Aronem

Uses

The activity of Cilastatin & Imipenem against an unusually broad spectrum of pathogens makes it particularly useful in the treatment of polymicrobic mixed aerobic/anaerobic infections as well as initial therapy prior to the identification of the causative organisms. Cilastatin & Imipenem is used for the treatment of the following infections due to susceptible organisms:

• Intra-abdominal infections
• Lower respiratory tract infections
• Gynaecological infections
• Septicaemia
• Genitourinary tract infections
• Bone and joint infections
• Skin and soft tissue infections
• Endocarditis

Aronem is also used to associated treatment for these conditions: Bloodstream Infections, Bone and Joint Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Endocarditis caused by staphylococcus aureus, Gynaecological infection, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Neutropenic Fever, Pyelonephritis, Skin and Subcutaneous Tissue Bacterial Infections, Surgical Site Infections, Uncomplicated Urinary Tract Infections, Hepatic abscessBloodstream Infections, Bone and Joint Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Infection, Complicated Urinary Tract Infection, Endocarditis caused by staphylococcus aureus, Gynaecological infection, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Pyelonephritis, Skin and Subcutaneous Tissue Bacterial Infections, Uncomplicated Urinary Tract Infections

How Aronem works

Cilastatin is a renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism of imipenem.

Imipenem acts as an antimicrobial through the inhibition of cell wall synthesis of various gram-positive and gram-negative bacteria. This inhibition of cell wall synthesis in gram-negative bateria is attained by binding to penicillin-binding proteins (PBPs). In E. coli and selected strains of P. aeruginosa, imipenem has shown to have the highest affinity to PBP-2, PBP-1a, and PBP-1b. This inhibition of PBPs prevents the bacterial cell from adding to the peptidoglycan polymer which forms the bacterial cell wall eventually leading to cell death.

Dosage

Aronem dosage

The total daily dosage of Imipenem should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogens, renal function and body-weight.

Imipenem & Cilastatin IV: Up to 500 mg dose should be given over 20 to 30 minutes; > 500 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Adult:Normal daily dose is 1-2 g administered in 3-4 divided doses. For the treatment of moderate infection, a 1 g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

• Mild infection: 250 mg 6 hourly (1 gm/day)
• Moderate infection: 500 mg 8 hourly or 1 gm 12 hourly (1.5-2 gm/day)
• Severe infection with fully susceptible microorganism: 500 mg 6 hourly (2gm/day)
• Severe infection with less susceptible organisms (primarily some strains of P. aeruginosa): 1 gm 3-4 times daily (3-4 gm/day)

Paediatric Dosing Schedule:

• ≥ 3 months of age: the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. The maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.
• ≤3 months of age: Following dosage schedule is recommended for non-CNS infections:
• <1 week of age: 25 mg/kg every 12 hrs
• 1-4 weeks of age: 25 mg/kg every 8 hrs
• 4 weeks-3 months of age: 25 mg/kg every 6 hrs.

Imipenem is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used. Imipenem and cilastatin for injection is not recommended in pediatric patients <30 kg with impaired renal function, as no data are available.

Side Effects

Most common side effects with imipenem are nausea and vomiting. Other side effects reported with this drug are diarrhea, rash, thrombophlebitis, thrombocytosis, neutro-penia, eosinophilia and derangements of liver and renal functions. Use of imipenem is not recommended for patient with history of anaphylactic reaction with penicillin.

Toxicity

In case of overdose with the combination product, including relebactam and imipenem, it is recommended to provide supportive care. Imipenem, cilastatin, and relebactam may be removed via hemodialysis.

In case of overdose with the combination product, including relebactam and cilastatin, it is recommended to provide supportive care. Imipenem, cilastatin, and relebactam may be removed via hemodialysis.

Precaution

Caution when used in patients with known hypersensitivity to other β-lactams due to possibility of cross-sensitivity. CNS disorders such as epilepsy; renal, hepatic impairment; pregnancy, lactation.

Interaction

Concurrent admin with probenecid may increase the half-life of cilastatin. Increased risk of generalised seizures when used concurrently with ganciclovir.

Volume of Distribution

Cilastatin has a volume of distribution of 14.6-20.1L.

The reported volume of distribution for imipenem ranges from 0.23-0.31 L/kg.

Elimination Route

Imipenem is not effectively absorbed from the gastrointestinal tract and therefore must be administered parenterally. The bioavailability of the IM injection is 89%.

Half Life

The half-life of cilastatin is approximately 1h.

When given via IV injection imipenem has a half-life of 1 h. The apparent half-life of the IM injection ranges from 1.3-5.1 h, likely due to slower absorption form the injection site.

Clearance

Cilastatin has a total clearance of 0.2 L/h/kg and a renal clearance of 0.10-0.16 L/h/kg.

The total clearance of imipenem is 0.2 L/h/kg. When used alone, the renal clearance is 0.05 L/h/kg. In combination with cilastatin the renal clearance of imipenem is 0.15 L/h/kg, likely due to the increased concentration of the parent drug.

Elimination Route

Cilastatin is reported by official FDA labeling to be 70% excreted in the urine, however published literature has reported values as high as 98%.

Approximately 70% of imipenem is excreted in the urine as the parent drug.

Pregnancy & Breastfeeding use

Pregnancy: Category C. There are no adequate and well controlled studies in pregnant women. Cispenam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: Imipenem has been detected in human milk. If the use of Cispenam is deemed essential, the patient should stop nursing.

Contraindication

Contraindicated in patients who have demonstrated hypersensitivity to this product.

Special Warning

Dosage adjustment in renal impairment:

• CrCl >71: No changes.
• CrCl 41-70: Max 37.5 mg/kg/day or 3 g/day. (Range: 9.4 - 37.5 mg/kg/day) divided q6-8h.
• CrCl 21-40: Max 25 mg/kg/day or 2 g/day. (Range: 6.25 - 25 mg/kg/day) divided q6-12h.
• CrCl 6-20: Max 12.5 mg/kg/day (max dose 1 g/day). Range: 6.25 - 12.5 mg/kg/day) divided q12h. (Usual: 250mg q12h)
• Dialysis Hemodialysis: 125 - 500 mg q12h. (Max 12.5 mg/kg/day). Give dose after dialysis.
• Peritonial Dialysis: 125 - 250 mg q12h

Acute Overdose

In the case of overdosage, discontinue Imipenem/Cilastatin, treat symptomatically, and institute supportive measures as required. Imipenem/Cilastatin Sodium is hemodialyzable.

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