A Comprehensive Monograph on Imipenem: Pharmacology, Clinical Efficacy, and Evolving Challenges

I. Introduction and Drug Profile

1.1. Historical Context and Development: From Thienamycin to a Clinical Cornerstone

Imipenem (DrugBank ID: DB01598) is a semi-synthetic β-lactam antibiotic that marked the genesis of the carbapenem class, a group of agents that have become indispensable in the management of severe bacterial infections.[1] Its development originated from the natural product thienamycin, which is produced by the soil bacterium

Streptomyces cattleya.[2] While thienamycin demonstrated exceptionally potent and broad-spectrum antibacterial activity, its inherent chemical instability in aqueous solutions rendered it clinically unviable.[2]

In a significant feat of medicinal chemistry, scientists at Merck in the mid-1970s embarked on a lengthy trial-and-error process to modify the thienamycin structure, seeking a derivative that retained the parent compound's potent activity while possessing the necessary stability for therapeutic use.[2] This research culminated in the synthesis of imipenem, which was patented in 1975 and received its first approval from the U.S. Food and Drug Administration (FDA) in 1985.[2] The introduction of imipenem established the carbapenem class, which is characterized by high resistance to the β-lactamase enzymes produced by many multi-drug resistant (MDR) Gram-negative bacteria. This property has made carbapenems, and imipenem in particular, critical last-resort agents for infections not readily treated with other antibiotics.[2]

However, the successful chemical stabilization of the molecule revealed a new biological challenge: imipenem was found to be rapidly metabolized by a human renal enzyme. This discovery dictated the drug's entire subsequent clinical development and therapeutic use. It has never been a standalone clinical agent; rather, its pharmacological profile and clinical efficacy are inextricably linked to its co-formulation with specific inhibitors designed to overcome both host metabolism and, later, bacterial resistance mechanisms. This evolution from a single active molecule to complex multi-component formulations reflects the ongoing arms race between antimicrobial drug development and the dual challenges of human pharmacology and microbial evolution.

1.2. Chemical and Physical Properties of Imipenem

Imipenem is classified as a small molecule, synthetic organic compound belonging to the penem antibacterial subgroup within the broader carbapenem class of β-lactam antibiotics.[1]

Its primary identifiers are DrugBank ID DB01598 and CAS Number 64221-86-9 for the anhydrous form.[1] The clinically used monohydrate form is identified by CAS Number 74431-23-5.[8] The molecule's chemical formula is

C12​H17​N3​O4​S, with an average molecular weight of approximately 299.35 g/mol and a monoisotopic mass of 299.093976737 Da.[1] Its systematic IUPAC name is (5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6--7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.[3] It is also known by several synonyms, including N-Formimidoylthienamycin, Imipemide, and the research code MK0787.[1]

Physically, imipenem appears as a white to off-white or slightly yellow crystalline solid or powder.[5] It is sparingly soluble in water and slightly soluble in methanol, with some sources noting solubility in water up to 10 mM.[5] The melting point is reported to be in the range of 106–111 °C.[5] Due to its chemical nature, it requires stringent storage conditions, typically in a dark, dry place and frozen at temperatures under -20°C to maintain stability.[5]

1.3. Formulations: The Rationale for Combination Products

The clinical utility of imipenem is entirely dependent on its co-formulation with other agents that protect it from degradation. This is a defining characteristic of the drug. Imipenem is rapidly hydrolyzed and inactivated by dehydropeptidase-I (DHP-I), a zinc metalloenzyme located in the brush border of the proximal renal tubules in humans.[2] This rapid metabolism not only limits the drug's efficacy, particularly for urinary tract infections, but can also lead to the formation of potentially nephrotoxic metabolites.[12]

Imipenem/Cilastatin (e.g., Primaxin®): To overcome this metabolic vulnerability, imipenem is always co-administered with cilastatin (DB01597), a specific and reversible inhibitor of the DHP-I enzyme.[1] Cilastatin itself possesses no antibacterial activity. Its sole purpose is to act as a pharmacological shield, preventing the renal degradation of imipenem.[8] This combination achieves several crucial objectives: it increases the plasma half-life of active imipenem, enhances its penetration into tissues, and ensures that therapeutically effective concentrations of the active antibiotic are excreted in the urine.[8] The fixed-dose combination of imipenem and cilastatin was first approved by the FDA in November 1985 under the brand name Primaxin®.[1]

Imipenem/Cilastatin/Relebactam (Recarbrio®): As bacterial resistance evolved, particularly through the production of carbapenem-hydrolyzing β-lactamase enzymes, the efficacy of imipenem/cilastatin became compromised against certain pathogens. To address this, a triple-combination product was developed. Recarbrio® adds relebactam (DB12377), a diazabicyclooctane β-lactamase inhibitor, to the imipenem/cilastatin backbone.[1] Relebactam protects imipenem from degradation by specific Ambler Class A (e.g.,

Klebsiella pneumoniae carbapenemase, KPC) and Class C serine β-lactamases, thereby restoring its activity against many carbapenem-resistant bacteria.[18] This advanced formulation was approved by the FDA for treating specific complicated infections caused by these resistant organisms.[18]

Property	Description	Source(s)
DrugBank ID	DB01598	1
Drug Type	Small Molecule	1
CAS Number	64221-86-9 (Anhydrous); 74431-23-5 (Monohydrate)	7
Chemical Formula	C12​H17​N3​O4​S	1
Average Weight	299.35 g/mol	1
Monoisotopic Weight	299.093976737 Da	1
IUPAC Name	(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6--7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid	3
Synonyms	N-Formimidoylthienamycin, Imipemide, MK0787	5
Appearance	White to off-white/yellow crystalline solid	5
Solubility	Sparingly soluble in water, slightly soluble in methanol	5
Melting Point	106–111 °C	5
Storage Conditions	Keep in dark place, sealed in dry, store in freezer, under -20°C	5
Topological Polar Surface Area	141.52 A˚2	3
XLogP	-3.02	3

II. Pharmacology and Mechanism of Action

2.1. Core Mechanism: Inhibition of Bacterial Cell Wall Synthesis

The fundamental antibacterial action of imipenem is bactericidal and stems from its ability to disrupt the synthesis of the bacterial cell wall.[1] This rigid outer layer, composed primarily of a complex polymer called peptidoglycan, is essential for maintaining the structural integrity of the bacterial cell and protecting it from osmotic lysis.[12] Imipenem targets and inhibits multiple essential Penicillin-Binding Proteins (PBPs), which are bacterial transpeptidases that catalyze the final cross-linking steps in peptidoglycan assembly.[4]

Imipenem's molecular structure allows it to mimic the D-alanyl-D-alanine (D-Ala-D-Ala) moiety of the natural peptidoglycan precursor.[12] This structural similarity enables it to bind with high affinity to the active site of various PBPs, forming a stable, covalent acyl-enzyme complex that effectively inactivates the enzyme.[12] In key Gram-negative pathogens such as

Escherichia coli and Pseudomonas aeruginosa, imipenem demonstrates a particularly high affinity for PBP-2, PBP-1a, and PBP-1b, with its lethal bactericidal effect being strongly associated with the inhibition of PBP-2 and PBP-1B.[1] The resulting inhibition of peptidoglycan cross-linking compromises the structural integrity of the cell wall, leading to cell elongation, lysis, and ultimately, bacterial death.[12]

2.2. The Essential Role of Cilastatin: Overcoming Renal Metabolism

As previously noted, the clinical viability of imipenem is wholly dependent on its co-administration with cilastatin. When administered alone, imipenem is extensively metabolized by the DHP-I enzyme located on the brush border of the renal tubules.[8] This rapid inactivation leads to low urinary concentrations of the active drug and a shortened systemic half-life, which would severely limit its therapeutic efficacy.[12]

Cilastatin functions as a potent and reversible competitive inhibitor of DHP-I, effectively preventing this renal metabolism of imipenem.[12] The benefits of this enzymatic blockade are twofold and profound. First, it significantly increases the systemic exposure to active imipenem by increasing its plasma half-life and enhancing its penetration into various body tissues.[8] Second, by preventing renal degradation, it allows a much larger fraction of the administered dose to be excreted in the urine as the active, unchanged parent drug. This increases the urinary recovery of active imipenem to approximately 70% of the dose, ensuring that clinically relevant and bactericidal concentrations are achieved in the urinary tract, a critical factor for its use in treating UTIs.[14]

2.3. Enhancing the Spectrum: The Role of Relebactam

While the unique carbapenem structure confers imipenem with a high degree of stability against many common β-lactamase enzymes, such as penicillinases and cephalosporinases, the emergence of more potent carbapenem-hydrolyzing enzymes (carbapenemases) has created a significant resistance challenge.[1] To counteract this, the triple-combination product Recarbrio® was developed, which includes the non-β-lactam β-lactamase inhibitor relebactam.[18]

Relebactam's mechanism is to protect imipenem from enzymatic degradation by specific serine β-lactamases, including Ambler Class A carbapenemases (most notably KPC) and Class C cephalosporinases (AmpC).[18] By binding to and inactivating these enzymes, relebactam restores the intrinsic activity of imipenem against many carbapenem-resistant strains of Enterobacterales and

P. aeruginosa that rely on these enzymes for resistance.[19] The "mechanism of action" of the most advanced clinical formulation of imipenem is therefore not a single molecular interaction but a sophisticated, multi-layered pharmacological strategy. It involves a cascade of three distinct interventions: cilastatin inhibiting host metabolism, relebactam inhibiting bacterial enzymatic defense, and finally, imipenem inhibiting bacterial cell wall synthesis. The failure of any one of these components can lead to overall therapeutic failure, underscoring the complexity of modern antibiotic therapy.

2.4. Spectrum of Antimicrobial Activity

Imipenem is renowned for its exceptionally broad spectrum of in vitro activity, which encompasses a wide range of Gram-positive aerobes, Gram-negative aerobes, and anaerobic bacteria, including many strains that are resistant to other classes of antibiotics.[1]

• Gram-Positive Coverage: Imipenem is active against many clinically important Gram-positive pathogens. This includes penicillinase-producing strains of Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae, Group A (S. pyogenes) and Group B (S. agalactiae) streptococci, and Enterococcus faecalis.[1] It also shows activity against organisms like Listeria monocytogenes and Nocardia spp..[23] However, there are critical gaps in its Gram-positive coverage. Imipenem is not active against methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus faecium, as these organisms possess altered PBPs to which imipenem does not effectively bind.[2]
• Gram-Negative Coverage: The activity of imipenem against Gram-negative bacteria is particularly robust. It is effective against the majority of Enterobacterales, including Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., and Serratia marcescens.[1] It also covers other important pathogens like Haemophilus influenzae and Acinetobacter spp..[1] Crucially, imipenem is one of the most potent carbapenems against Pseudomonas aeruginosa, a frequent cause of severe nosocomial infections.[1] Similar to its Gram-positive spectrum, there are notable intrinsic gaps. Imipenem is not active against Stenotrophomonas maltophilia, which produces a chromosomal metallo-β-lactamase, or against certain strains of Burkholderia cepacia.[15]
• Anaerobic Coverage: Imipenem provides excellent coverage against a vast array of clinically significant anaerobic bacteria. This includes gram-negative anaerobes like Bacteroides fragilis and other Bacteroides species, as well as Gram-positive anaerobes such as Clostridium spp. (excluding C. difficile), Peptostreptococcus spp., and Fusobacterium spp..[1] This potent anaerobic activity makes it a valuable agent for treating polymicrobial infections, such as complicated intra-abdominal infections.

III. Pharmacokinetics and Pharmacodynamics (ADME)

3.1. Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

The pharmacokinetic profile of imipenem is defined by its parenteral administration route and its interaction with the renal enzyme DHP-I, which necessitates its combination with cilastatin.

• Absorption: Imipenem is not effectively absorbed from the gastrointestinal tract and must be administered either intravenously (IV) or intramuscularly (IM).[1] Following IM injection, the bioavailability is high, reported to be between 60% and 89% for imipenem and nearly complete (95–100%) for cilastatin.[1]
• Distribution: After administration, the drug combination distributes rapidly and widely into most body tissues and fluids.[13] The volume of distribution (Vd) for imipenem is relatively small, ranging from 0.23 to 0.31 L/kg, suggesting distribution primarily within the extracellular fluid.[1] Plasma protein binding is low for imipenem at approximately 13–21%, allowing a large fraction of the drug to remain free and active.[1] Cilastatin exhibits higher protein binding at around 35–40%.[13] The combination achieves high concentrations in key infection sites such as pleural fluid, interstitial fluid, and peritoneal fluid.[13] However, penetration across the blood-brain barrier is modest, and concentrations in the cerebrospinal fluid are generally low.[10]
• Metabolism: As a central feature of its pharmacology, imipenem is metabolized in the kidneys by the DHP-I enzyme. This metabolic pathway is effectively blocked by the co-administered DHP-I inhibitor, cilastatin.[1] In patients with severe renal dysfunction, a non-renal metabolic clearance pathway for imipenem becomes more prominent; this pathway is not affected by cilastatin.[14]
• Excretion: The primary route of elimination for both compounds is renal.[14] When protected by cilastatin, approximately 70% of an administered imipenem dose is recovered in the urine as the unchanged, active drug.[1] The elimination half-life ( t1/2​) following IV infusion in healthy volunteers with normal renal function is approximately 1 hour for both imipenem and cilastatin.[1] The apparent half-life after IM administration is considerably longer, ranging from 1.3 to 5.1 hours, which is attributed to a slower rate of absorption from the muscle tissue.[1] The total clearance of imipenem is approximately 0.2 L/h/kg.[1] The renal clearance of imipenem alone is low (0.05 L/h/kg) but increases threefold to 0.15 L/h/kg in the presence of cilastatin, as higher concentrations of the parent drug are available for renal excretion rather than metabolism.[1] Both imipenem and cilastatin are efficiently removed from the blood by hemodialysis.[14]

Parameter	Imipenem	Cilastatin	Source(s)
Bioavailability (IM)	60–89%	95–100%	1
Volume of Distribution (Vd)	0.23–0.31 L/kg	14.6–20.1 L	1
Plasma Protein Binding	13–21%	35–40%	1
Half-life (t1/2​) (IV, normal renal function)	~1 hour	~1 hour	1
Apparent Half-life (t1/2​) (IM)	1.3–5.1 hours	Not Available	1
Metabolism	Renal DHP-I (inhibited by cilastatin)	Not Available	1
% Renal Excretion (Unchanged, with Cilastatin)	~70%	~70%	1
Total Clearance	0.2 L/h/kg	0.2 L/h/kg	1

3.2. Pharmacokinetic Considerations in Special Populations

The well-defined pharmacokinetic parameters observed in healthy volunteers can be dramatically altered in specific patient populations, necessitating careful dose adjustments and monitoring.

• Renal Impairment: Renal dysfunction profoundly affects the elimination of both imipenem and cilastatin. As renal function declines, the half-life of both compounds is significantly prolonged.[13] In functionally anephric patients (those with no kidney function), the terminal half-life of imipenem increases to over 4 hours, while that of cilastatin extends to approximately 16 hours.[14] This substantial accumulation necessitates significant dose reductions and/or extension of the dosing interval to prevent the attainment of toxic drug concentrations, particularly the neurotoxic effects associated with imipenem.[14]
• Critically Ill Patients (ICU): The pharmacokinetics of imipenem/cilastatin are highly variable and unpredictable in critically ill patients due to dynamic physiological changes, including altered fluid status, organ dysfunction, and the use of extracorporeal therapies.[30] Studies in ICU patients undergoing continuous renal replacement therapies (CRRT), such as continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHDF), have shown that these modalities substantially increase the clearance of imipenem.[31] The clearance by the CRRT membrane itself can account for 25–32% of the total systemic clearance.[31] This augmented clearance can lead to sub-therapeutic drug concentrations, especially for treating pathogens with higher minimum inhibitory concentrations (MICs). Consequently, standard dosing regimens developed in healthier populations may be inadequate for critically ill patients, potentially leading to treatment failure and the selection of resistant organisms.[30] This variability underscores a strong rationale for the use of therapeutic drug monitoring (TDM) in the ICU setting to individualize dosing and ensure therapeutic targets are met.
• Pharmacodynamic Principles: As with other β-lactam antibiotics, the bactericidal activity of imipenem is time-dependent. The key pharmacodynamic (PD) parameter that best correlates with clinical efficacy is the percentage of the dosing interval during which the free (unbound) drug concentration remains above the MIC of the infecting pathogen (%fT>MIC).[28] To optimize this parameter, administration via prolonged or continuous infusion has been explored. However, studies have shown that simply extending the infusion time with a reduced total daily dose may not be sufficient. For example, a 3-hour infusion of 0.5 g every 6 hours was found to be inadequate for treating infections caused by pathogens with an MIC of ≥2 mg/L when compared to a standard 30-minute infusion of 1 g every 8 hours, despite the longer infusion time.[32] This highlights the complex interplay between dose, infusion time, and pathogen susceptibility in achieving the desired pharmacodynamic target.

IV. Clinical Efficacy and Approved Indications

4.1. Review of Pivotal Clinical Trials

Imipenem, in its combination formulations, has undergone extensive clinical investigation over several decades, establishing its efficacy across a wide range of serious bacterial infections. Its development pathway has included numerous trials across all clinical phases.

• Phase 1 Trials: Foundational studies focused on establishing the safety, tolerability, and pharmacokinetic profile of imipenem with and without cilastatin. These trials were conducted in healthy volunteers as well as in subjects with varying degrees of renal function to define the parameters for dose adjustment.[33] Basic science studies also explored intrapulmonary pharmacokinetics to understand drug concentrations at the site of respiratory infections.[33]
• Phase 2 Trials: These studies provided initial evidence of efficacy in specific infectious diseases. Completed Phase 2 trials have demonstrated imipenem's effectiveness in treating challenging infections such as ventilator-associated bacterial pneumonia (VABP), abdominal abscesses, and other forms of bacterial pneumonia.[34]
• Phase 3 Trials: Large, randomized, controlled trials have solidified imipenem's role in therapy. These trials have confirmed its efficacy for numerous severe infections, including complicated urinary tract infections (cUTIs), acute pancreatitis, and complicated intra-abdominal infections (cIAIs).[35] More recently, the development of the triple-combination product with relebactam was supported by pivotal Phase 3 trials. The RESTORE-IMI 2 trial, for instance, was a multinational, randomized, double-blind study that demonstrated the non-inferiority of imipenem/cilastatin/relebactam compared to piperacillin/tazobactam for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP).[19]

4.2. FDA-Approved Indications

The approved indications for imipenem vary depending on the specific combination product, reflecting an evolution in its therapeutic role from a broad-spectrum workhorse to a more targeted agent for resistant pathogens. Imipenem is only indicated for use in combination with cilastatin, with or without the addition of relebactam.[1]

The evolution of these indications over several decades provides a clear illustration of the shifting landscape of infectious diseases. The original approval for imipenem/cilastatin in 1985 came with a very broad label, reflecting its novel and powerful activity against a wide array of bacteria common at the time. In contrast, the approval of imipenem/cilastatin/relebactam decades later was for a much more restricted set of indications, specifically targeting infections caused by resistant pathogens and often limited to patients with few or no other treatment options. This demonstrates a paradigm shift in antibiotic regulation and clinical use, moving away from a "one-size-fits-all" approach toward a more deliberate, stewardship-driven deployment of new antimicrobial agents as targeted solutions for specific resistance problems.

Formulation	Indication	Limitations of Use / Specific Pathogens	Source(s)
Imipenem/Cilastatin (e.g., Primaxin®)	Lower Respiratory Tract Infections	Caused by susceptible strains of S. aureus, Acinetobacter spp., Enterobacter spp., E. coli, H. influenzae, Klebsiella spp., S. marcescens	38
	Urinary Tract Infections (Complicated & Uncomplicated)	Caused by susceptible strains of E. faecalis, S. aureus, Enterobacter spp., E. coli, Klebsiella spp., P. aeruginosa, etc.	38
	Intra-Abdominal Infections	Caused by susceptible strains of E. faecalis, S. aureus, Enterobacter spp., E. coli, Klebsiella spp., P. aeruginosa, Bacteroides spp.	38
	Gynecologic Infections	Caused by susceptible strains of E. faecalis, S. aureus, S. agalactiae, Enterobacter spp., E. coli, G. vaginalis, Bacteroides spp.	38
	Bacterial Septicemia	Caused by susceptible strains of E. faecalis, S. aureus, Enterobacter spp., E. coli, Klebsiella spp., P. aeruginosa, Bacteroides spp.	38
	Bone and Joint Infections	Caused by susceptible strains of E. faecalis, S. aureus, S. epidermidis, Enterobacter spp., P. aeruginosa	38
	Skin and Skin Structure Infections	Caused by susceptible strains of E. faecalis, S. aureus, Acinetobacter spp., Enterobacter spp., E. coli, Klebsiella spp., P. aeruginosa	38
	Endocarditis	Caused by susceptible strains of S. aureus	38
Imipenem/Cilastatin/Relebactam (Recarbrio®)	Hospital-Acquired & Ventilator-Associated Bacterial Pneumonia (HABP/VABP)	Caused by susceptible Gram-negative organisms including Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, E. coli, K. pneumoniae, P. aeruginosa, S. marcescens	19
	Complicated Urinary Tract Infections (cUTI), including Pyelonephritis	Indicated in patients ≥18 years old with limited or no alternative treatment options. Caused by susceptible Gram-negative organisms including E. cloacae, E. coli, K. pneumoniae, P. aeruginosa	18
	Complicated Intra-Abdominal Infections (cIAI)	Indicated in patients ≥18 years old with limited or no alternative treatment options. Caused by susceptible Gram-negative organisms including various Bacteroides species, E. coli, K. pneumoniae, P. aeruginosa	18

4.3. Dosage and Administration Guidelines

The dosing of imipenem-containing products is complex and must be individualized based on the type and severity of infection, the patient's age and weight, and, most critically, their renal function. All dosages are expressed in terms of the imipenem component.

• Adults with Normal Renal Function (CrCl ≥90 mL/min): The dose typically ranges from 250 mg IV every 6 hours for uncomplicated UTIs to 1 g IV every 6 or 8 hours for severe, life-threatening infections.[8] For mild to moderate infections like lower respiratory tract or skin infections, 500–750 mg IV every 12 hours may be used.[39] The total maximum daily dose should not exceed 50 mg/kg or 4 g, whichever is lower.[39] An intramuscular formulation is also available for less severe infections, typically dosed at 500 mg or 750 mg every 12 hours.[42]
• Pediatric Patients: Dosing in children is based on body weight (mg/kg) and varies significantly with age due to developmental changes in renal function.[39]
• Neonates (<1 week): 25 mg/kg IV every 12 hours.
• Infants (1–4 weeks): 25 mg/kg IV every 8 hours.
• Infants (4 weeks–3 months): 25 mg/kg IV every 6 hours.
• Children (>3 months): 15–25 mg/kg IV every 6 hours.
• The total daily dose should not exceed 2 g/day for fully susceptible organisms or 4 g/day for moderately susceptible organisms.[39] Due to an increased risk of seizures, imipenem/cilastatin is not recommended for use in pediatric patients with CNS infections.[39]
• Patients with Renal Impairment: Dose reduction is mandatory for any patient with a creatinine clearance (CrCl) below 90 mL/min to prevent the accumulation of the drug and associated neurotoxicity.[39] A tiered dosing schedule based on CrCl levels is recommended, with both the dose and the dosing interval being adjusted as renal function declines.[22] For patients with a CrCl <15 mL/min, the drug is not recommended unless hemodialysis is initiated within 48 hours.[39] Because both imipenem and cilastatin are cleared by hemodialysis, a supplemental dose should be administered after each dialysis session.[14]
• Administration: For intravenous administration, doses of 500 mg or less should be infused over 20 to 30 minutes. Doses greater than 500 mg should be infused over a longer period of 40 to 60 minutes.[39] If a patient experiences nausea during the infusion, the rate of infusion may be slowed to improve tolerability.[39]

Patient Population	Creatinine Clearance (CrCl)	Recommended IV Dosage Regimen (for Susceptible Organisms)	Source(s)
Adults	≥90 mL/min	500 mg q6h OR 1000 mg q8h	39
	<90 to ≥60 mL/min	400 mg q6h OR 500 mg q6h	39
	<60 to ≥30 mL/min	300 mg q6h OR 500 mg q8h	39
	<30 to ≥15 mL/min	200 mg q6h OR 500 mg q12h	39
	<15 mL/min (on Hemodialysis)	200 mg q6h OR 500 mg q12h (Administer after dialysis)	39
Pediatrics	Normal Renal Function
	<1 week, >1.5 kg	25 mg/kg q12h	41
	1-4 weeks, >1.5 kg	25 mg/kg q8h	41
	4 weeks - 3 months, >1.5 kg	25 mg/kg q6h	41
	>3 months	15-25 mg/kg q6h (Max: 2-4 g/day)	41
	<30 kg with renal impairment	Not Recommended	39

V. Safety, Tolerability, and Risk Management

5.1. Adverse Effect Profile

The safety profile of imipenem/cilastatin is well-characterized, with adverse effects ranging from common, mild reactions to rare but severe toxicities.

• Common Adverse Effects (Incidence 1–10%):
• Local Reactions: The most frequent adverse events are local reactions at the injection site, including pain, phlebitis, erythema, and induration.[39]
• Gastrointestinal Effects: Nausea, vomiting, and diarrhea are common, occurring in 1–2% of patients.[2] Nausea can sometimes be managed by slowing the infusion rate.[39]
• Hematologic Changes: Eosinophilia is reported in up to 4% of patients. A potentially false-positive direct Coombs test can also occur.[22]
• Dermatologic Reactions: Skin rash and pruritus are observed in a small percentage of patients.[41]
• Less Common and Rare Adverse Effects (Incidence <1%):
• Hepatotoxicity: Transient and asymptomatic elevations in serum aminotransferase levels are observed in approximately 6% of patients receiving therapy for 5 to 14 days.[8] Clinically apparent liver injury is rare, with cholestatic jaundice reported in approximately 0.1% of patients in prospective trials.[8] The onset is typically within 1 to 3 weeks of therapy, and the course is usually self-limiting. However, at least one case of vanishing bile duct syndrome has been linked to carbapenem use.[8]
• Hypersensitivity Reactions: As with all β-lactam antibiotics, imipenem can cause allergic reactions, ranging from mild urticaria to severe, life-threatening anaphylaxis.[43]
• Clostridioides difficile-Associated Diarrhea (CDAD): Treatment with imipenem, like nearly all antibacterial agents, alters the normal colonic flora and can lead to the overgrowth of C. difficile. This can result in a spectrum of illness from mild diarrhea to severe, fulminant, or fatal pseudomembranous colitis.[18]

5.2. Focus on Neurotoxicity: Seizure Risk

The most significant and dose-limiting toxicity of imipenem is its potential to induce central nervous system (CNS) adverse reactions, most notably seizures.[2]

• Risk Factors: The risk of seizures is not uniform and is significantly increased by several key factors. These include the use of high doses, pre-existing CNS disorders such as brain lesions or a history of epilepsy, and, most importantly, the presence of renal impairment.[18] Impaired renal function leads to the accumulation of imipenem to concentrations that can cross the seizure threshold. This makes accurate assessment of renal function and appropriate dose adjustment absolutely critical for safe use.
• Incidence: The FDA-approved product labeling notes a seizure frequency of approximately 0.4% for imipenem.[47] A comprehensive meta-analysis of randomized controlled trials provided a more nuanced view, finding that imipenem use was associated with an absolute risk increase of 4 seizures per 1000 patients when compared to non-carbapenem antibiotics, corresponding to an odds ratio (OR) of 3.50.[47]
• Mechanism: The neurotoxicity of β-lactam antibiotics, including carbapenems, is believed to be mediated through their interaction with and antagonism of the γ-aminobutyric acid type A (GABAA​) receptor in the CNS.[45] GABA is the primary inhibitory neurotransmitter in the brain, and by blocking its action, β-lactams can lead to neuronal hyperexcitability and seizures. The drug's design presents an inherent tension: cilastatin is essential for therapeutic efficacy because it increases systemic imipenem levels, but this same action simultaneously narrows the therapeutic window and can exacerbate the risk of this primary dose-dependent toxicity, particularly when renal clearance is compromised.[46]

5.3. Clinically Significant Drug-Drug Interactions

Imipenem is associated with several clinically important drug-drug interactions, some of which necessitate avoiding co-administration entirely.

Interacting Drug(s)	Clinical Consequence	Proposed Mechanism	Recommended Management	Source(s)
Valproic Acid / Divalproex Sodium	Decreased serum concentrations of valproic acid, leading to loss of seizure control.	Carbapenems may inhibit the hydrolysis of the valproic acid glucuronide metabolite (VPA-g) back to active valproic acid.	Avoid combination. Monitor valproic acid levels closely if co-administration is unavoidable.	39
Ganciclovir / Valganciclovir	Increased risk of generalized seizures.	Unknown; likely additive neurotoxic effects.	Avoid combination unless the potential benefit outweighs the significant risk.	39
Probenecid	Increased plasma levels and prolonged half-life of imipenem and cilastatin.	Probenecid competes for active tubular secretion in the kidneys, decreasing renal clearance.	Avoid combination. Not generally recommended.	39
Live Bacterial Vaccines (e.g., Cholera, BCG)	Decreased efficacy of the vaccine.	The antibacterial activity of imipenem can kill the live attenuated bacteria in the vaccine strain.	Avoid co-administration. Ensure antibiotic therapy is completed well before (e.g., 14 days for cholera vaccine) administering the vaccine.	39
Anticoagulants (e.g., Warfarin, Acenocoumarol)	Increased risk of bleeding; elevated International Normalized Ratio (INR).	Alteration of gut flora affecting Vitamin K synthesis; potential direct interaction.	Monitor coagulation parameters (INR) closely.	1

5.4. Contraindications, Warnings, and Precautions

• Contraindications: The primary contraindication for imipenem/cilastatin is a history of a severe hypersensitivity reaction (e.g., anaphylaxis) to either imipenem, cilastatin, or any other component in the formulation.[39]
• Warnings and Precautions:
• Hypersensitivity and Cross-Reactivity: Caution should be exercised when administering imipenem to patients with a known allergy to other β-lactam antibiotics, such as penicillins and cephalosporins, due to the potential for allergic cross-reactivity.[2]
• CDAD: As with other broad-spectrum antibiotics, the potential for C. difficile-associated diarrhea must be considered in any patient who develops diarrhea during or after therapy. If CDAD is suspected or confirmed, appropriate management should be instituted.[18]
• Antimicrobial Stewardship: To reduce the development of drug-resistant bacteria, imipenem-containing products should only be used to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. Prescribing in the absence of such evidence is unlikely to benefit the patient and increases the risk of promoting resistance.[18]

VI. The Challenge of Antimicrobial Resistance

6.1. Overview of Carbapenem Resistance Mechanisms

The emergence and global dissemination of carbapenem resistance, particularly among Gram-negative pathogens, represents one of the most urgent public health threats of the modern era.[4] The mechanisms by which bacteria develop resistance to carbapenems like imipenem are diverse and can occur in combination, often leading to multidrug-resistant phenotypes that severely limit therapeutic options. These mechanisms can be broadly classified into three major categories:

1. Enzymatic Hydrolysis: This is the most clinically significant mechanism and involves the production of β-lactamase enzymes capable of hydrolyzing the carbapenem molecule, known as carbapenemases. These enzymes are frequently encoded on mobile genetic elements like plasmids and transposons, which allows for their rapid horizontal transfer between different bacterial species and strains, facilitating the swift spread of resistance.[53]
2. Decreased Permeability: Gram-negative bacteria possess an outer membrane that acts as a selective barrier. Carbapenems must traverse this barrier through aqueous channels formed by proteins called porins to reach their PBP targets in the periplasmic space. The loss, mutation, or downregulation of these specific porin channels (such as the OprD porin in P. aeruginosa) can significantly reduce the intracellular concentration of the antibiotic, thereby conferring resistance.[50]
3. Efflux Pump Upregulation: Bacteria can also acquire resistance by overexpressing multidrug efflux pumps. These are protein complexes that span the bacterial membranes and actively transport antibiotics out of the cell before they can reach their target, effectively lowering the intracellular drug concentration.[55]

6.2. Specific Resistance Mechanisms Affecting Imipenem

The predominant mechanisms of resistance to imipenem vary significantly between different key pathogens.

• Carbapenemases: These enzymes are the primary drivers of carbapenem resistance in Enterobacterales. They are categorized into Ambler classes:
• Class A (Serine Carbapenemases): This class includes the Klebsiella pneumoniae carbapenemase (KPC), which is widespread globally and is a primary target of the β-lactamase inhibitor relebactam.[20]
• Class B (Metallo-β-Lactamases, MBLs): These enzymes, which include NDM (New Delhi Metallo-β-lactamase), VIM (Verona Integron-encoded Metallo-β-lactamase), and IMP (Imipenemase), utilize zinc ions for catalysis. They represent a major therapeutic challenge as they are not inhibited by current clinical serine β-lactamase inhibitors like relebactam, avibactam, or vaborbactam.[50]
• Class D (Oxacillinases, OXA): This is a diverse group of enzymes. The OXA-48-like enzymes are a significant cause of carbapenem resistance in Enterobacterales, while enzymes like OXA-23 are predominant in Acinetobacter baumannii.[57]
• Resistance in Pseudomonas aeruginosa: While P. aeruginosa can acquire carbapenemase genes, the most prevalent mechanism of imipenem resistance in this organism is non-enzymatic. It is most commonly caused by the loss or functional inactivation of the OprD porin, which is the specific outer membrane channel through which imipenem enters the cell.[60] This loss can occur through various genetic events, including point mutations that introduce premature stop codons or frameshifts, or the disruption of the oprD gene by mobile insertion sequences.[60] This mechanism is often coupled with the upregulation of intrinsic efflux pump systems (e.g., MexAB-OprM, MexXY) and the overproduction of the chromosomal AmpC β-lactamase, which together create a high-level resistance phenotype.[55] Notably, prior exposure to imipenem is a strong selective pressure that promotes the emergence of these OprD-deficient, imipenem-resistant P. aeruginosa (IRPA) strains.[63]

This fundamental difference in predominant resistance mechanisms between Enterobacterales (enzymatic) and P. aeruginosa (porin loss) has profound therapeutic implications. A combination agent like imipenem/cilastatin/relebactam is designed to overcome enzymatic resistance (e.g., KPC). However, it would be predictably ineffective against an imipenem-resistant P. aeruginosa strain whose resistance is due to the loss of the OprD porin, as the antibiotic cannot be inhibited if it cannot enter the cell to begin with. This reality creates a critical need for rapid diagnostics that can identify the specific mechanism of resistance, moving beyond a simple "susceptible" or "resistant" report to guide the appropriate use of highly targeted and expensive combination therapies.

6.3. Clinical and Public Health Implications

The consequences of carbapenem resistance are severe. Infections caused by carbapenem-resistant organisms are consistently associated with significantly higher rates of morbidity and mortality, longer hospital stays, and substantially increased healthcare costs compared to infections caused by susceptible counterparts.[51] The spread of these pathogens dramatically limits treatment options, often forcing clinicians to revert to older, more toxic antibiotics such as the polymyxins (e.g., colistin), which have less favorable efficacy and safety profiles.[4]

The epidemiology of carbapenem resistance is also geographically diverse. Different carbapenemase genes are predominant in different parts of the world—for instance, KPC in the Americas and parts of Europe, NDM in the Indian subcontinent, and OXA-48 in the Mediterranean and Middle East.[57] This geographic variability necessitates a strong understanding of local and regional epidemiology to inform appropriate empiric antibiotic choices for critically ill patients.

VII. Comparative Analysis and Place in Therapy

7.1. Imipenem in the Context of the Carbapenem Class

The carbapenem class has diversified since the introduction of imipenem, with each agent possessing distinct properties that define its clinical niche.

• Comparison versus Meropenem: Meropenem is the most similar carbapenem to imipenem. Their spectrum of activity is largely overlapping and very broad, although some in vitro data suggest meropenem may be slightly more potent against P. aeruginosa.[15] Both have short half-lives of approximately 1 hour, requiring frequent dosing (typically every 6 to 8 hours).[15] The key differentiating feature is metabolic stability: meropenem is stable to the renal enzyme DHP-I and therefore does not require co-administration with an inhibitor like cilastatin.[15] Regarding safety, a widespread clinical perception holds that imipenem carries a higher risk of seizures. However, a large meta-analysis, while confirming that imipenem's seizure risk is higher than that of non-carbapenem antibiotics, found no statistically significant difference in epileptogenicity in head-to-head trials comparing imipenem directly with meropenem.[47] Despite this evidence, meropenem is generally the preferred carbapenem for treating bacterial meningitis due to this perceived lower seizure risk and better CNS penetration.[47]
• Comparison versus Ertapenem: Ertapenem represents a strategic divergence within the class. Its antimicrobial spectrum is significantly narrower than that of imipenem, most notably lacking reliable activity against key nosocomial pathogens such as P. aeruginosa, Acinetobacter spp., and Enterococcus spp..[15] Its major advantage lies in its pharmacokinetics; a long half-life of approximately 4 hours allows for convenient once-daily administration.[15] This profile makes ertapenem well-suited for treating community-acquired infections where anti-pseudomonal coverage is not required, for de-escalation therapy, and for outpatient parenteral antibiotic therapy (OPAT). Conversely, imipenem and meropenem are reserved for more severe, hospital-acquired, and polymicrobial infections where broad coverage, including against P. aeruginosa, is essential.[15]
• Comparison versus Doripenem: Doripenem's properties are very similar to those of meropenem. Some in vitro studies suggest it may possess even more potent activity against P. aeruginosa.[15]

Feature	Imipenem/Cilastatin	Meropenem	Ertapenem	Doripenem
Activity vs. P. aeruginosa	Yes (Potent)	Yes (Potent)	No (Poor activity)	Yes (Potent)
Activity vs. Enterococcus faecalis	Yes	Yes	No	Yes
DHP-I Stability	No (Requires Cilastatin)	Yes	Yes	Yes
Typical Dosing Frequency	Every 6-8 hours	Every 8 hours	Every 24 hours	Every 8 hours
Seizure Risk Profile	Higher than non-carbapenems; not statistically different from meropenem in direct comparisons.	Lower perceived risk than imipenem; preferred for CNS infections.	Low	Low

7.2. Comparative Efficacy and Safety Against Newer Antibiotics

With the rise of carbapenem resistance, a new generation of antibiotics and combination agents has been developed. Meta-analyses comparing these new agents to carbapenems have yielded interesting results.

A systematic review and meta-analysis of randomized controlled trials for complicated urinary tract infections (cUTIs) compared newer antibiotics (such as ceftazidime-avibactam and plazomicin) with carbapenems (imipenem or meropenem).[71] The analysis found no statistically significant difference between the groups in terms of clinical success rates or composite cure rates (a combination of clinical and microbiological success). However, the newer antibiotic treatments were found to be statistically superior to carbapenems in achieving

microbiological eradication.[71] The safety profiles, including the rates of adverse events, were comparable between the two groups.[71]

This finding—that newer agents achieve better microbiological cure despite equivalent clinical cure—is particularly noteworthy because it occurred in trials where overt carbapenem resistance was largely absent. One plausible explanation for this discrepancy relates to the collateral effects of the antibiotics on the host microbiome. Carbapenems like imipenem possess potent activity against a wide range of anaerobic bacteria, which are key components of the protective gut and vaginal microbiota. In contrast, many of the newer comparator agents have poor or no activity against anaerobes. It has been hypothesized that the potent anaerobic activity of carbapenems may disrupt the colonization resistance of the native microbiota, allowing for re-colonization of the urinary tract by pathogens like E. coli from the intestinal reservoir. This could lead to a higher rate of microbiological relapse or reinfection, even if the initial clinical symptoms resolved.[71] This suggests that an antibiotic's "broader" spectrum is not universally advantageous and may even be a liability in certain clinical scenarios by causing ecological disruption that undermines long-term microbiological success.

Meanwhile, a separate meta-analysis focusing on the novel carbapenem–β-lactamase inhibitor combinations, including imipenem/cilastatin/relebactam, found that these agents were superior to their comparators (often older agents like colistin) in terms of both clinical cure and patient survival when treating complicated infections caused by resistant pathogens, while maintaining a comparable safety profile.[76]

VIII. Conclusion and Future Directions

8.1. Summary of Imipenem's Enduring Role

As the progenitor of the carbapenem class, imipenem has maintained its status as a formidable, broad-spectrum antibiotic for over three decades. Its enduring role is in the treatment of severe, hospital-acquired, and polymicrobial infections where broad coverage against Gram-positive, Gram-negative, and anaerobic pathogens is required. The clinical utility of imipenem is a testament to successful pharmaceutical engineering, defined by its necessary combination products: first with cilastatin, to overcome its inherent metabolic instability in humans, and more recently with the β-lactamase inhibitor relebactam, to counter specific, evolving mechanisms of bacterial resistance.

However, its powerful efficacy is balanced by significant limitations. The primary safety concern remains its potential for neurotoxicity, a risk that is magnified in patients with impaired renal function and necessitates meticulous dose adjustment. Furthermore, its continued effectiveness is perpetually threatened by the relentless evolution of bacterial resistance. The rise of metallo-β-lactamases, for which current inhibitors are ineffective, and the high prevalence of non-enzymatic resistance mechanisms like OprD porin loss in P. aeruginosa represent major challenges to its future utility.

8.2. Future Outlook: Navigating the Landscape of Increasing Resistance

The future of imipenem, and indeed the entire carbapenem class, hinges on a multi-faceted strategy that balances potent therapeutic application with concerted efforts to preserve long-term efficacy.

First, antimicrobial stewardship is paramount. This involves the judicious use of all carbapenems, guided by principles of de-escalation and spectrum optimization. This means selecting narrower-spectrum agents like ertapenem for infections where anti-pseudomonal activity is not needed, thereby sparing broader agents like imipenem and meropenem for infections where they are truly required.

Second, the effective use of advanced combination products like Recarbrio® is critically dependent on diagnostic advancement. The development and widespread clinical implementation of rapid, mechanism-based diagnostic tests are essential. Moving beyond simple susceptibility reporting to identify the specific genetic basis of resistance (e.g., KPC vs. NDM vs. OprD loss) will be crucial to ensure that these highly targeted and valuable agents are deployed only against pathogens they can effectively inhibit.

Third, the success of the imipenem-relebactam combination provides a clear template for future drug development. The ongoing search for new inhibitors that can be paired with the carbapenem backbone to overcome other resistance mechanisms, particularly the formidable challenge of metallo-β-lactamases, will be a key area of research.

Ultimately, the story of imipenem—from its origins as a stabilized natural product to its current form as a component in a sophisticated three-drug combination—is a microcosm of the dynamic and escalating challenge of treating infectious diseases. Its journey underscores the continuous need for innovation, vigilance, and stewardship to maintain our ability to combat the most serious bacterial pathogens.

Works cited

1. Imipenem: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598
2. Imipenem - Wikipedia, accessed August 12, 2025, https://en.wikipedia.org/wiki/Imipenem
3. www.guidetopharmacology.org, accessed August 12, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10821
4. Carbapenem resistance: overview of the problem and future perspectives - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4735501/
5. Imipenem | 64221-86-9 - ChemicalBook, accessed August 12, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5695768.htm
6. Imipenem | C12H17N3O4S | CID 104838 - PubChem, accessed August 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Imipenem
7. CAS No : 64221-86-9 | Chemical Name : Imipenem - Pharmaffiliates, accessed August 12, 2025, https://www.pharmaffiliates.com/en/64221-86-9-imipenem-api-pa090890000.html
8. Imipenem-Cilastatin - LiverTox - NCBI Bookshelf, accessed August 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548708/
9. Imipenem / Cilastatin Formulation - Merck.com, accessed August 12, 2025, https://www.merck.com/docs/product/safety-data-sheets/hh-sds/Imipenem%20and%20Cilastatin%20Formulation_HH_ID_6N.pdf
10. Imipenem, beta-lactam antibiotic (CAS 64221-86-9) | Abcam, accessed August 12, 2025, https://www.abcam.com/en-us/products/biochemicals/imipenem-beta-lactam-antibiotic-ab141030
11. 64221-86-9|(5R,6S)-3-((2-Formimidamidoethyl)thio)-6-((R)-1-hydroxyethyl) - BLDpharm, accessed August 12, 2025, https://www.bldpharm.com/products/64221-86-9.html
12. What is the mechanism of Imipenem? - Patsnap Synapse, accessed August 12, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-imipenem
13. Imipenem/cilastatin - Wikipedia, accessed August 12, 2025, https://en.wikipedia.org/wiki/Imipenem/cilastatin
14. An overview of the pharmacology of imipenem/cilastatin - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/3546249/
15. Comparative review of the carbapenems - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/17488146/
16. Cilastatin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01597
17. Cilastatin, Imipenem Drug Combination | C28H43N5O9S2 | CID 17756656 - PubChem, accessed August 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/imipenem-cilastatin
18. FDA Approves Merck's RECARBRIO™ (imipenem, cilastatin, and relebactam) For the Treatment of Adults with Complicated Urinary Tract and Complicated Intra-Abdominal Bacterial Infections Where Limited or No Alternative Treatment Options Are Available - Merck.com, accessed August 12, 2025, https://www.merck.com/news/fda-approves-mercks-recarbrio-imipenem-cilastatin-and-relebactam-for-the-treatment-of-adults-with-complicated-urinary-tract-and-complicated-intra-abdominal-bacterial-infections-w/
19. FDA Approves Merck's RECARBRIO™ (imipenem, cilastatin, and ..., accessed August 12, 2025, https://www.merck.com/news/fda-approves-mercks-recarbrio-imipenem-cilastatin-and-relebactam-for-the-treatment-of-adults-with-hospital-acquired-and-ventilator-associated-bacterial-pneumonia-habp-vabp/
20. Global Resistance of Imipenem/Relebactam against Gram-Negative Bacilli: Systematic Review and Meta-Analysis - PubMed Central, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10758719/
21. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212819s002lbl.pdf
22. Imipenem: Mechanism of Action, Side Effects and Dosage - Urology Textbook, accessed August 12, 2025, https://www.urology-textbook.com/imipenem.html
23. Primaxin Label - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050587s072,050630s035lbl.pdf
24. What is the mechanism of action of Imipenem (Imipenem-Cilastatin) and Cilastatin? - Dr.Oracle AI, accessed August 12, 2025, https://www.droracle.ai/articles/114985/mechanism-of-imipenem-and-cilastin
25. go.drugbank.com, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598#:~:text=Imipenem%20is%20a%20semisynthetic%20thienamycin,bacteria%2C%20including%20many%20multiresistant%20strains.
26. Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/8741235/
27. Imipenem PDF - Picmonic, accessed August 12, 2025, https://www.picmonic.com/api/v3/picmonics/179/pdf
28. Comparative Review of the Carbapenems - ResearchGate, accessed August 12, 2025, https://www.researchgate.net/publication/6343567_Comparative_Review_of_the_Carbapenems
29. Multiple-dose pharmacokinetics of imipenem-cilastatin | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed August 12, 2025, https://journals.asm.org/doi/10.1128/aac.26.5.715
30. Population pharmacokinetics and dosing optimisation of imipenem in critically ill patients, accessed August 12, 2025, https://ejhp.bmj.com/content/31/5/434
31. Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients - PMC - PubMed Central, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1140495/
32. Pharmacokinetics of imipenem in critically ill patients during empirical treatment of nosocomial pneumonia: a comparison of 0.5-h and 3-h infusions - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/25216543/
33. Imipenem Completed Phase 1 Trials for Bacterial Infections Basic Science - DrugBank, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598/clinical_trials?conditions=DBCOND0027917&phase=1&purpose=basic_science&status=completed
34. Imipenem Completed Phase 2 Trials for Ventilator Associated Bacterial Pneumonia (VABP) / Abdominal Abscess / Bacterial Pneumonia / Pneumonia / Bacterial Infections Treatment - DrugBank, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598/clinical_trials?conditions=DBCOND0031404%2CDBCOND0027917%2CDBCOND0030505%2CDBCOND0014196%2CDBCOND0149717&phase=2&purpose=treatment&status=completed
35. Imipenem Completed Phase 3 Trials for Acute Pancreatitis / Acute Tubulo-Interstitial Nephritis / Complicated Urinary Tract Infection Treatment - DrugBank, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598/clinical_trials?conditions=DBCOND0039135%2CDBCOND0129204%2CDBCOND0040639&phase=3&purpose=treatment&status=completed
36. Imipenem Completed Phase 3 Trials for Urinary Tract Infection Treatment | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598/clinical_trials?conditions=DBCOND0024122&phase=3&purpose=treatment&status=completed
37. Imipenem Completed Phase 3 Trials for Complicated Intra-Abdominal Infections (cIAIs) / Complicated Urinary Tract Infection Treatment | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB01598/clinical_trials?conditions=DBCOND0079243%2CDBCOND0040639&phase=3&purpose=treatment&status=completed
38. PRIMAXIN (imipenem and cilastatin) - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050587s074lbl.pdf
39. Primaxin (imipenem/cilastatin) dosing, indications, interactions ..., accessed August 12, 2025, https://reference.medscape.com/drug/primaxin-imipenem-cilastatin-342562
40. Cilastatin/imipenem Interactions - Drugs.com, accessed August 12, 2025, https://www.drugs.com/drug-interactions/cilastatin-imipenem.html
41. Imipenem/Cilastatin: Side Effects, Uses, Dosage, Interactions ..., accessed August 12, 2025, https://www.rxlist.com/imipenem_cilastatin/generic-drug.htm
42. Imipenem and cilastatin (intravenous route, intramuscular route ..., accessed August 12, 2025, https://www.mayoclinic.org/drugs-supplements/imipenem-and-cilastatin-intravenous-route-intramuscular-route/description/drg-20062005
43. Imipenem/Cilastatin | Davis's Drug Guide for Rehabilitation Professionals, accessed August 12, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139014209
44. Imipenem and Cilastatin Injection: MedlinePlus Drug Information, accessed August 12, 2025, https://medlineplus.gov/druginfo/meds/a686013.html
45. Comparison of the OR for seizures with imipenem (IPM) versus meropenem (MEM). 17,20,21,23,26,29,33 - ResearchGate, accessed August 12, 2025, https://www.researchgate.net/figure/Comparison-of-the-OR-for-seizures-with-imipenem-IPM-versus-meropenem-MEM_fig1_261773013
46. Carbapenem associated seizure in a severe melioidosis patient: A case report - DergiPark, accessed August 12, 2025, https://dergipark.org.tr/en/download/article-file/62296
47. risk of seizures among the carbapenems: a meta-analysis | Journal ..., accessed August 12, 2025, https://academic.oup.com/jac/article/69/8/2043/2911216
48. The risk of seizures among the carbapenems: a meta-analysis - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/24744302/
49. Imipenem; Cilastatin Injection - Cleveland Clinic, accessed August 12, 2025, https://my.clevelandclinic.org/health/drugs/18863-imipenem-cilastatin-injection
50. Carbapenem Resistance: A Review - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5872158/
51. Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace | The Journal of Infectious Diseases | Oxford Academic, accessed August 12, 2025, https://academic.oup.com/jid/article/215/suppl_1/S28/3092084
52. Carbapenem Resistance: A Review - MDPI, accessed August 12, 2025, https://www.mdpi.com/2076-3271/6/1/1
53. A Review of Carbapenem Resistance in Enterobacterales and Its Detection Techniques, accessed August 12, 2025, https://www.mdpi.com/2076-2607/11/6/1491
54. Carbapenem Resistance Mechanisms, Carbapenemase Genes Dissemination , and Laboratory Detection Methods: A Review - International Journal of Pharmaceutical Research and Allied Sciences, accessed August 12, 2025, https://ijpras.com/article/carbapenem-resistance-mechanisms-carbapenemase-genes-dissemination-and-laboratory-detection-metho-tp9a1flxx9koy5t
55. Carbapenem-resistant Gram-negative bacteria (CR-GNB ... - Frontiers, accessed August 12, 2025, https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2024.1376513/full
56. Carbapenem Resistance in Gram-Negative Bacteria: A Hospital-Based Study in Egypt, accessed August 12, 2025, https://www.mdpi.com/1648-9144/59/2/285
57. Epidemiology and Diagnostics of Carbapenem Resistance in Gram ..., accessed August 12, 2025, https://academic.oup.com/cid/article/69/Supplement_7/S521/5624000
58. Carbapenem-Resistant Enterobacterales - StatPearls - NCBI Bookshelf, accessed August 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK551704/
59. Mechanisms of Action of Carbapenem Resistance - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8944602/
60. Complexity of resistance mechanisms to imipenem in intensive care ..., accessed August 12, 2025, https://academic.oup.com/jac/article/68/8/1772/866289
61. Molecular Epidemiology and Mechanisms of Carbapenem Resistance in Pseudomonas aeruginosa | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed August 12, 2025, https://journals.asm.org/doi/10.1128/aac.00574-09
62. Pseudomonas Aeruginosa: Resistance to the Max - Frontiers, accessed August 12, 2025, https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2011.00065/full
63. Imipenem Resistance in Pseudomonas aeruginosa Emergence, Epidemiology, and Impact on Clinical and Economic Outcomes - Cambridge University Press, accessed August 12, 2025, https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/imipenem-resistance-in-pseudomonas-aeruginosa-emergence-epidemiology-and-impact-on-clinical-and-economic-outcomes/DE9907C183A117DADE2F6107BC350A56
64. Emergence of Antibiotic-Resistant Pseudomonas aeruginosa: Comparison of Risks Associated with Different Antipseudomonal Agents - ASM Journals, accessed August 12, 2025, https://journals.asm.org/doi/10.1128/aac.43.6.1379
65. Impact of carbapenem resistance on mortality in patients infected with Enterobacteriaceae: a systematic review and meta-analysis | BMJ Open, accessed August 12, 2025, https://bmjopen.bmj.com/content/11/12/e054971
66. Clinical Impact of Colonization with Carbapenem-Resistant Gram-Negative Bacteria in Critically Ill Patients Admitted for Severe Trauma - MDPI, accessed August 12, 2025, https://www.mdpi.com/2076-0817/11/11/1295
67. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections | Clinical Infectious Diseases | Oxford Academic, accessed August 12, 2025, https://academic.oup.com/cid/article/69/Supplement_7/S565/5623998
68. Application error: a client-side exception has occurred, accessed August 12, 2025, https://www.pharmacytimes.com/view/a-brief-review-of-carbapenems
69. The risk of seizures among the carbapenems: a meta-analysis. - Semantic Scholar, accessed August 12, 2025, https://www.semanticscholar.org/paper/The-risk-of-seizures-among-the-carbapenems%3A-a-Cannon-Lee/db0b91e4ec404505262f4eb89abee5db60fb6466
70. Emerging Drug List - ERTAPENEM, accessed August 12, 2025, https://www.cda-amc.ca/sites/default/files/pdf/108_No25_ertapenem_edrug_e.pdf
71. Efficacy and safety of carbapenems versus new antibiotics for treatment of adult patients with complicated urinary tract infections: A systematic review and meta-analysis - ResearchGate, accessed August 12, 2025, https://www.researchgate.net/publication/346167368_Efficacy_and_safety_of_carbapenems_versus_new_antibiotics_for_treatment_of_adult_patients_with_complicated_urinary_tract_infections_A_systematic_review_and_meta-analysis
72. Efficacy and Safety of Carbapenems vs New Antibiotics for Treatment of Adult Patients With Complicated Urinary Tract Infections: - Oxford Academic, accessed August 12, 2025, https://academic.oup.com/ofid/article-pdf/9/5/ofaa480/43411123/ofaa480.pdf
73. Efficacy and Safety of Carbapenems vs New Antibiotics for Treatment of Adult Patients With Complicated Urinary Tract Infections: A Systematic Review and Meta-analysis - PubMed Central, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9031024/
74. Efficacy and Safety of Carbapenems vs New Antibiotics for Treatment of Adult Patients With Complicated Urinary Tract Infections: A Systematic Review and Meta-analysis - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/35474756/
75. Efficacy and Safety of Carbapenems vs New Antibiotics for Treatment of Adult Patients With Complicated Urinary Tract Infections: A Systematic Review and Meta-analysis | Open Forum Infectious Diseases | Oxford Academic, accessed August 12, 2025, https://academic.oup.com/ofid/article-abstract/9/5/ofaa480/5920690
76. Efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations: Results from phase II and III trials - Frontiers, accessed August 12, 2025, https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.925662/full