Imipenem + Cilastatin

Intravenous
Bacterial endocarditis, Bacterial septicaemia, Bone and joint infections, Complicated urinary tract infections, Gynaecological infections, Intra-abdominal infections, Lower respiratory tract infections, Skin and soft tissue infections, Uncomplicated urinary tract infections

Patients with CrCl <15 mL/min who are undergoing haemodialysis (only if dialysis is initiated within 48 hours): 200 mg 6 hourly or 500 mg 12 hourly.

CrCl (mL/min)	Dosage
≥15-<30	200 mg 6 hourly or 500 mg 12 hourly.
≥30-<60	300 mg 6 hourly or 500 mg 6 or 8 hourly.
≥60-<90	400 mg or 500 mg 6 hourly, or 750 mg 8 hourly.

Doses are given after haemodialysis session. Dosage is expressed in terms of imipenem and individualised based on the type and severity of infection, and the degree of pathogen susceptibility (refer to detailed product guideline).

Reconstitute vial with approx 10 mL of compatible diluent (e.g. NaCl 0.9%, dextrose 5% in water, dextrose 5% in water with NaCl 0.9%, dextrose 5% in water with NaCl 0.225% or NaCl 0.45%). Further dilute with a compatible infusion solution to a final concentration of not exceeding 5 mg/mL. May repeat the process of reconstitution with another 10 mL of compatible diluent to ensure a complete transfer of contents to the infusion solution.

Lactate, and other antibiotics.

Hypersensitivity to imipenem, cilastatin, or to any other carbapenems; severe hypersensitivity to other β-lactam antibiotics (e.g. penicillins or cephalosporins).

Patient with CNS disorders (e.g. brain lesions or history of seizures), myasthenia gravis, history of colitis, or those who experienced diarrhoea after antibiotic use. Not recommended for children weighing <30 kg with renal impairment, or with CNS infections. Renal and hepatic impairment. Neonates, and children. Pregnancy and lactation.

Significant: CNS effects (e.g. seizures, myoclonic activity, hallucinations, confusional states). Rarely, aggravation of myasthenia gravis.
Blood and lymphatic system disorders: Eosinophilia, pancytopenia, neutropenia including agranulocytosis, leucopenia, thrombocytopenia, thrombocytosis. Rarely, haemolytic anaemia, bone marrow depression.
Cardiac disorders: Hypotension. Rarely, tachycardia or palpitations.
Ear and labyrinth disorders: Hearing loss, tinnitus.
Eye disorders: Ocular myasthenia.
Gastrointestinal disorders: Diarrhoea, vomiting, nausea, staining of teeth and/or tongue, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, increased salivation, taste perversion.
General disorders and administration site conditions: Fever, injection site reaction (e.g. pain, induration, erythema).
Hepatobiliary disorders: Rarely, hepatic failure, hepatitis, fulminant hepatitis.
Investigations: Increased serum AST, serum ALT, serum LDH, serum alkaline phosphatase, serum bilirubin, serum creatinine, and BUN; decreased haemoglobin, prolonged prothrombin time.
Nervous system disorders: Dizziness, somnolence, headache, agitation, vertigo, dyskinesia, paresthesia, encephalopathy.
Renal and urinary disorders: Oliguria, anuria, polyuria.
Respiratory, thoracic, and mediastinal disorders: Dyspnoea, hyperventilation.
Skin and subcutaneous tissue disorders: Rash, urticaria, pruritus, angioedema, erythema multiforme, pruritus vulvae, flushing, hyperhidrosis.
Vascular disorders: Thrombophlebitis.
Potentially Fatal: Serious hypersensitivity/anaphylactic reactions; Clostridioides difficile-associated diarrhoea (CDAD), pseudomembranous colitis.

Parenteral: C

This drug may cause dizziness or sleepiness, if affected, do not drive, or operate machinery.

Perform culture and susceptibility tests prior to treatment initiation; consult local institutional recommendations before treatment initiation due to antibiotic resistance risks. Monitor LFT, renal and haematologic function tests. Assess for signs and symptoms of anaphylaxis during 1st dose.

May induce generalised seizures with ganciclovir. Increased plasma levels and half-life with probenecid. May increase anticoagulant effect of warfarin.
Imipenem: May decrease the serum concentration of valproic acid which can lead to inadequate seizure control.

May result to positive direct Coombs' test. Interferes with urinary glucose determinations using Clinitest®.

Description:
Mechanism of Action: Imipenem is a broad-spectrum carbapenem β-lactam antibiotic and a semisynthetic derivative of thienamycin. It inhibits the bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins (PBPs), thereby blocking the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls resulting in cell wall assembly arrest and eventually bacterial cell lysis. Imipenem is susceptible to degradation by dehydropeptidase I (DHP-I), an enzyme in the brush border of the proximal renal tubules.
Cilastatin is a competitive, reversible, and specific inhibitor of DHP-I. When given concomitantly, it prevents the renal metabolism of imipenem into its inactive and potentially nephrotoxic metabolites. It has no clinically significant antibacterial activity nor affects the antibacterial effect of imipenem.
Pharmacokinetics:
Distribution: Crosses the placenta, enters breast milk (small amounts).
Imipenem: Widely distributed in body tissues and fluids. Plasma protein binding: Approx 20%.
Cilastatin: Plasma protein binding: Approx 40%.
Metabolism: Partially metabolised in the kidneys by DHP-I into inactive and nephrotoxic metabolites. Also metabolised to some extent via nonspecific hydrolysis of the β-lactam ring by a nonrenal mechanism unrelated to DHP-I.
Cilastatin: Partially metabolised in the kidneys to N-acetylcilastatin.
Excretion: Elimination half-life: Approx 60 minutes.
Imipenem: Mainly via urine (approx 70% as unchanged drug); faeces (<1%).
Cilastatin: Mainly via urine (approx 70% as unchanged drug, approx 12% as N-acetyl metabolite); faeces (<2%).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 104838, Imipenem. https://pubchem.ncbi.nlm.nih.gov/compound/Imipenem. Accessed Oct. 26, 2023.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 6435415, Cilastatin. https://pubchem.ncbi.nlm.nih.gov/compound/Cilastatin. Accessed Oct. 26, 2023.

Intact vial: Store below 25°C. Reconstituted solutions: Store at 25°C for 4 hours or at 5°C for 24 hours. Do not freeze.

Other Beta-Lactams

J01DH51 - imipenem and cilastatin ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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Anon. Imipenem and Cilastatin Sodium. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 17/07/2023.

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Douglas Pharmaceuticals Ltd. Imipenem + Cilastatin RBX 500 mg/500 mg Powder for Solution for Infusion data Sheet 30 September 2021. Medsafe. http://www.medsafe.govt.nz. Accessed 17/07/2023.

Imipenem and Cilastatin (Pediatric and Neonatal Lexi-Drugs). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 27/09/2023.

Imipenem and Cilastatin Sodium, MSD IV Infusion (Merck Sharp & Dohme [Malaysia] Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 17/07/2023.

Imipenem/Cilastatin 500 mg/500 mg Powder for Solution for Infusion (Accord Healthcare Limited). MHRA. https://products.mhra.gov.uk. Accessed 17/07/2023.

Imipenem; Cilastatin. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 28/09/2023.

Joint Formulary Committee. Imipenem with Cilastatin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 17/07/2023.

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Primaxin IV Injection, Powder, for Solution (Merck Sharp & Dohme LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 17/07/2023.