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Meropenem

Meropenem is a synthetic, broad-spectrum indicated for the of serious bacterial , including complicated and structure and bacterial in pediatric patients aged 3 months and older, as well as intra-abdominal (including in neonates under 3 months). It exerts bactericidal activity by binding to , thereby inhibiting bacterial cell wall synthesis and leading to cell death; it is particularly stable against many β-lactamases produced by and . Administered intravenously, meropenem achieves peak plasma concentrations of approximately 23 mcg/mL after a 500 mg dose and 49 mcg/mL after a 1 g dose over a 30-minute , with a of about 1 hour in adults with normal renal function, and is primarily excreted unchanged in the urine. Developed by Sumitomo Pharmaceuticals as a more stable derivative of the natural thienamycin (discovered in 1976 from Streptomyces cattleya), meropenem features a 1β-methyl group that confers resistance to renal dehydropeptidase I hydrolysis, eliminating the need for a co-administered like cilastatin (used with imipenem). First approved by the U.S. in 1996 under the brand name Merrem IV, it is available as a sterile powder for reconstitution in 500 mg and 1 g vials containing meropenem trihydrate and . Unlike earlier s, meropenem demonstrates enhanced activity against certain Gram-negative pathogens, such as Pseudomonas aeruginosa, while maintaining efficacy against methicillin-susceptible staphylococci and streptococci. Meropenem is reserved for infections caused by susceptible to minimize the risk of development, and its use requires caution in patients with to β-lactams, disorders, or renal impairment due to potential adverse effects including , convulsions, and . In 2017, a fixed-dose combination of meropenem with vaborbactam (Vabomere) was approved for complicated urinary tract infections resistant to other antibiotics, highlighting its role in combating multidrug-resistant pathogens.

Medical uses

Indications

Meropenem is a broad-spectrum antibiotic with activity against aerobic and anaerobic Gram-positive and , including . It is indicated for the of complicated and structure infections in adults and pediatric patients aged 3 months and older, caused by susceptible isolates such as methicillin-susceptible , , and . Meropenem is also approved for complicated intra-abdominal infections in adults and children aged 3 months and older due to pathogens including , , P. aeruginosa, and . Additionally, it is indicated for bacterial in pediatric patients aged 3 months and older caused by , , or penicillin-susceptible , with evidence of efficacy in eliminating concurrent bacteremia. Meropenem is recommended for empirical therapy in hospitalized patients with severe , , and polymicrobial infections, as well as for in neutropenic patients suspected of bacterial infection. The Infectious Diseases Society of America (IDSA) guidelines recommend meropenem as a preferred for treating severe infections outside the urinary tract caused by extended-spectrum (ESBL)-producing , based on data showing lower mortality compared to alternatives like piperacillin-tazobactam. Clinical trials have demonstrated high for meropenem in complicated intra-abdominal infections, with clinical rates of 93-94% at test-of- in microbiologically evaluable populations. Overall response rates exceed 80% in severe cases, supporting its role as monotherapy for polymicrobial intra-abdominal infections.

Limitations and resistance considerations

Meropenem exhibits limited activity against certain Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium, which are uniformly resistant due to intrinsic mechanisms such as altered penicillin-binding proteins and efflux pumps. It also lacks efficacy against most fungi and viruses, as it targets bacterial cell wall synthesis and does not affect eukaryotic or viral replication pathways. Additionally, meropenem has poor activity against atypical bacteria like Mycoplasma species, which lack cell walls and are thus unaffected by beta-lactam antibiotics. A major limitation arises from the increasing prevalence of carbapenem resistance, primarily driven by the production of carbapenemase enzymes such as Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM) in pathogens including Klebsiella pneumoniae and Acinetobacter baumannii. These enzymes hydrolyze the beta-lactam ring of meropenem, rendering it ineffective, and are often plasmid-mediated, facilitating rapid dissemination among Gram-negative bacteria. Resistance in A. baumannii may also involve additional mechanisms like efflux pumps and porin loss, exacerbating treatment challenges in hospital settings. Global surveillance data highlight the escalating threat of carbapenem resistance. According to the World Health Organization's 2025 report, antibiotic resistance in has risen in over 40% of monitored pathogen-antibiotic combinations between 2018 and 2023, with showing 44.8% resistance to third-generation cephalosporins (a proxy for broader resistance trends) and K. pneumoniae at 55.2%. In the United States, the Centers for Control and Prevention reported a more than 460% surge in infections caused by NDM-producing (CRE) from 2019 to 2023, particularly affecting and . Resistance rates for carbapenem-non-susceptible Gram-negatives can reach 20-50% in high-burden regions like parts of and the . To mitigate resistance, programs emphasize reserving meropenem for confirmed multidrug-resistant infections, such as those caused by extended-spectrum (ESBL)-producing or CRE pathogens, rather than empirical use in mild cases. Guidelines from the Infectious Diseases Society of America (IDSA) recommend avoiding meropenem in unless resistant pathogens are identified through microbiological testing, favoring narrower-spectrum agents like / inhibitor combinations for initial therapy. The American Thoracic Society similarly advises against routine use in non-severe to preserve efficacy against hospital-acquired resistant strains. For infections involving meropenem-resistant strains, alternatives such as ceftazidime-avibactam are recommended, particularly for KPC-producing CRE, as avibactam inhibits serine-based beta-lactamases while ceftazidime provides broad Gram-negative coverage. IDSA guidance prioritizes ceftazidime-avibactam over for susceptible resistant isolates, with rates exceeding 90% against many multidrug-resistant Gram-negatives in clinical studies. Other options like meropenem-vaborbactam may be considered for specific profiles, but selection should be guided by local patterns.

Administration and dosing

Routes and forms

Meropenem is administered exclusively by the route, either as a short over 15 to 30 minutes or as a bolus injection over 3 to 5 minutes, to ensure effective delivery and minimize vein irritation. Intramuscular administration is not recommended, as it is not approved and can cause significant injection site pain due to the absence of local anesthetics in the formulation. The primary dosage form is a sterile powder for reconstitution supplied in single-dose vials containing 500 mg or 1 g of meropenem (as the trihydrate) blended with anhydrous . For settings, pre-mixed ready-to-use solutions are available in DUPLEX containers, which combine 500 mg or 1 g of meropenem with 50 mL of 0.9% injection, facilitating quicker preparation for full adult doses. Preparation involves reconstituting the vial powder with sterile (10 mL for 500 vial or 20 mL for 1 g vial) to yield a 50 /mL concentration, followed by shaking and allowing it to stand until clear. For infusion, the reconstituted solution is further diluted in compatible fluids such as 0.9% to concentrations of 1 to 20 /mL; it is compatible with central venous catheters for extended . Post-reconstitution bolus solutions (up to 50 /mL) remain stable for 3 hours at (up to 25°C) or 13 hours refrigerated (5°C), while infusion solutions in 0.9% are stable for 1 hour at or 15 hours refrigerated; solutions must not be frozen. For pediatric and neonatal use, the same vial sizes are employed, with reconstitution and dilution adjusted according to weight-based dosing requirements to accommodate smaller volumes.

Dosage regimens

Meropenem is administered intravenously as the standard route for systemic infections. The recommended adult dosage is 500 mg every 8 hours for complicated and structure infections (1 g every 8 hours if Pseudomonas aeruginosa is suspected or documented), 1 g every 8 hours for complicated intra-abdominal infections, with a maximum of 2 g every 8 hours specifically for bacterial . For patients with renal impairment, dosage adjustments are necessary to prevent accumulation due to the drug's primary renal excretion. In adults with creatinine clearance (CrCl) of 26-50 mL/min, the standard dose is reduced to every 12 hours; for CrCl 10-25 mL/min, half the standard dose is given every 12 hours; and for CrCl less than 10 mL/min, half the standard dose is administered every 24 hours.
Creatinine Clearance (mL/min)Dosage Adjustment (Adults)
>50Standard dose every 8 hours
26-50Standard dose every 12 hours
10-25½ standard dose every 12 hours
<10½ standard dose every 24 hours
Pediatric dosing in children aged 3 months and older with normal renal function is weight-based: 10 mg/kg (maximum 500 mg) every 8 hours for skin infections (20 mg/kg, maximum 1 g, if Pseudomonas aeruginosa is suspected), 20 mg/kg (maximum 1 g) every 8 hours for intra-abdominal infections, increasing to 40 mg/kg (maximum 2 g) every 8 hours for meningitis. For neonates and infants under 3 months with intra-abdominal infections, doses range from 20 mg/kg every 12 hours (for preterm infants less than 32 weeks gestational age and postnatal age under 2 weeks) to 30 mg/kg every 8 hours (for term infants 32 weeks or more gestational age and postnatal age 2 weeks or more). The duration of meropenem therapy generally ranges from 7 to 14 days, tailored to the site and severity of the infection, with clinical response guiding completion. In critically ill patients, extended infusions over 3 hours are recommended to optimize the time above the , improving pharmacokinetic/pharmacodynamic target attainment compared to standard 30-minute infusions. Therapeutic drug monitoring is advised in cases of obesity or augmented renal clearance to ensure adequate exposure, as standard dosing may result in subtherapeutic levels in these populations.

Contraindications and precautions

Absolute contraindications

Meropenem is absolutely contraindicated in patients with known hypersensitivity to meropenem itself, any component of the formulation, or other drugs in the carbapenem class. This includes individuals with a documented history of anaphylaxis or severe allergic reactions to beta-lactam antibiotics, such as penicillins or cephalosporins, owing to the structural similarities that can lead to cross-reactivity. Although the overall risk of cross-reactivity between penicillins and carbapenems like meropenem is low—estimated at less than 1% in patients with confirmed penicillin allergy—the potential for life-threatening hypersensitivity reactions necessitates strict avoidance in such cases. The European Medicines Agency aligns with this guidance, prohibiting use in patients hypersensitive to meropenem or related beta-lactams. No black-box warnings are associated with meropenem regarding contraindications as of 2025.

Use in special populations

Limited published data on meropenem use in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage; it should be used during pregnancy only if the potential benefits justify the risks, such as in cases of maternal sepsis or severe infections. Animal reproduction studies in rats and monkeys at doses up to 3.2 times the maximum recommended human dose showed no adverse effects on embryofetal development or fertility. Meropenem is excreted into breast milk in low concentrations, with average levels around 480 mcg/L and an estimated infant dose of 0.13% of the maternal weight-adjusted dose; it is generally considered compatible with breastfeeding, though infants should be monitored for potential gastrointestinal effects like diarrhea. No adverse effects, such as thrush or dermatitis, have been reported in breastfed infants exposed to meropenem via milk. In elderly patients, meropenem dosing requires adjustment based on renal function due to age-related declines in creatinine clearance, with no overall differences in safety or efficacy otherwise observed; they may also face a heightened risk of Clostridium difficile-associated diarrhea. Routine assessment of renal function is recommended prior to and during therapy in this population. For pediatric patients, meropenem is approved and safe for use in those aged 3 months and older for indications like bacterial meningitis, intra-abdominal infections, and skin infections, with dosing typically at 20 mg/kg every 8 hours; safety is not established in infants under 3 months except for specific intra-abdominal cases, and caution is advised in preterm neonates due to immature renal function. No data exist on its use in pediatric patients with renal impairment. In patients with renal impairment, meropenem doses must be reduced based on creatinine clearance (CrCl): for CrCl 26-50 mL/min, administer 1 g every 12 hours; for CrCl 10-25 mL/min, 500 mg every 12 hours; and for CrCl <10 mL/min, 500 mg every 24 hours, to avoid accumulation and toxicity like thrombocytopenia. No dose adjustment is necessary for hepatic impairment, as pharmacokinetics remain unaffected. In obese patients, particularly critically ill individuals, meropenem's volume of distribution increases with body mass index, but clearance is primarily driven by renal function; weight-based dosing using total body weight in CrCl calculations or extended infusions (e.g., 2 g every 8 hours over 3 hours) may be required to achieve adequate pharmacokinetic/pharmacodynamic targets against pathogens with higher minimum inhibitory concentrations. Therapeutic drug monitoring is suggested for optimization in this group to ensure exposure.

Adverse effects

Common side effects

Meropenem is generally well tolerated, with common side effects primarily involving the gastrointestinal tract, injection site, and mild laboratory abnormalities occurring in more than 1% of patients in clinical trials. Gastrointestinal disturbances are the most frequent, including diarrhea (reported in 2.5-4.8% of patients across studies involving over 5,000 individuals), nausea (3-5%), and vomiting (part of the 1.2-3.6% combined nausea/vomiting incidence). These effects are typically mild and transient, stemming from data in pivotal trials such as those reviewed by the . Injection site reactions, such as phlebitis, pain, inflammation, or rash, affect 1-3% of patients receiving intravenous administration, often related to the infusion process and resolving without intervention. Hematologic and hepatic changes include mild elevations in liver enzymes, with increased in 5-7% and in approximately 6% of adult patients from clinical trial data (n=2,904), alongside less frequent bilirubin elevations (around 2%). These are usually asymptomatic and reversible upon discontinuation. Other common adverse effects encompass headache (2.3%) and non-severe rash (1.4-2%), both observed in multiple trials, as well as oral moniliasis in select pediatric populations. Management of these side effects is generally symptomatic; for instance, antiemetics can alleviate nausea and vomiting, while monitoring suffices for laboratory changes.

Serious adverse effects

Meropenem, like other beta-lactam antibiotics, can rarely cause serious hypersensitivity reactions, including anaphylaxis and severe cutaneous adverse reactions such as and . These reactions occur in less than 0.1% of patients and are more likely in individuals with a history of multiple drug allergies or prior beta-lactam hypersensitivity. The mechanism involves immune-mediated responses, potentially triggered by the beta-lactam ring structure, leading to rapid onset of symptoms like hypotension, bronchospasm, or widespread skin detachment; immediate discontinuation is required, and supportive care including epinephrine may be necessary. Seizures represent another serious adverse effect of meropenem, with an incidence of approximately 0.5-1% in clinical trials, though rates can be higher (up to several percent) in patients with renal impairment, central nervous system disorders, or a history of epilepsy. This neurotoxicity is linked to meropenem's ability to penetrate the and potentially inhibit in the central nervous system, exacerbating seizure risk in predisposed individuals. Monitoring for symptoms such as confusion or myoclonus is essential, particularly in high-risk groups, and dose adjustments based on renal function can mitigate this risk. Clostridioides difficile-associated diarrhea (CDAD), ranging from mild to life-threatening colitis, can occur in meropenem-treated patients due to disruption of normal gut flora and overgrowth of toxin-producing C. difficile. This risk is inherent to broad-spectrum antibiotics like meropenem, which suppress beneficial bacteria, allowing pathogenic proliferation; prompt evaluation of persistent diarrhea is critical to prevent complications like pseudomembranous colitis. Incidence may vary by patient factors such as prolonged hospitalization or prior antibiotic exposure. Hematologic abnormalities, including thrombocytopenia and neutropenia, are rare in clinical trials and are typically reversible upon discontinuation of meropenem. Thrombocytopenia is more common in patients with renal impairment, where reduced clearance may lead to drug accumulation and bone marrow suppression, while neutropenia can manifest as agranulocytosis in prolonged therapy. These effects stem from immune-mediated destruction or direct myelotoxicity, necessitating periodic blood count monitoring in at-risk patients. Post-marketing surveillance has identified additional rare serious effects, including encephalopathy (manifesting as altered mental status or convulsions) and hemolytic anemia, often in patients with underlying conditions like renal failure or prolonged exposure. As of May 2025, rhabdomyolysis has also been reported, characterized by muscle pain, weakness, dark urine, or elevated creatine phosphokinase levels; discontinuation is recommended if suspected. These reports highlight the importance of vigilance beyond clinical trial data, with risk factors including advanced age, comorbidities, and concurrent medications that impair clearance. Adverse events should be reported to systems like FDA MedWatch to support ongoing pharmacovigilance and updates to safety profiles.

Interactions

Drug-drug interactions

Meropenem exhibits several notable drug-drug interactions, primarily involving alterations in renal excretion, anticonvulsant levels, and synergistic antimicrobial effects. Co-administration with probenecid inhibits the renal tubular secretion of meropenem, leading to increased plasma concentrations by approximately 56% and prolongation of its half-life by 38%; this interaction necessitates avoidance or dose reduction of meropenem to prevent potential toxicity. A significant pharmacokinetic interaction occurs with valproic acid, where meropenem reduces serum valproate concentrations by approximately 50-70%, potentially within 24 hours, through an unclear mechanism possibly involving enhanced metabolism or reduced absorption; this can precipitate breakthrough seizures, and concurrent use is generally not recommended, with close monitoring of valproate levels required if unavoidable. Pharmacodynamically, meropenem demonstrates additive or synergistic activity when combined with aminoglycosides, such as or , particularly against isolates, enhancing bactericidal effects against Gram-negative bacteria without notable pharmacokinetic interference. Meropenem does not significantly interact with cytochrome P450 enzymes, minimizing risks with drugs metabolized via these pathways. Food has minimal effects on meropenem's absorption or efficacy, as it is administered intravenously. Clinical guidelines, such as those from prescribing information, recommend evaluating these interactions on a case-by-case basis and considering alternatives when possible.

Other interactions

Meropenem can interfere with certain laboratory tests, potentially leading to inaccurate results that may affect clinical decision-making. It may cause false-positive results for urine glucose when using copper-reduction methods, such as , due to its reducing properties as a beta-lactam antibiotic; enzymatic glucose oxidase methods, like or , are recommended instead to avoid this interference. Additionally, meropenem has been associated with positive direct or indirect in post-marketing reports, which may indicate immune-mediated hemolysis and requires confirmation with alternative testing if hemolytic anemia is suspected. No clinically significant interaction occurs with alcohol, allowing concurrent use without adjustment. Meropenem is compatible with dialysis, as it is hemodialyzable (removing about 30-50% per session), necessitating supplemental dosing—typically 500 mg—immediately after hemodialysis to maintain therapeutic levels. Guidelines for laboratory monitoring during meropenem therapy include baseline and periodic evaluations of renal function (e.g., serum creatinine, eGFR), complete blood count (for thrombocytopenia or anemia), liver enzymes (for potential hepatotoxicity), and therapeutic drug monitoring of meropenem trough levels (targeting 2-4 mg/L) in critically ill patients or those with unstable pharmacokinetics to optimize efficacy and minimize toxicity.

Pharmacology

Mechanism of action

Meropenem, a carbapenem-class β-lactam antibiotic, exerts its bactericidal action by binding covalently to penicillin-binding proteins (PBPs) in susceptible bacteria, thereby inhibiting the final transpeptidation step in peptidoglycan cross-linking during cell wall synthesis. This disruption weakens the bacterial cell wall, activating endogenous autolysins that cause cell lysis and death. Meropenem demonstrates high affinity for key PBPs in both Gram-positive and Gram-negative bacteria, including PBPs 2, 3, and 4 in Escherichia coli and Pseudomonas aeruginosa, as well as PBPs 1, 2, and 4 in Staphylococcus aureus. However, it exhibits low affinity for PBP2a, the mecA-encoded PBP responsible for methicillin resistance in MRSA, which accounts for its limited activity against this pathogen. The antibiotic's structural features confer stability against hydrolysis by many β-lactamases, such as AmpC cephalosporinases produced by Enterobacteriaceae and extended-spectrum β-lactamases (ESBLs) like CTX-M variants, allowing effective penetration and target engagement in resistant strains. In contrast, meropenem is susceptible to hydrolysis by carbapenemases, including class A enzymes like KPC and class B metallo-β-lactamases like NDM, which rapidly degrade it and confer resistance. For susceptible Gram-negative bacteria such as E. coli, meropenem achieves low minimum inhibitory concentrations (), typically ≤0.25 mg/L, reflecting its potent inhibition at sub-micromolar levels.

Pharmacodynamics

Meropenem, as a carbapenem beta-lactam antibiotic, demonstrates time-dependent antibacterial activity, where its efficacy is primarily determined by the duration of exposure rather than peak concentrations. The key pharmacodynamic index is the percentage of the dosing interval during which the unbound (free) drug concentration exceeds the minimum inhibitory concentration (), with targets of greater than 40% fT>MIC required for bacteriostatic effects and 40-50% fT>MIC for bactericidal activity against susceptible pathogens. Studies in animal models and in vitro simulations have shown that achieving 100% fT>MIC correlates with 90% maximal bactericidal efficacy, particularly for Gram-negative bacteria, underscoring the benefit of dosing strategies like extended infusions to prolong this exposure. Meropenem also exhibits a post-antibiotic effect (PAE), a persistent suppression of bacterial regrowth following short-term drug exposure, which extends its therapeutic window. Against such as , , and , the PAE duration is concentration-dependent, typically ranging from 1 to 2 hours at concentrations around 4-8 times the , though it can extend to 2-5 hours in some strains. This effect is shorter against Gram-positive organisms but contributes to less frequent dosing needs compared to other beta-lactams without notable PAE. The inoculum effect represents a limitation in meropenem's , where activity diminishes at high bacterial densities due to increased MICs and reduced drug efficacy. models simulating high inoculum sizes (e.g., >10^7 CFU/mL) show markedly reduced killing rates and potential for resistance emergence against pathogens like , as the drug's beta-lactamase stability is overwhelmed by greater production or altered target expression. This phenomenon highlights the need for in infections with heavy bacterial loads, such as abscesses or biofilms. Synergistic interactions enhance meropenem's against challenging bacterial states. Combinations with aminoglycosides like tobramycin or fluoroquinolones like demonstrate additive or synergistic effects, improving penetration and killing within biofilms formed by or , where monotherapy fails due to matrix barriers. Similarly, meropenem paired with agents like sulbactam shows enhanced activity against intracellular pathogens, such as species in , by overcoming limited drug penetration into host cells. These synergies are supported by PK/PD models indicating improved fT> attainment and reduced regrowth in co-culture systems.

Pharmacokinetics

Meropenem is administered intravenously due to its poor oral , resulting in negligible through the , while intravenous administration achieves 100% . Following intravenous , meropenem exhibits a of approximately 0.25 L/kg in adults, indicating primarily extracellular distribution. It demonstrates good penetration into various tissues, including the (up to 30-40% of concentrations in the presence of inflamed ), lungs, and soft tissues. is low at about 2%, which facilitates its availability for antibacterial activity at infection sites. Meropenem undergoes minimal metabolism and is not metabolized by hepatic enzymes; approximately 70% (range 50-75%) of the dose is excreted unchanged in the , with the remainder recovered as an inactive open-β-lactam formed through chemical and minor enzymatic pathways. Elimination is predominantly renal, with approximately 70% of the dose excreted unchanged in the via glomerular and . The elimination is about 1 hour in adults with normal renal function but is prolonged in patients with renal impairment, necessitating dosage adjustments to maintain therapeutic concentrations relative to the time above (fT>MIC).

Chemistry

Chemical structure and properties

Meropenem has the molecular formula C₁₇H₂₅N₃O₅S and a molecular weight of 383.5 g/mol. Its IUPAC name is (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, and the canonical SMILES notation is C[C@@H]1[C@@H]2C@HC@@HO. The of meropenem features a bicyclic β-lactam ring fused to a pyrroline ring, characteristic of antibiotics, with key side chains including a thio-linked ring bearing a dimethylcarbamoyl group at the 5-position and a 1-hydroxyethyl at the 6-position. This β-lactam core provides the structural basis for its antibacterial activity by mimicking the D-alanyl-D-alanine substrate in bacterial synthesis. Meropenem appears as a white to pale yellow crystalline powder. It exhibits pKa values of approximately 2.9 for the group and 7.4 for the group. In terms of solubility, meropenem is sparingly soluble in (approximately 5.63 g/L), very slightly soluble in hydrated , and practically insoluble in acetone or . The compound demonstrates greater stability in acidic conditions ( around 6–6.5) compared to alkaline environments, where β-lactam accelerates degradation.

Synthesis and stability

Meropenem is synthesized through a multi-step semi-synthetic process starting from thienamycin, a natural antibiotic produced via of . The process involves protection of the β-lactam ring to prevent degradation during subsequent reactions, followed by attachment of the protected (3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl side chain via nucleophilic thioether formation, and final deprotection steps to yield the active trihydrate form. The original synthesis was developed by Sumitomo Pharmaceuticals, with key patents such as US 4,943,569 covering the core process, which expired in 2010, enabling generic production. Generic routes typically employ similar chemical strategies, often optimized for higher yields and avoiding cryogenic conditions, while retaining the thienamycin fermentation precursor step. Meropenem exhibits chemical instability primarily due to of the β-lactam ring amide bond, analogous to enzymatic β-lactamase mechanisms but occurring non-enzymatically in aqueous environments. As a sterile for injection, it maintains with a of 2–3 years when stored at controlled (15–30°C), protected from light and moisture. In solution after reconstitution, stability is markedly reduced. For IV infusion administration (1–20 mg/mL) in 0.9% , solutions are stable for up to 1 hour at (≤25°C) or 15 hours refrigerated (≤5°C); in 5% dextrose, use immediately. For IV bolus (50 mg/mL), up to 3 hours at or 13 hours refrigerated. Do not freeze. Beyond these times, potency may drop below 90%. Major degradation products include open-ring penems formed by β-lactam and dimeric species from intermolecular aminolysis, which are microbiologically inactive and potentially immunogenic. Storage recommendations specify at 2–8°C for reconstituted solutions to minimize degradation, with immediate use preferred after preparation. Per the () , meropenem for injection must meet strict impurity limits, including not more than 0.8% for the primary degradant at relative retention time 0.45 and 0.6% for another at relative retention time 1.9, ensuring product purity through chromatographic analysis. Total unspecified impurities are limited to 1.0%, with overall related substances not exceeding 3.0% to maintain therapeutic safety and efficacy.

History

Development and discovery

Meropenem's development originated from the discovery of thienamycin, a naturally occurring carbapenem antibiotic isolated in 1976 from the soil bacterium Streptomyces cattleya by researchers at Merck & Co. Inc. during a screening program for novel beta-lactam compounds. Thienamycin exhibited potent broad-spectrum antibacterial activity but suffered from rapid degradation by renal dehydropeptidase I, limiting its clinical utility and prompting efforts to create more stable synthetic derivatives. In response, pharmaceutical companies pursued structural modifications to enhance stability and reduce toxicity. Imipenem, a semi-synthetic analog of thienamycin developed by Merck, addressed some instability but still required co-administration with the dehydropeptidase inhibitor cilastatin to prevent renal metabolism and associated . Sumitomo Pharmaceuticals, seeking a that could be used without such a companion drug, initiated research in the early to design compounds resistant to enzymatic degradation while maintaining efficacy. The team, led by chemists including Makoto Sunagawa, focused on introducing a 1β-methyl group at the core— an innovation initially explored by Lederle Laboratories— to sterically hinder dehydropeptidase access, combined with a (2S,4S)-2-[(3S)-3-carboxy-1-pyrrolidinylcarbonyl]pyrrolidin-4-ylthio side chain at the C-2 position to minimize neurotoxic potential. Akira Yoshida and colleagues at Sumitomo contributed key synthetic methodologies, such as side-chain substitution reactions on 2-arylsulfinyl intermediates, enabling efficient production of these modified structures. The first synthesis of meropenem (initially coded as SM-7338) was achieved in the late 1980s through these efforts, with a pivotal (US 4,943,569) filed by Sumitomo on October 8, 1987, describing the compound and its preparation. Preclinical evaluations in animal models, including mice, rats, and dogs, demonstrated meropenem's superior stability and broad-spectrum activity against Gram-positive and Gram-negative pathogens compared to imipenem, with notably lower seizure induction in assays—attributed to the optimized reducing antagonism. Early efficacy data from systemic infection models, such as those against and , confirmed protective doses comparable or better than imipenem without the need for enzyme inhibition, supporting its advancement. These findings, detailed in structure-activity relationship studies published in 1990, underscored meropenem's potential as a standalone injectable .

Regulatory approvals and milestones

Meropenem underwent phase III clinical trials in the 1990s, including randomized, double-blind studies comparing its efficacy to imipenem/cilastatin for treating intra-abdominal infections, where it demonstrated non-inferiority in clinical response rates. These trials involved hospitalized patients with serious bacterial infections and supported meropenem's broad-spectrum activity against Gram-positive, Gram-negative, and pathogens. The granted initial marketing authorization for meropenem (as Meronem) on July 12, 1997, for indications including complicated intra-abdominal and skin infections in adults. , the approved meropenem (as Merrem IV) on June 21, 1996, initially for complicated skin and skin structure infections, intra-abdominal infections, and in adults and children aged 3 months and older. Expanded pediatric indications followed, including approval for abdominal infections in infants under 3 months in 2015. Key milestones include meropenem's inclusion on the World Health Organization's Model List of Essential Medicines in 2017, recognizing its role in treating severe infections like in cancer patients. The original U.S. patent expired around 2010, leading to the first generic approval by the FDA that year, which increased accessibility and reduced costs. Pediatric exclusivity extensions have been granted under the Best Pharmaceuticals for Children Act, providing six-month market protections to incentivize studies in pediatric populations. Post-approval developments emphasize , with meropenem subject to restrictions in many hospital programs to curb carbapenem-resistant infections, such as requiring infectious disease consultation for initiation. No major withdrawals or bans have occurred, though ongoing monitoring addresses emerging resistance patterns through updated susceptibility testing guidelines.

Society and culture

Trade names and branding

Meropenem is primarily marketed under the brand name Merrem in the United States and Meronem internationally, with these trademarks originally held by following a licensing agreement with in the 1990s. In 2016, acquired the global commercialization rights to Merrem and Meronem (excluding certain Asian markets) from , continuing its distribution as a broad-spectrum antibiotic for severe hospital-treated infections. Regionally, meropenem is sold under names such as in by and various generics in , including (formerly ) and (). Worldwide, over 50 trade names exist for meropenem products, reflecting its availability through multiple manufacturers in diverse markets. Upon patent expiration in the early 2010s, generic versions proliferated, produced by companies including , (now part of ), and (a division), enabling broader access to non-branded formulations. The drug was branded and launched as a next-generation , emphasizing its stability against renal dehydropeptidase-I and broad coverage against Gram-positive, Gram-negative, and compared to predecessors like imipenem. Packaging is designed for institutional use, typically as sterile powder vials for intravenous reconstitution in settings, with no marketing.

Availability and legal status

Meropenem is available exclusively by prescription in major markets, including the (Rx-only), (S4), (Rx-only), and the (POM), where it is administered intravenously in settings due to its injection-only . Globally, it is widely stocked in hospitals for treating severe infections, but retail availability is limited, particularly in low- and middle-income countries (LMICs), where averages around 40% for essential antibiotics like meropenem. In LMICs, supply constraints and challenges further restrict over-the-counter or community-level distribution, confining use primarily to care facilities. As an , meropenem is not subject to scheduling akin to narcotics; however, its use is regulated through programs (ASPs) worldwide to mitigate resistance development. These programs, implemented in hospitals and health systems, involve prospective audits, dosing optimization, and restriction protocols to ensure appropriate prescribing, with studies showing reductions in meropenem consumption by up to 50% without compromising outcomes. In the and other regions, ASPs are mandated under broader antibiotic resistance action plans. In the United States as of 2025, generic meropenem pricing ranges from approximately $5 to $20 per gram for 1 g vials, while branded versions like Merrem can cost $50 to $100 per gram depending on supplier and volume. The World Health Organization (WHO) prequalified its first meropenem product in 2020, facilitating affordable generic access in LMICs through vetted manufacturers, which has helped lower costs to under $10 per gram in supported programs. Meropenem is included on the WHO Model List of Essential Medicines, promoting its procurement for critical conditions like sepsis. Supply shortages of meropenem occurred periodically between 2020 and 2022, primarily due to active pharmaceutical ingredient () disruptions from manufacturing delays and global issues exacerbated by the . These shortages led to increased use of alternatives and heightened costs in affected regions, with distribution often coordinated through UN agencies like to stabilize supplies in LMICs. Access initiatives, such as WHO's sepsis management guidelines and procurement mechanisms, support its availability in developing regions for treating multidrug-resistant infections, though gaps persist in rural and low-resource settings.

Research directions

Emerging indications

Meropenem is being investigated for several investigational applications beyond its established uses, particularly in infections where bacterial co-pathologies or complicate . Recent clinical trials from 2020 onward have explored its role in managing bacterial complications associated with pandemics and multidrug-resistant conditions, leveraging its broad-spectrum activity against Gram-negative pathogens. In the context of , meropenem has shown potential as an adjunct for treating (VAP) in patients with bacterial co-infections, with studies between 2020 and 2023 highlighting its utility in critically ill cohorts despite challenges like emergence. For instance, case reports and observational data indicate challenges with meropenem-resistant pathogens in secondary bacterial pneumonias in intubated patients, with outcomes varying with pathogen susceptibility. Combination therapy with meropenem and rifampin has demonstrated promising early bactericidal activity against (MDR-TB) in phase II studies. The COMRADE trial, a randomized phase 2A study, evaluated meropenem (with clavulanate) at doses up to 6 g daily, alone or with rifampin, in patients with drug-susceptible pulmonary TB, reporting a median daily fall in colony-forming units of 0.22 log10 CFU/ for the 2 g three-times-daily arm, indicating significant activity comparable to standard regimens but limited by gastrointestinal tolerability issues. These findings support further exploration of beta-lactam-based regimens for shortening MDR-TB durations. Exploratory applications of meropenem target biofilm-related infections, such as those in prosthetic infections (PJI), where its penetration into enhances eradication of adherent pathogens. A 2024 study on single-stage revision combined with intra-articular meropenem (50,000 µg/mL) achieved mean peak synovial concentrations of 5,819.1 µg/mL, exceeding the minimum biofilm eradication concentration and sustaining therapeutic levels for up to 8 days without significant adverse events. Additionally, case reports describe successful adjunct use with personalized against biofilms in chronic PJI, achieving infection resolution when standard antibiotics failed. Limited data exist on meropenem's synergies in bacterial superinfections complicating diseases, positioning it as a potential adjunct to mitigate secondary bacterial invasions in conditions like . Reviews of therapeutic options note its role in addressing carbapenem-resistant superinfections amid , though remains preliminary and focused on empirical use in severe cases. Ongoing trials as of 2024-2025, such as the BALANCE+ platform study (NCT05893147), are evaluating treatment strategies for Gram-negative , including potential extensions to , to optimize outcomes in high-risk populations where antibiotics like meropenem may be used. A recent case of prosthetic valve further illustrates meropenem's efficacy in combination with ceftolozane/tazobactam, achieving rapid bacteremia clearance and sterile valve cultures post-treatment.

Resistance and novel formulations

Meropenem resistance, primarily driven by carbapenemase-producing (CPE), has prompted the development of beta-lactamase inhibitor combinations to restore its efficacy. Meropenem-vaborbactam, approved by the FDA in 2017 for complicated urinary tract infections and intra-abdominal infections caused by susceptible strains, targets class A carbapenemases like KPC through vaborbactam's inhibition of enzymes. Recent expansions include ongoing trials evaluating its use in pediatric populations and against (CRE), demonstrating promising safety and microbiological cure rates in severe KPC-producing infections as of 2025. Similarly, imipenem-relebactam, though not directly paired with meropenem, represents a parallel approach with relebactam inhibiting class A and C s, informing broader combo strategies against meropenem-resistant pathogens. Novel formulations aim to enhance meropenem's delivery, particularly for infections where limits local concentrations. Liposomal encapsulation of meropenem has shown improved and antibacterial activity against , with formulations combining it with biosurfactants like rhamnolipids achieving sustained release and reduced dosing frequency in preclinical models as of 2025. Inhaled antibiotic strategies for often incorporate meropenem alongside agents like . These approaches build on insights from meropenem's chemical properties to overcome barriers in respiratory environments. Genomic surveillance of carbapenemase spread utilizes advanced tools like CRISPR-based systems to track resistance genes in real-time. Studies employing CRISPR-Cas dynamics reveal that isolates lacking these systems are more prone to acquiring carrying blaKPC or blaNDM genes, facilitating rapid dissemination of meropenem resistance among and other . CRISPR-AMRtracker and Cas12a-based assays enable sensitive detection and monitoring of carbapenemase gene transfer, supporting global efforts to map resistance hotspots and inform targeted interventions. Whole-genome sequencing complements these methods, highlighting the role of plasmids in propagating resistance, with projections indicating sustained spread without enhanced surveillance. Pharmacokinetic enhancements, such as oral , are in early development to improve meropenem's , which is currently limited to intravenous use due to gastric instability. strategies involving lipophilic promoieties have demonstrated increased in preclinical evaluations, potentially enabling outpatient of resistant by 2030. These modifications aim to inhibit renal tubular secretion and protect against enzymatic degradation, enhancing overall exposure against carbapenem-resistant strains. NIH funding supports stewardship models to curb meropenem , with grants like the Large Projects for Combating initiative allocating resources for studies and tracking. These efforts, aligned with the National Action Plan for Combating (2020-2025), aim to reduce the impact of through optimized prescribing and surveillance.