, fallopian tubes), muscles, heart valves, skin, interstitial fluid, peritoneal fluid, and cerebrospinal fluid. Plasma protein binding is approximately 2%. The drug is partially metabolized to at least one microbially inactive metabolite. Approximately 70% of the intravenously administered dose is excreted unchanged in the urine via renal tubular secretion and glomerular filtration. In healthy volunteers, 30 minutes after a single intravenous infusion of meropenem (IV), the mean peak plasma concentration was approximately 23 μg/mL (range 14–26 μg/mL) in the 500 mg dose group and approximately 49 μg/mL (range 39–58 μg/mL) in the 1 g dose group. In healthy volunteers, 5 minutes after an intravenous bolus injection of meropenem (IV), the mean peak plasma concentration was approximately 45 μg/mL (range 18–65 μg/mL) in the 500 mg dose group and approximately 112 μg/mL (range 83–140 μg/mL) in the 1 g dose group. Following an intravenous injection of 500 mg meropenem, the mean plasma concentration typically decreases to approximately 1 μg/mL within 6 hours. In healthy volunteers with normal renal function, no accumulation of meropenem in plasma was observed with either a dosing regimen of 500 mg every 8 hours or 1 g every 6 hours.

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Metabolites/Metabolites
Primarily excreted unchanged. One metabolite is nonmicrobially active.
Meropenem has one nonmicrobially active metabolite.

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Biological Half-Life
The biological half-life is approximately 1 hour in adults with normal renal function and children aged 2 years and older. The plasma half-life in children aged 3 months to 2 years is approximately 1.5 hours.
The plasma half-life of meropenem is approximately 1 hour in adults with normal renal function and approximately 1.5 hours in children aged 3 months to 2 years. Patients with renal impairment have a prolonged plasma half-life and reduced drug clearance.

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After intravenous injection of 500 mg, Cmax was 26 mg/L and AUC was 27.2–32.4 mg·h/L; after intravenous injection of 1000 mg, Cmax was 50–60 mg/L and AUC was 66.9–77.5 mg·h/L [2]
The half-life is about 1 hour [2]
The protein binding rate is about 2% [2]
The volume of distribution is 0.23–0.35 L/kg [2]
About 70% is excreted unchanged in the urine [2]
In patients with meningitis, the drug penetrates well into the interstitial fluid, lung tissue, colon, gallbladder, skin, gynecological tissue and cerebrospinal fluid [2]

Hepatotoxicity
Elevated serum transaminases have been reported in 1% to 6% of patients receiving intravenous meropenem for up to 14 days. These elevations are usually transient, mild, and asymptomatic; dose adjustments are rarely required. Meropenem has also been associated with rare cases of cholestatic jaundice, which usually appears 1 to 3 weeks after treatment. Immune allergy may be present, but is rarely pronounced. Autoantibodies are rare. Most cases are mild and resolve spontaneously, but at least one case of disappearing bile duct syndrome associated with meropenem treatment has been published (Case 1). There have been no reports of meropenem causing acute liver failure.
Probability score: D (likely to cause clinically significant liver injury, albeit rarely).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
While there is currently no information regarding the use of meropenem during lactation, its concentration in breast milk appears to be low, and β-lactam antibiotics are generally not expected to have adverse effects on breastfed infants. Reports indicate that β-lactam antibiotics may occasionally cause gastrointestinal flora imbalance in infants, leading to diarrhea or thrush, but these effects have not been fully assessed. Vaborbactam (used in combination with meropenem in the product Vabomere) has not been studied in breastfeeding women, but similar risks are expected with combination therapy as with meropenem alone.
◉ Effects on breastfed infants
One mother received intravenous meropenem for 7 days at a dose of 1 gram every 8 hours while exclusively breastfeeding her newborn. Upon subsequent inquiry, she stated that her infant did not develop symptoms requiring antifungal treatment, such as thrush, watery diarrhea, or diaper dermatitis, within one month of meropenem treatment.
One infant was exclusively breastfed until 4 months postpartum (feeding extent not specified). When the infant was 2 months old, the mother received a 2-week course of tobramycin and meropenem (dosage not specified) for an acute exacerbation of cystic fibrosis. The infant's bowel regularity did not change during the mother's treatment, and renal function was normal at 6 months of age.
◉ Effects on breastfeeding and breast milk
No relevant published information was found as of the revision date.

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Drug interactions
Case reports in the literature have shown that concomitant use of carbapenems (including meropenem) in patients taking valproic acid or sodium valproate can lead to a decrease in valproic acid concentrations. This interaction may result in valproic acid concentrations below the therapeutic range, thereby increasing the risk of seizures. Although the mechanism of this interaction is not clear, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid glucuronide metabolite (VPA-g) to valproic acid, thereby reducing serum valproic acid concentrations. If meropenem is required, adjunctive anticonvulsant therapy should be considered.

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Protein binding rate:
Approximately 2%.

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The most common adverse reactions include local injection site irritation, diarrhea, rash, nausea, vomiting, and pruritus [2].
The incidence of seizures is lower than that of imipenem; meropenem is indicated for meningitis[2].
Mild to moderate elevations in liver enzymes, serum creatinine, and urea have been reported in <1% of subjects[2].
Thrombocytosis and eosinophilia have been reported in <2% of subjects[2].
Drug-related neutropenia is uncommon[2].

[1]. J Antimicrob Chemother. 1989 Sep;24 Suppl A:183-6.

[2]. Drugs. 2007;67(7):1027-52.

[3]. Pancreas. 2003 Oct;27(3):247-52.

[4]. J Antimicrob Chemother.1995 Jul;36 Suppl A:1-17.

[5]. J Antimicrob Chemother.1989 Sep;24 Suppl A:9-29.

[6]. Pharm Res.2001 Sep;18(9):1320-6.

Meropenem trihydrate is a hydrate and an antibacterial drug containing meropenem molecules. Meropenem is a broad-spectrum carbapenem antibacterial drug. Synthetic meropenem inhibits cell wall synthesis in Gram-positive and Gram-negative bacteria. It can penetrate cell walls and bind to penicillin-binding protein targets. Meropenem is effective against both aerobic and anaerobic bacteria, including Klebsiella spp., Escherichia coli, Enterococcus spp., and Clostridium spp. (NCI04) It is a thiamethoxam derivative antibacterial agent that is more stable than imipenem and less susceptible to degradation by renal dehydropeptidase I, but does not require combination with enzyme inhibitors such as cilastatin. It is used to treat bacterial infections, including those in immunocompromised patients. See also: Meropenem (note moved to). Meropenem trihydrate (SM 7338) is an injectable carbapenem antibiotic [1].
This study compared its in vitro activity with that of imipenem, piperacillin, ceftriaxone, ceftazidime, and ciprofloxacin [1].
The study showed that meropenem remained active against β-lactamase-producing Neisseria gonorrhoeae, Haemophilus influenzae, and Haemophilus ducreyi strains [1].
In this test system, meropenem showed significantly better activity against Haemophilus influenzae than imipenem [1].
Meropenem is a broad-spectrum carbapenem antibiotic that is stable against dehydropeptidase-1. (DHP-1), no need for combination therapy with DHP-1 inhibitors [2]
Mainly used to treat moderate to severe nosocomial infections and multimicrobial infections [2]
Has post-antibiotic effects against both Gram-positive and Gram-negative bacteria, with a post-antibiotic effect lasting 4 hours against Escherichia coli and 5 hours against Pseudomonas aeruginosa [2]
Ineffective against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Pseudomonas aeruginosa (some drug-resistant strains) or Stenotrophomonas maltophilia [2]
Only available in injectable form [2]

C17H31N3O8S

437.51

383.151

C, 46.67; H, 7.14; N, 9.60; O, 29.25; S, 7.33

119478-56-7

Meropenem;96036-03-2;Meropenem-d6;1217976-95-8; 96036-03-2 (free); 119478-56-7 (hydrate); 211238-34-5 (sodium)

441129

White to yellow solid powder

1.4±0.1 g/cm3

627.4±55.0 °C at 760 mmHg

333.2±31.5 °C

0.0±4.2 mmHg at 25°C

1.639

-2.59

6

10

5

29

679

6

S([C@]1([H])C([H])([H])N([H])[C@]([H])(C(N(C([H])([H])[H])C([H])([H])[H])=O)C1([H])[H])C1=C(C(=O)O[H])N2C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])[C@@]2([H])[C@@]1([H])C([H])([H])[H])=O

CTUAQTBUVLKNDJ-OBZXMJSBSA-N

InChI=1S/C17H25N3O5S.3H2O/c1-7-12-11(8(2)21)16(23)20(12)13(17(24)25)14(7)26-9-5-10(18-6-9)15(22)19(3)4;;;/h7-12,18,21H,5-6H2,1-4H3,(H,24,25);3*1H2/t7-,8-,9+,10+,11-,12-;;;/m1.../s1

(4R,5S,6S)-3-(((3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate

Meropenem trihydrate; Meropenem hydrate; ICI 194660; ICI-194660; ICI194660; SM-7338; 119478-56-7; Meropenem (trihydrate); FV9J3JU8B1; (4R,5S,6S)-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate; UNII-FV9J3JU8B1; MFCD08600005; SM-7338; SM 7338; SM7338; Vabomere.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~228.57 mM)
H2O : ~12.5 mg/mL (~28.57 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (228.57 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)