Cilastatin,Imipenem
Overview
The combination of cilastatin and imipenem pairs a broad‑spectrum carbapenem antibiotic (imipenem) with a renal enzyme inhibitor (cilastatin) to prolong the antibacterial activity of imipenem. Imipenem exerts bactericidal action by inhibiting synthesis of bacterial cell walls through binding to penicillin‑binding proteins, leading to disruption of cell integrity and death in susceptible organisms. Cilastatin itself has no intrinsic antibacterial activity but inhibits renal dehydropeptidase‑I, the enzyme responsible for breaking down imipenem in the kidney, thereby increasing systemic exposure and reducing toxic metabolites. This fixed combination is administered parenterally, typically by intravenous infusion, and is important in managing a variety of severe and complicated bacterial infections caused by susceptible aerobic and anaerobic Gram‑positive and Gram‑negative pathogens. Its broad spectrum and enhanced stability against enzymatic degradation make it a cornerstone in hospital‑based treatment of serious infections.
Background and Date of Approval
Imipenem combined with cilastatin was developed to overcome rapid renal degradation of imipenem and to extend its therapeutic effectiveness. The combination was approved for use in the United States by the Food and Drug Administration in 1985, reflecting regulatory assessment of efficacy and safety in severe bacterial infections. The original marketed product was known under the brand name Primaxin, with subsequent generic versions made available. Regulatory approval outside the United States has varied by region and product; nationally authorised medicinal products containing the active substances are listed through European Medicines Agency procedures, but specific EU‑wide approval dates for the basic combination have not been centrally documented in publicly accessible summaries for the parent combination independent of newer triple combinations.
Uses
Cilastatin with imipenem is used for the treatment of a wide range of severe bacterial infections due to susceptible organisms. Standard clinical indications include complicated skin and soft tissue infections, lower respiratory tract infections including pneumonia, complicated intra‑abdominal infections, complicated urinary tract infections including pyelonephritis, bone and joint infections, bacterial septicemia, and endocarditis. Its use is generally restricted to hospitalized patients with serious infections where broad‑spectrum activity is required, and therapy is guided by clinical microbiology and susceptibility patterns.
Administration
The combination is administered by intravenous infusion, typically dosing imipenem and cilastatin together every six to eight hours. Total daily doses and schedule are adjusted based on the severity of infection and patient renal function, with dose reductions necessary for patients with impaired renal clearance to avoid toxicity. Standard regimens historically involve doses in the range of 250 mg to 1000 mg of imipenem with an equivalent amount of cilastatin per dose, administered over a period of five to fourteen days depending on infection type and clinical response. Intramuscular administration is less common and limited by formulation availability. Close monitoring of renal function and clinical response guides treatment duration and dosing adjustments.
Side Effects
Frequently observed side effects with the imipenem and cilastatin combination include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, local reactions at the infusion or injection site such as pain and redness, and the occasional occurrence of skin rash and pruritus. Symptom severity and frequency can vary among patients, and most adverse effects are manageable under attentive medical supervision, with clinical judgment guiding supportive care as needed.
Warnings
Serious adverse reactions associated with this combination include hypersensitivity reactions, including severe allergic responses in patients with a history of beta‑lactam allergy, and central nervous system effects such as seizures, particularly in patients with preexisting CNS disorders or impaired renal function. The drug should be used cautiously or avoided in individuals with known hypersensitivity to carbapenem antibiotics, and clinicians should interrupt therapy if severe toxicity emerges. Clostridium difficile–associated diarrhea, ranging from mild to life‑threatening colitis, may occur with nearly all antibacterial agents, including this combination.
Precautions
Baseline assessments prior to initiating therapy include renal function evaluation to determine appropriate dosing and monitoring requirements. Caution is warranted in patients with renal impairment, a history of seizures, or allergic reactions to beta‑lactam antibiotics. Drug interactions of clinical significance include potential increases in seizure risk when co‑administered with valproic acid or divalproex sodium. As a biologically driven antibiotic combination, classical metabolic drug interactions are less common, but monitoring for additive neurotoxicity or gastrointestinal disturbances is prudent. Vaccines and other live bacterial vaccines may have altered efficacy during antibiotic therapy, and coordination with immunization schedules should consider clinical context.
Expert Tips
Patient selection for this combination should focus on individuals with confirmed or strongly suspected severe bacterial infections where broad‑spectrum coverage is clinically justified. Baseline renal function and neurological status should be assessed before initiating therapy, with dose adjustments guided by creatinine clearance. Counsel patients and caregivers on expected administration routes and potential side effects, emphasizing the importance of reporting severe diarrhea or neurologic symptoms promptly. During infusion, monitor for infusion‑related reactions and coordinate with combination therapies based on antimicrobial stewardship principles, tailoring coverage as susceptibility results become available. In hospitalized settings, multidisciplinary coordination with microbiology and pharmacy teams enhances appropriate usage and minimises resistance development.