Imipenem + cilastatin

Intravenous
Uncomplicated urinary tract infections, Bacterial septicaemia, Gynaecological infections, Complicated urinary tract infections, Bacterial endocarditis, Bone and joint infections, Skin and soft tissue infections, Lower respiratory tract infections, Intra-abdominal infections
Adult: Imipenem 250 mg and cilastatin 250 mg powder for solution for infusion Imipenem 500 mg and cilastatin 500 mg powder for solution for infusion 500 mg 6 hourly or 1,000 mg 6-8 hourly. Max: 4,000 mg daily. 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). All doses are given via infusion over 20-30 minutes for doses ≤500 mg; over 40-60 minutes for doses >500 mg. The rate of infusion may be reduced in patients who experience nausea during the infusion.
Child: Imipenem 250 mg and cilastatin 250 mg powder for solution for infusion Imipenem 500 mg and cilastatin 500 mg powder for solution for infusion Recommended doses for non-CNS infections: ≥3 months 15-25 mg/kg 6 hourly. Max: 4,000 mg daily. 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). All doses are given via infusion over 20-30 minutes for doses ≤500 mg; over 40-60 minutes for doses >500 mg. The rate of infusion may be reduced for patients who experience nausea during the infusion.
Renal impairment: Patients with CrCl <15 mL/min who are undergoing haemodialysis (only if dialysis is instituted within 48 hours): 200 mg 6 hourly or 500 mg 12 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).

CrCl (ml/min)	Dosage Recommendation
≥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.

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

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.

May induce generalised seizures with ganciclovir. Increased plasma levels and half-life with probenecid. May decrease serum concentration of valproic acid below therapeutic range. 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<207>®<190.

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.
Absorption:
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: Imipenem: 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-N-acetyl metabolite); faeces (<2%).

Intravenous: 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