A Comprehensive Monograph on Meropenem: Pharmacology, Clinical Efficacy, and Safety

Section 1: Introduction and Drug Identification

1.1. Overview

Meropenem is a potent, broad-spectrum antibiotic administered intravenously and classified within the carbapenem subclass of β-lactam agents.[1] As a "small molecule" drug, it represents a critical tool in the modern medical armamentarium for combating severe and complex bacterial infections, particularly those acquired in hospital settings.[3] Its clinical utility extends to a wide array of life-threatening conditions, including complicated intra-abdominal infections, complicated skin and skin structure infections, bacterial meningitis, sepsis, and pneumonia.[1] Marketed under primary brand names such as Merrem, Meronem, and others globally, Meropenem is often reserved as a last-resort therapy when infections are caused by multidrug-resistant (MDR) pathogens that have developed resistance to other classes of antibiotics, such as penicillins and cephalosporins.[1] This strategic positioning underscores its importance in critical care medicine but also places it at the forefront of the global challenge of antimicrobial resistance, necessitating stringent antibiotic stewardship to preserve its efficacy for future generations.[5]

1.2. Chemical and Physical Properties

Meropenem is chemically defined as a carbapenemcarboxylic acid and is classified by the U.S. Food and Drug Administration (FDA) as a penem antibacterial agent.[7] In its commercial form, it is supplied as a sterile, white to light yellow or off-white crystalline powder for reconstitution.[1] This formulation is not pure meropenem but rather a carefully prepared blend of meropenem trihydrate and anhydrous sodium carbonate.[1] The sodium carbonate serves as an essential buffering agent, enhancing the drug's stability in solution after it is reconstituted for intravenous administration. The molecular formula of meropenem is

C17​H25​N3​O5​S, corresponding to a molecular weight of 383.46 g/mol.[2]

The drug demonstrates solubility in various solvents, including dimethyl sulfoxide (DMSO), ethanol, and water.[3] Its hydrophilic nature is a defining characteristic that, while facilitating its distribution in bodily fluids, concurrently contributes to its poor permeability across the gastrointestinal epithelium, rendering it unsuitable for oral administration.[1] A pivotal feature of its molecular architecture is the presence of a 1-β-methyl group. This specific structural modification confers a significant clinical advantage by providing stability against hydrolysis by human renal dehydropeptidase-I (DHP-I), an enzyme that readily degrades earlier carbapenems like imipenem.[12]

Meropenem's chemistry embodies a notable paradox. The stereochemistry of its β-lactam ring is engineered to be highly resistant to degradation by a wide range of bacterial β-lactamase enzymes, which is the basis of its broad-spectrum activity against many resistant organisms.[1] However, this same ring is intrinsically unstable in aqueous environments and is highly susceptible to non-enzymatic hydrolysis.[1] This chemical instability leads to a relatively rapid degradation of the drug in solution, reducing its antibacterial potency over time. This degradation process is often accompanied by a visible color change in the reconstituted solution, shifting from colorless or pale yellow to a more vivid yellowish hue, which serves as a visual indicator of the hydrolysis of the β-lactam ring's amide bond.[1]

Table 1: Chemical and Physical Identifiers of Meropenem

Identifier	Value	Source(s)
Drug Name	Meropenem	1
DrugBank ID	DB00760	1
Type	Small Molecule	[User Query]
CAS Number	96036-03-2 (anhydrous)	2
Related CAS Number	119478-56-7 (trihydrate)	3
Molecular Formula	C17​H25​N3​O5​S	2
Molecular Weight	383.46 g/mol	2
IUPAC Name	(4R,5S,6S)-3-sulfanyl-6--4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	3
InChI	InChI=1S/C17H25N3O5S/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)/t7-,8-,9+,10+,11-,12-/m1/s1	1
InChIKey	DMJNNHOOLUXYBV-PQTSNVLCSA-N	1
SMILES	C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)C(=O)N(C)C)C(=O)O)[C@@H](C)O	3
Synonyms	Merrem, Penem, Ronem, SM-7338, ICI 194660, Meropen	1

Section 2: Historical Context and Development

The development of meropenem is a story not of serendipitous discovery but of deliberate, rational drug design, born from the necessity to overcome the pharmacological shortcomings of its predecessors. Its history is deeply intertwined with the escalating battle against bacterial resistance to β-lactam antibiotics.[12] The journey began in the 1970s with the discovery of naturally occurring compounds like the olivanic acids from

Streptomyces clavuligerus. These molecules possessed the core "carbapenem backbone" and showed β-lactamase inhibitory activity, but they were too chemically unstable and had poor bacterial cell penetration, precluding their clinical development.[12]

A watershed moment came with the isolation of thienamycin from the bacterium Streptomyces cattleya.[12] Thienamycin was the first true carbapenem and exhibited exceptionally potent, broad-spectrum antibacterial activity, establishing it as the parent compound and structural model for all subsequent drugs in this class.[12] However, like the olivanic acids, thienamycin suffered from chemical instability, which spurred the search for more robust derivatives suitable for clinical use.

This search led to the development of imipenem, the first carbapenem to be commercialized, which became available in 1985.[12] Imipenem offered improved chemical stability over thienamycin, but its clinical use revealed a significant metabolic liability. It was rapidly hydrolyzed and inactivated in the kidneys by a human enzyme, dehydropeptidase-I (DHP-I).[12] This not only reduced the drug's efficacy but also led to the formation of potentially nephrotoxic metabolites.[13] The solution to this problem was to co-administer imipenem with cilastatin, a specific DHP-I inhibitor that protected imipenem from degradation, ensuring therapeutic concentrations in the urine and body.[12] While effective, this two-drug combination was pharmacologically complex.

The development of meropenem represents the next, more elegant step in this evolutionary process. Medicinal chemists sought to design a carbapenem that was intrinsically stable to DHP-I, thereby eliminating the need for a co-administered inhibitor. The critical breakthrough was a specific, targeted synthetic modification: the addition of a methyl group at the 1-β position of the carbapenem core structure.[12] This seemingly minor structural change sterically hindered the DHP-I enzyme, rendering meropenem resistant to its hydrolytic activity.[13] This innovation was a triumph of medicinal chemistry, directly solving the primary metabolic problem of imipenem. As a result, meropenem could be administered as a single agent, simplifying therapy and offering a superior pharmacokinetic profile.

Meropenem was first used clinically in 1994 and received its initial U.S. FDA approval in 1996, marking its entry as a "second-generation" carbapenem.[4] Recognizing the continuous evolution of bacterial resistance, particularly the emergence of carbapenemase-producing organisms, the therapeutic landscape continued to evolve. In August 2017, the FDA approved Vabomere, a combination product containing meropenem and vaborbactam, a novel β-lactamase inhibitor designed to protect meropenem from degradation by certain classes of carbapenemases, further extending the utility of this vital antibiotic.[7]

Section 3: Clinical Pharmacology

3.1. Mechanism of Action

Meropenem, like all β-lactam antibiotics, exerts its potent bactericidal (cell-killing) effects by disrupting the synthesis of the bacterial cell wall, a structure essential for bacterial integrity and survival.[1] The process begins with the drug's ability to readily penetrate the outer layers of both Gram-positive and Gram-negative bacteria, allowing it to access its molecular targets within the periplasmic space.[8]

At the molecular level, the core of meropenem's activity lies in its covalent and irreversible binding to a group of essential bacterial enzymes known as Penicillin-Binding Proteins (PBPs).[8] PBPs play a crucial role in the final stages of peptidoglycan synthesis, specifically the transpeptidation step that cross-links the peptide chains of the glycan strands. This cross-linking process is what confers the rigid, mesh-like structure to the peptidoglycan layer, providing the cell wall with the mechanical strength necessary to withstand the high internal osmotic pressure of the bacterial cytoplasm.[14]

By acylating the active site of these PBP enzymes, meropenem effectively inhibits their function. This disruption of peptidoglycan synthesis and repair leads to the formation of a defective, weakened cell wall.[14] The compromised cell wall can no longer contain the cell's internal pressure, resulting in cell lysis and, ultimately, bacterial death.[7] Meropenem demonstrates a strong binding affinity for multiple PBP targets, which contributes to its broad spectrum of activity. Its strongest affinities have been identified for PBP 2, PBP 3, and PBP 4 in key Gram-negative pathogens like

Escherichia coli and Pseudomonas aeruginosa, and for PBP 1, PBP 2, and PBP 4 in the Gram-positive pathogen Staphylococcus aureus.[8] This multi-target engagement makes it more difficult for bacteria to develop resistance through a single PBP mutation.

3.2. Pharmacodynamics

The antibacterial efficacy of meropenem is best described by a time-dependent killing model.[22] This pharmacodynamic principle dictates that the crucial determinant of successful bacterial eradication is not the peak concentration (

Cmax​) achieved by the drug, but rather the cumulative duration of time that the free (non-protein-bound) drug concentration in the plasma remains above the Minimum Inhibitory Concentration (MIC) for the target pathogen. This parameter is expressed as the percentage of the dosing interval where the free drug concentration exceeds the MIC (%T>MIC).[22]

For meropenem, extensive clinical and microbiological studies have established that a bactericidal effect and optimal clinical outcomes are typically achieved when the %T>MIC is approximately 40% or greater.[22] This pharmacodynamic target is the scientific foundation for the recommended dosing regimens. The relatively short half-life of meropenem necessitates frequent administration, typically every 8 hours, to ensure that drug concentrations are maintained above the MIC for a sufficient portion of the dosing interval to achieve this 40% target, especially against less susceptible organisms. In critically ill patients or for infections caused by pathogens with higher MICs, strategies such as extended or continuous infusions are sometimes employed to maximize the %T>MIC and improve the probability of a successful outcome.

3.3. Spectrum of Antibacterial Activity

Meropenem is distinguished by its exceptionally broad spectrum of in vitro activity, which covers a vast range of clinically significant bacteria, including aerobic and anaerobic Gram-positive and Gram-negative species.[1]

Gram-Negative Activity: Meropenem is highly potent against most Enterobacteriaceae, such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter species.[1] It is particularly valued for its consistent and potent activity against the opportunistic and often difficult-to-treat pathogen

Pseudomonas aeruginosa.[1] Compared to the first-generation carbapenem imipenem, meropenem generally exhibits slightly greater potency against Gram-negative organisms.[1]

Gram-Positive Activity: The drug is also effective against many Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pneumoniae (including penicillin-susceptible isolates), Streptococcus pyogenes, Streptococcus agalactiae, and viridans group streptococci.[24] It also has activity against vancomycin-susceptible isolates of

Enterococcus faecalis.[24] Its activity against Gram-positive cocci is generally considered robust, though slightly less potent than that of imipenem.[1]

Anaerobic Activity: Meropenem provides excellent coverage against a wide range of anaerobic bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron, and Peptostreptococcus species, making it a suitable monotherapy agent for mixed aerobic/anaerobic infections such as complicated intra-abdominal infections.[1]

Activity against Resistant Strains: A cornerstone of meropenem's clinical value is its stability in the presence of many β-lactamase enzymes, including the extended-spectrum β-lactamases (ESBLs) that confer resistance to most third-generation cephalosporins.[1] This makes it a first-line therapy for serious infections caused by ESBL-producing organisms. However, its effectiveness is compromised by the emergence of bacteria that produce carbapenem-hydrolyzing enzymes, known as carbapenemases. It is particularly susceptible to hydrolysis by metallo-β-lactamases (MBLs), such as NDM-1 and VIM types, and certain serine carbapenemases like KPC and some OXA types.[1]

Table 2: Meropenem Minimum Inhibitory Concentration (MIC) Breakpoints for Key Pathogens

The clinical interpretation of in vitro susceptibility testing is guided by established MIC breakpoints. These values, defined by regulatory bodies like the FDA, categorize a bacterial isolate as Susceptible, Intermediate, or Resistant, thereby informing the clinical decision to use meropenem.

Pathogen	MIC (μg/mL) for Susceptible (S) strains	MIC (μg/mL) for Intermediate (I) strains	MIC (μg/mL) for Resistant (R) strains
Enterobacteriaceae	≤1	2	≥4
Pseudomonas aeruginosa	≤2	4	≥8
Streptococcus pneumoniae	≤0.25	0.5	≥1
Anaerobic bacteria	≤4	8	≥16

Source: [19]

Section 4: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of meropenem dictates its route of administration, dosing frequency, and suitability for treating infections in various body compartments. Its journey through the body is characterized by poor oral absorption, wide distribution, minimal metabolism, and rapid renal excretion.

4.1. Absorption

Meropenem exhibits extremely poor oral bioavailability, estimated to be less than 2%.[1] This is a direct consequence of two key physicochemical properties. First, its hydrophilic (water-loving) nature significantly hinders its ability to passively diffuse across the lipid-rich membranes of the intestinal epithelium.[1] Second, it is chemically unstable in aqueous environments and susceptible to degradation within the gastrointestinal tract.[1] This poor absorption is further compounded by the action of intestinal efflux transporters, particularly P-glycoprotein (P-gp), which can actively pump any absorbed drug back into the gut lumen, effectively preventing it from reaching systemic circulation.[1]

The clinical consequence of this pharmacokinetic barrier is absolute. Meropenem cannot be administered orally and is formulated exclusively for parenteral use via the intravenous (IV) route in humans.[1] While animal studies have demonstrated high bioavailability following intramuscular (IM) or subcutaneous (SC) administration, these routes are not approved for clinical use in human patients.[1]

4.2. Distribution

Once in the bloodstream, meropenem distributes extensively throughout the body, penetrating most tissues and fluids to a clinically significant degree.[16] A key factor facilitating this wide distribution is its very low rate of binding to plasma proteins, which is only about 2%.[11] This means that approximately 98% of the drug in circulation is "free" or unbound, and therefore pharmacologically active and available to diffuse from the bloodstream into infection sites.

The steady-state volume of distribution (Vd) in healthy adult volunteers ranges from approximately 12.5 to 21 liters, a value that suggests good penetration beyond the plasma into tissues.[16] Clinical studies have confirmed that meropenem achieves therapeutic concentrations in a wide variety of tissues relevant to its approved indications, including:

• Intra-abdominal tissues: Peritoneal fluid, colon wall, gallbladder, omentum, and fascia.[22]
• Pulmonary tissues: Lung parenchyma, bronchial mucosa, and epithelial lining fluid (ELF).[22]
• Other tissues: Skin, muscle, cardiac tissue (including valves), and gynecological tissues.[2]

Critically for its use in CNS infections, meropenem effectively crosses the blood-brain barrier, particularly in the presence of meningeal inflammation, and achieves therapeutic concentrations in the cerebrospinal fluid (CSF).[14] This property underpins its specific FDA approval for the treatment of bacterial meningitis in pediatric patients.[24]

4.3. Metabolism

Meropenem undergoes minimal metabolism in the body.[26] The primary metabolic transformation is the non-enzymatic hydrolysis of the β-lactam ring, which opens the ring structure to form a single, primary metabolite.[8] This metabolite is microbiologically inactive and does not contribute to the drug's therapeutic effect.[8] As established during its development, meropenem is structurally resistant to hydrolysis by the human renal enzyme DHP-I, a key distinction from its predecessor, imipenem, which allows it to be administered without a metabolic inhibitor.[13]

4.4. Excretion

The primary and predominant route of elimination for meropenem is renal excretion.[11] Approximately 70% of an administered intravenous dose is recovered from the urine as unchanged, active drug over a 12-hour period, with very little further excretion thereafter.[8] This high concentration of active drug in the urinary tract contributes to its efficacy in treating urinary tract infections.

The elimination half-life (t1/2​) of meropenem in adults with normal renal function is short, approximately 1 hour.[8] In pediatric patients between 3 months and 2 years of age, the half-life is slightly extended to about 1.5 hours.[8] This rapid elimination profile is a major driver of the need for frequent (e.g., every 8 hours) dosing to maintain therapeutic concentrations.

The heavy reliance on renal clearance has a profound clinical implication: dosage adjustments are mandatory for patients with renal impairment. Failure to reduce the dose in patients with decreased kidney function will lead to drug accumulation, prolonged half-life, and a significantly increased risk of dose-related toxicities, most notably seizures.[14]

Table 3: Key Pharmacokinetic Parameters of Meropenem in Adults with Normal Renal Function

Parameter	Value	Clinical Significance & Source(s)
Bioavailability (Oral)	<2% (negligible)	Requires exclusive intravenous (IV) administration for systemic effect. 1
Plasma Protein Binding	~2%	High fraction of free, pharmacologically active drug is available for distribution to tissues. 11
Volume of Distribution (Vd​)	12.5 – 21 L	Indicates wide distribution into most body tissues and fluids, including the CNS. 16
Elimination Half-Life (t1/2​)	~1 hour	Short half-life necessitates frequent (q8h) dosing to maintain therapeutic concentrations (%T>MIC). 8
Metabolism	Minimal; one inactive metabolite	The parent compound is responsible for virtually all antibacterial activity. Not susceptible to DHP-I. 8
Primary Excretion Route	Renal (via filtration and secretion)	Dosage adjustment based on creatinine clearance is critical in patients with renal impairment. 16
% Unchanged in Urine	~70%	High concentrations of active drug are achieved in the urine. 8

Section 5: Clinical Applications and Efficacy

5.1. Approved Indications (FDA)

The U.S. Food and Drug Administration (FDA) has approved meropenem for the treatment of specific, serious bacterial infections. A guiding principle for its use, emphasized in its labeling, is the importance of antibiotic stewardship: meropenem should be reserved for infections that are proven or strongly suspected to be caused by susceptible bacteria to mitigate the development of drug resistance.[18]

The official FDA-approved indications are:

• Complicated Skin and Skin Structure Infections (cSSSI): Meropenem is indicated for cSSSI in both adult and pediatric patients aged 3 months and older.[1] The spectrum of approved pathogens for this indication includes Gram-positives such as Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, and viridans group streptococci; vancomycin-susceptible Enterococcus faecalis; and various Gram-negatives including Pseudomonas aeruginosa.[24]
• Complicated Intra-abdominal Infections (cIAI): It is approved for treating cIAI, such as complicated appendicitis and peritonitis, in adults and pediatric patients.[1] Notably, this is the one indication with specific dosing guidelines for neonates and infants younger than 3 months.[24] The covered pathogens include viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and important anaerobic bacteria like Bacteroides fragilis and Peptostreptococcus species.[24]
• Bacterial Meningitis: Meropenem is specifically indicated for the treatment of bacterial meningitis, but only in the pediatric population (ages 3 months and older).[1] The approved pathogens are Haemophilus influenzae, Neisseria meningitidis, and penicillin-susceptible isolates of Streptococcus pneumoniae. The labeling also notes that meropenem has been found effective in eliminating concurrent bacteremia that is often associated with bacterial meningitis.[24]

5.2. Off-Label and Other Significant Uses

Beyond its formal FDA-approved indications, the clinical utility of meropenem extends to several other critical areas, where its use is guided by clinical practice guidelines, extensive clinical experience, and its favorable pharmacological profile. This reliance on off-label prescribing is particularly prominent in treating the most critically ill patient populations where conducting large-scale, randomized controlled trials is often ethically or logistically prohibitive.

• Febrile Neutropenia: Meropenem is widely used as an empiric monotherapy for high-risk febrile neutropenia, a common and life-threatening complication in patients undergoing chemotherapy for cancer, especially hematological malignancies.[1] Its extremely broad spectrum provides reliable coverage against the most likely bacterial pathogens in these immunocompromised hosts.
• Nosocomial (Hospital-Acquired) and Ventilator-Associated Pneumonia: Although not a primary labeled indication in all jurisdictions, meropenem is a cornerstone therapy for severe hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), particularly when multidrug-resistant organisms, including P. aeruginosa, are suspected.[1]
• Infections in Neonates and Infants (<3 months): While the FDA label is restrictive for this age group (except for cIAI), there is significant and necessary off-label use of meropenem in neonatal intensive care units (NICUs).[31] It is often employed to treat severe infections such as neonatal sepsis, necrotizing enterocolitis, and peritonitis, where its broad coverage and CNS penetration are invaluable in a population at high risk of mortality.[6]
• Complicated Urinary Tract Infections (UTIs): For severe UTIs requiring hospitalization, such as pyelonephritis or urosepsis, clinical guidelines support the use of meropenem, especially when resistant Gram-negative bacteria are the suspected cause.[32] This constitutes a common off-label use.
• Systemic Anthrax: Meropenem is also listed as a potential treatment for systemic anthrax, another off-label application for a high-consequence pathogen.[1]

The significant gap between the formal regulatory label and real-world clinical practice underscores a fundamental reality in critical care medicine. Clinicians must often extrapolate from a drug's known pharmacology—its broad spectrum, CNS penetration, and safety profile—to make life-saving decisions in situations where randomized trial data is lacking. This creates a dynamic where "practice-based evidence" and expert guidelines fill the void left by the formal regulatory process, solidifying meropenem's role as an indispensable agent far beyond its labeled indications.

Section 6: Dosage and Administration Guidelines

The correct dosing and administration of meropenem are paramount to ensuring clinical efficacy while minimizing the risk of toxicity and the development of resistance. Dosing regimens vary significantly based on patient age, weight, renal function, and the specific type and severity of the infection.

6.1. Adult Dosing (Normal Renal Function)

For adult patients with normal renal function (Creatinine Clearance [CrCl] > 50 mL/min), the following standard doses apply:

• Complicated Skin and Skin Structure Infections (cSSSI): 500 mg administered intravenously (IV) every 8 hours.[24]
• cSSSI caused by Pseudomonas aeruginosa: The dose should be increased to 1 gram IV every 8 hours to ensure adequate coverage against this less susceptible pathogen.[24]
• Complicated Intra-abdominal Infections (cIAI): 1 gram IV every 8 hours.[24]
• Nosocomial Pneumonia (per IDSA guidelines): 1 gram IV every 8 hours is a common recommendation. For very severe infections or those caused by less susceptible pathogens, doses may be increased to 2 grams IV every 8 hours.[29]

6.2. Pediatric Dosing (Normal Renal Function)

Pediatric dosing is highly specific and must be calculated carefully based on age and body weight.

Table 5: Recommended Dosing Regimen for Pediatric Patients

Age Group	Type of Infection	Dose (mg/kg)	Maximum Dose per Administration	Dosing Interval	Source(s)
< 3 months	Complicated Intra-abdominal Infections (cIAI)				24
	<32 wks GA & <2 wks PNA	20 mg/kg	N/A	Every 12 hours
	<32 wks GA & ≥2 wks PNA	20 mg/kg	N/A	Every 8 hours
	≥32 wks GA & <2 wks PNA	20 mg/kg	N/A	Every 8 hours
	≥32 wks GA & ≥2 wks PNA	30 mg/kg	N/A	Every 8 hours
≥ 3 months	Complicated Skin and Skin Structure Infections (cSSSI)	10 mg/kg	500 mg	Every 8 hours	24
	cSSSI caused by P. aeruginosa	20 mg/kg	1 gram	Every 8 hours	24
	Complicated Intra-abdominal Infections (cIAI)	20 mg/kg	1 gram	Every 8 hours	24
	Bacterial Meningitis	40 mg/kg	2 grams	Every 8 hours	24

Note: For pediatric patients weighing over 50 kg, standard adult dosages should be used. There is no experience or specific dosing recommendation for pediatric patients with renal impairment.[24]

6.3. Dosing in Special Populations (Renal Impairment)

As meropenem is primarily cleared by the kidneys, dose adjustment in patients with renal impairment is mandatory to prevent drug accumulation and associated toxicities. The following recommendations apply to adult patients; data for pediatric patients with renal impairment is lacking.[24] Creatinine clearance (CrCl) can be estimated using the Cockcroft-Gault formula or other standard methods.[24]

Table 4: Recommended Dosing Regimen for Adults with Renal Impairment

Creatinine Clearance (CrCl) (mL/min)	Dose Adjustment	Dosing Interval	Source(s)
> 50	Recommended Dose (e.g., 500 mg or 1 g)	Every 8 hours	29
26 – 50	Recommended Dose	Every 12 hours	29
10 – 25	One-half Recommended Dose (e.g., 250 mg or 500 mg)	Every 12 hours	29
< 10	One-half Recommended Dose	Every 24 hours	29

For patients undergoing hemodialysis, meropenem is effectively removed by the procedure. Therefore, the dose should be administered after the completion of a hemodialysis session to restore therapeutic drug levels.[10] There is insufficient data to provide dosing recommendations for patients on peritoneal dialysis.[10]

6.4. Preparation, Administration, and Stability

• Reconstitution: Vials of meropenem powder for injection should be reconstituted with a compatible sterile diluent. For intravenous bolus administration, Sterile Water for Injection is used. For intravenous infusion, 0.9% Sodium Chloride Injection is commonly used. The typical reconstituted concentration is 50 mg/mL.[29] The solution should be shaken until the powder is dissolved and the solution is clear.[34]
• Administration: Meropenem can be administered in two ways:

1. Intravenous Infusion: Given over approximately 15 to 30 minutes.[29] For pediatric patients younger than 3 months, a 30-minute infusion is required.[29]
2. Intravenous Bolus Injection: Doses up to 1 gram may be given as a slow IV bolus over approximately 3 to 5 minutes.[29] There is limited safety data supporting a 40 mg/kg bolus dose in pediatric patients.[34]

• Stability: Reconstituted meropenem solutions have limited stability due to hydrolysis of the β-lactam ring.[1] This is a critical point for clinical practice.
• When reconstituted with 0.9% Sodium Chloride, the solution is stable for up to 3 hours at room temperature (up to 25°C) and for up to 24 hours when refrigerated (2–8°C).[1]
• When reconstituted with 5% Dextrose Injection, the solution is less stable and should be used immediately.[29]
• Solutions should not be frozen.[29]

Section 7: Safety and Tolerability Profile

While meropenem is often described as being generally well-tolerated, especially in comparison to older carbapenems, this assessment must be carefully contextualized within its use for critically ill patients with life-threatening infections.[4] Its safety profile is favorable relative to the high-stakes clinical scenarios it is used in, but it is associated with a spectrum of adverse reactions ranging from common and mild to rare but severe and potentially fatal.

7.1. Adverse Drug Reactions (ADRs)

Table 6: Summary of Adverse Reactions Associated with Meropenem

System Organ Class	Incidence	Adverse Reaction	Source(s)
Gastrointestinal	Common (1-10%)	Diarrhea, Nausea, Vomiting, Constipation	1
	Postmarketing	Clostridioides difficile-Associated Diarrhea (CDAD), Pseudomembranous Colitis	25
Dermatologic	Common (1-10%)	Rash (including diaper rash), Pruritus (itching)	1
	Postmarketing	Severe Cutaneous Adverse Reactions (SCARs): Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Erythema Multiforme (EM), Acute Generalized Exanthematous Pustulosis (AGEP)	27
Nervous System	Common (1-10%)	Headache	1
	Uncommon (0.1-1%)	Seizures, Paresthesia (tingling/numbness), Dizziness, Delirium	1
Local Site Reactions	Common (1-10%)	Inflammation, Pain, Phlebitis/Thrombophlebitis at injection site	1
Hematologic	Common (1-10%)	Thrombocytosis (high platelet count), Anemia	4
	Uncommon (0.1-1%)	Thrombocytopenia (low platelet count), Eosinophilia, Leukopenia (low white blood cell count)	38
	Postmarketing	Agranulocytosis, Hemolytic Anemia	41
Hepatic	Common (1-10%)	Increased liver enzymes (ALT, AST, ALP)	4
Immune System	Postmarketing	Anaphylaxis, Angioedema	1
Musculoskeletal	Postmarketing	Rhabdomyolysis	37

The most frequently reported adverse events are gastrointestinal disturbances (diarrhea, nausea, vomiting), headache, rash, and local injection site reactions.[1] However, clinicians must be vigilant for the signs of more serious reactions:

• Hypersensitivity and Anaphylaxis: Serious and occasionally fatal hypersensitivity reactions are a known risk with all β-lactam antibiotics. Patients with a history of allergy to penicillins, cephalosporins, or other allergens are at a significantly higher risk of experiencing a reaction to meropenem.[1]
• Severe Cutaneous Adverse Reactions (SCARs): These are rare but life-threatening dermatologic emergencies that necessitate immediate discontinuation of the drug and specialized care.[27]
• Neurological Toxicity: Seizures are the most concerning CNS side effect. The risk is highest in patients with underlying CNS disorders (e.g., brain lesions, history of epilepsy), bacterial meningitis, or, most importantly, compromised renal function where the drug can accumulate to toxic levels.[1]
• Clostridioides difficile-Associated Diarrhea (CDAD): Disruption of the normal gut microbiome by this broad-spectrum antibiotic can lead to the overgrowth of C. difficile, causing severe, persistent diarrhea and colitis that can manifest up to two months or more after therapy has ended.[1]

7.2. Contraindications, Warnings, and Precautions

The safety profile of meropenem is defined by one absolute contraindication and a comprehensive list of warnings and precautions issued by regulatory agencies.

• Contraindications: Meropenem is contraindicated in patients with a history of a known serious hypersensitivity reaction (e.g., anaphylaxis) to meropenem, any of its components, or to other drugs in the carbapenem class. It is also contraindicated in patients who have experienced anaphylactic reactions to other β-lactam antibiotics.[36]
• FDA Warnings and Precautions: Notably, meropenem does not carry an FDA "Black Box Warning".[18] A black box warning is the agency's most stringent advisory, reserved for drugs with potentially fatal risks that may warrant significant restrictions on use. The absence of such a warning for meropenem, despite its potential for severe adverse events, is a significant regulatory distinction. It suggests a determination that the risks, while serious, are considered manageable through appropriate patient selection, careful dosing (especially with renal adjustment), and vigilant clinical monitoring. This places a high degree of responsibility on the prescribing clinician. The key warnings on the FDA label include [18]:
• Hypersensitivity Reactions
• Severe Cutaneous Adverse Reactions (SCARs)
• Seizure Potential
• Risk of Breakthrough Seizures due to interaction with Valproic Acid
• Clostridioides difficile–Associated Diarrhea (CDAD)
• Development of Drug-Resistant Bacteria
• Overgrowth of Nonsusceptible Organisms
• Thrombocytopenia in patients with renal impairment

7.3. Significant Drug-Drug Interactions

Meropenem has several clinically significant drug-drug interactions that can alter its efficacy or increase the risk of toxicity. The most critical interactions are those affecting renal excretion and the concurrent use of valproic acid.

Table 7: Clinically Significant Drug Interactions with Meropenem

Interacting Drug/Class	Interaction Severity	Effect of Interaction	Clinical Recommendation & Source(s)
Valproic Acid / Divalproex Sodium	Major	Co-administration of meropenem significantly reduces serum concentrations of valproic acid, often to subtherapeutic levels. This can lead to a loss of seizure control and an increased risk of breakthrough seizures.	Concomitant use is generally not recommended. Alternative antibacterial agents should be considered for patients whose seizures are well-controlled on valproic acid. If meropenem use is necessary, supplemental anti-convulsant therapy should be considered and valproic acid levels monitored. 21
Probenecid	Major	Probenecid competes with meropenem for active tubular secretion in the kidneys, thereby inhibiting its renal excretion. This results in a prolonged half-life and significantly increased plasma concentrations of meropenem.	Co-administration is not recommended, as it can lead to potentially toxic levels of meropenem and complicates dosing. 18
Live Bacterial Vaccines (e.g., Typhoid, Cholera, BCG)	Major	As a potent antibacterial agent, meropenem can inactivate live bacterial vaccines, rendering them ineffective.	Avoid co-administration. Vaccination should be timed appropriately relative to the antibiotic course. 40
Anticoagulants (e.g., Warfarin, Acenocoumarol)	Moderate	Meropenem may enhance the anticoagulant effect of these agents, increasing the international normalized ratio (INR) and the risk of bleeding. The exact mechanism is not fully elucidated but may involve disruption of gut flora that synthesize vitamin K.	Monitor coagulation parameters (e.g., INR, PTT) closely during and after co-administration. Dose adjustment of the anticoagulant may be necessary. 8
Drugs Affecting Renal Excretion (e.g., NSAIDs)	Moderate	Drugs that decrease renal clearance (e.g., non-steroidal anti-inflammatory drugs like aceclofenac) can reduce the excretion of meropenem, leading to higher serum levels and an increased risk of toxicity. Conversely, some drugs may increase its excretion.	Use with caution. Monitor for signs of meropenem efficacy and toxicity when co-administered with drugs known to significantly affect renal function or tubular secretion. 8

Section 8: The Challenge of Bacterial Resistance

The sustained clinical utility of meropenem, a cornerstone of modern antibacterial therapy, is under profound threat from the global proliferation of antimicrobial resistance (AMR).[5] The emergence and spread of bacteria capable of resisting carbapenems represents one of the most urgent public health crises of our time.

8.1. Mechanisms of Resistance

Bacteria have evolved several sophisticated mechanisms to evade the bactericidal action of meropenem. These can be broadly categorized into enzymatic degradation, reduced drug entry, and active drug removal.[19]

• Enzymatic Inactivation: This is the most prevalent and clinically significant mechanism of high-level resistance. It involves the production of β-lactamase enzymes with the ability to hydrolyze the carbapenem ring, known as carbapenemases. These enzymes effectively neutralize the antibiotic before it can reach its PBP targets. There are several major classes of carbapenemases:
• Metallo-β-lactamases (MBLs): These are Class B β-lactamases that require zinc ions for their activity. They exhibit a very broad hydrolysis spectrum, inactivating nearly all β-lactams, including meropenem. Prominent examples include NDM (New Delhi Metallo-β-lactamase), VIM (Verona Integron-encoded Metallo-β-lactamase), and IMP types.[1]
• Serine-β-lactamases: These enzymes use a serine residue in their active site. Key carbapenem-hydrolyzing enzymes in this group include the KPC (Klebsiella pneumoniae carbapenemase) family (Class A) and the OXA (oxacillinase) family (Class D), such as OXA-48 and its variants.[5]
• Efflux Pumps: Some bacteria, particularly non-fermenting Gram-negatives like Pseudomonas aeruginosa and Acinetobacter baumannii, can develop resistance by overexpressing multidrug efflux pumps. These are membrane-spanning protein complexes that function as molecular pumps, actively transporting meropenem and other antibiotics out of the bacterial cell. This prevents the drug from accumulating to therapeutic concentrations at its intracellular target. Examples include the MexAB-OprM and MexXY-OprM systems in P. aeruginosa and the AbuO pump in A. baumannii.[19]
• Target Site Modification and Reduced Permeability: While less common as a sole mechanism for high-level resistance, alterations in the drug's target or entry pathway can contribute. Mutations in the genes encoding PBPs can reduce meropenem's binding affinity. More significantly, the loss or modification of outer membrane porin channels (e.g., OprD in P. aeruginosa), which meropenem uses to enter the periplasmic space of Gram-negative bacteria, can decrease drug permeability and lead to low-level resistance or work synergistically with other mechanisms to produce high-level resistance.[5]

8.2. Clinical Implications and Mitigation Strategies

The spread of carbapenem-resistant organisms, especially Carbapenem-Resistant Enterobacteriaceae (CRE), poses a grave threat to patient safety, as it leaves clinicians with very few, and often more toxic, treatment options for severe infections.[6] Addressing this challenge requires a multi-pronged approach.

• Antibiotic Stewardship: The most fundamental strategy is the judicious use of meropenem and all carbapenems. This involves strict adherence to guidelines, avoiding use for non-bacterial infections or when a narrower-spectrum agent would suffice, and ensuring appropriate dosing and duration of therapy. The goal is to minimize selective pressure that drives the emergence of resistance.[14]
• Infection Control: Rigorous infection prevention and control measures in healthcare settings are essential to prevent the transmission of resistant organisms between patients.
• Susceptibility Testing: Routine and rapid microbiological testing to determine the MIC of an infecting organism is critical for guiding therapy. This ensures that meropenem is only used when the pathogen is susceptible and helps identify resistant isolates early.[19]
• Combination Therapy with β-Lactamase Inhibitors: A key pharmacological strategy to combat resistance is to co-administer meropenem with a β-lactamase inhibitor. The combination product meropenem/vaborbactam (Vabomere) pairs meropenem with vaborbactam, a boronic acid-based inhibitor that is potent against serine-β-lactamases like KPC.[19] This combination restores meropenem's activity against many KPC-producing CRE. However, vaborbactam is not active against MBLs or OXA-48-like enzymes. Active research is exploring novel triple-drug combinations that pair a carbapenem with both a serine-β-lactamase inhibitor and an MBL inhibitor to provide even broader protection.[5]

Section 9: Global Formulations and Brand Information

Meropenem is marketed globally by numerous pharmaceutical companies under a wide variety of brand names, reflecting its status as a foundational antibiotic in hospitals worldwide. While Merrem and Meronem are among the most widely recognized originator brands, a multitude of generic and branded generic versions are available.

Table 8: Selected International Brand Names of Meropenem

Brand Name	Selected Countries/Regions	Manufacturer(s)	Source(s)
Merrem	USA, Canada, Mexico, Italy	Pfizer, AstraZeneca	43
Meronem	Europe, UK, Asia, Latin America	Pfizer, AstraZeneca	10
Vabomere (combination with Vaborbactam)	USA	Rempex / The Medicines Company	20
Mepem	China, Taiwan	Sumitomo, Dainippon	15
Ronem	Bangladesh, Indonesia, Peru	Opsonin, Fahrenheit, OQ Pharma	7
Penem	Thailand, India	M & H Manufacturing, Sanjivani	7
Maxpenem	Vietnam	JW Pharmaceutical	44
Itanem	Serbia, Bosnia & Herzegovina	Galenika	44
Meropenem Sandoz	Canada, Spain, Switzerland, Poland	Sandoz	44
Meropenem Kabi	Europe, Canada, Australia	Fresenius Kabi	44
DBL Meropenem	Australia, New Zealand	Hospira	44
Aspen Meropenem	South Africa	Pharmacare	44
Painon	China	Haibin Pharmaceutical	44
Merocrit	India	Cipla	44
Biopenem	Argentina	Lafedar	44

This table represents a small selection of the hundreds of brand names available worldwide. For a comprehensive list, resources such as international drug databases should be consulted. Source: [44]

Section 10: Conclusion and Expert Synthesis

Meropenem stands as a paradigm of modern antibacterial therapy—a powerful, broad-spectrum agent born from the principles of rational drug design to address the clinical and pharmacological limitations of its predecessors. Its development, marked by the strategic addition of a 1-β-methyl group to confer stability against human renal dehydropeptidase-I, solved a key metabolic challenge and established it as a more versatile and pharmacokinetically favorable carbapenem.

The clinical strengths of meropenem are formidable and well-established. Its exceptionally broad spectrum of activity against Gram-positive, Gram-negative (including P. aeruginosa), and anaerobic pathogens, combined with its stability against many common β-lactamases like ESBLs, makes it an indispensable tool for treating complex, polymicrobial, and severe infections. Its ability to penetrate tissues widely, including the cerebrospinal fluid, solidifies its role in managing life-threatening conditions such as intra-abdominal sepsis and bacterial meningitis.

However, these strengths are balanced by significant liabilities. The requirement for intravenous administration limits its use to the inpatient setting. Its safety profile, while often described as favorable in the context of critical illness, includes a risk of serious and potentially fatal adverse events, including anaphylaxis, severe cutaneous reactions, and neurological toxicity. The management of these risks, particularly the prevention of seizures through meticulous dose adjustment in patients with renal impairment, demands a high level of clinical vigilance.

The most profound challenge to the future of meropenem is not its intrinsic pharmacology but the extrinsic and relentless pressure of antimicrobial resistance. The global spread of carbapenemase-producing organisms threatens to render this last-resort antibiotic ineffective, pushing medicine toward a post-antibiotic era for some infections. Meropenem is therefore not merely a drug but a finite and invaluable public health resource. Its preservation is dependent on a concerted global effort encompassing aggressive antibiotic stewardship programs to ensure its judicious use, robust infection control to prevent the spread of resistant pathogens, and continued innovation in the development of novel β-lactamase inhibitor combinations. The ongoing utility of meropenem is a direct reflection of our collective commitment to confronting the crisis of antimicrobial resistance.

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