Imipenem/ cilastatin contains imipenem, a broad spectrum antibiotic ( belongs to the carbapenems group ) that inhibits cell wall synthesis. Cilastatin inhibits the renal metabolism of imipenem.

Imipenem and cilastatin are used to treat the following infections:

• Bacterial septicemia:
  • It is used to treat patients with septicemia caused by:
    • Enterococcus faecalis,
    • penicillnase-producing Staphylococcus aureus,
    • Escherichia coli,
    • Klebsiella species,
    • Pseudomonas aeruginosa,
    • Serratia species,
    • Enterobacter species,
    • Bacteroides species including Bacteroides fragilis.
• Bone and joint infections:
  • It is used to treat patients with bones and joint infections caused by:
    • E. faecalis,
    • penicillinase-producing S. aureus,
    • Staphylococcus epidermidis,
    • Enterobacter species,
    • P. aeruginosa.
• Endocarditis:
  • Treatment of endocarditis caused by penicillinase-producing S. aureus.
• Gynecologic infections:
  • Treatment of gynecologic infections caused by
    • E. faecalis
    • Penicillinase-producing S. aureus
    • S. epidermidis
    • Streptococcus agalactiae (group B streptococci),
    • E. coli,
    • Klebsiella species,
    • Proteus species,
    • Enterobacter species,
    • Bifidobacterium species,
    • Bacteroides species (including B. fragilis),
    • Gardnerella vaginalis;
    • Peptococcus species,
    • Peptostreptococcus species,
    • Cutibacterium species.
• Intra-abdominal infections:
  • Treatment of intra-abdominal infections caused by:
    • E. faecalis,
    • Penicillinase-producing S. aureus,
    • S. epidermidis,
    • E. coli,
    • Klebsiella species,
    • Enterobacter species,
    • Proteus species,
    • Morganella morganii,
    • P. aeruginosa,
    • Citrobacter species,
    • Clostridium species,
    • Bacteroides species (including B. fragilis),
    • Fusobacterium species,
    • Peptococcus species,
    • Peptostreptococcus species,
    • Eubacterium species,
    • Cutibacterium species,
    • Bifidobacterium species.
• Lower respiratory tract infections:
  • Treatment of lower respiratory tract infections caused by:
  • Penicillinase-producing S. aureus
  • E. coli,
  • Klebsiella species,
  • Enterobacter species,
  • Haemophilus influenzae,
  • Haemophilus parainfluenzae,
  • Acinetobacter species,
  • Serratia marcescens.
• Skin and skin structure infections:
  • Treatment of skin and skin structure infections caused by:
    • E. faecalis,
    • Penicillinase-producing S. aureus,
    • S. epidermidis,
    • E. coli,
    • Klebsiella species,
    • Enterobacter species,
    • Proteus vulgaris,
    • Providencia rettgeri,
    • M. morganii,
    • P. aeruginosa,
    • Serratia species,
    • Citrobacter species,
    • Acinetobacter species,
    • Bacteroides species (including B. fragilis),
    • Fusobacterium species,
    • Peptococcus species,
    • Peptostreptococcus species.
• Complicated and uncomplicated Urinary tract infections:
  • Treatment of uncomplicated and complicated urinary tract infections caused by:
    • E. faecalis,
    • Penicillinase-producing S. aureus
    • E. coli,
    • Klebsiella species,
    • Enterobacter species,
    • P. vulgaris,
    • Providencia rettgeri,
    • M. morganii,
    • P. aeruginosa.

Off-Label Use in Adults:

• • Burkholderia pseudomallei (melioidosis);
  • Neutropenic fever;
  • Nontuberculous mycobacterial disease;
  • Skin and soft tissue necrotizing infections;
  • Surgical-site infection

Note:

• Imipenem is not indicated in patients with meningitis (safety and efficacy have not been established).
• It is also not recommended in pediatric patients with CNS infections because of the risk of seizures.

Imipenem/ cilastatin Dose in Adults

Note: The doses mentioned here are based on imipenem content.

The Usual intravenous dosage range:

• Susceptible bacterial organisms:
  • 500 mg every 6 hours or 1,000 mg every 8 hours
  • The maximum dose is 4,000 mg/day.
• Intermediate susceptibility bacterial organisms:
  • 1,000 mg every 6 hours
  • 4,000 mg/day is maximum dose

Dosing based on specific indications:

• Off label use in melioidosis Burkholderia pseudomallei:
  • Up to 25 mg/kg (up to 1 g) every 6 hours for at least 10 days, administered at a rate of 20 mg/kg every 8 hours.
  • Parenteral therapy should be continued until clinical improvement.

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• Complicated Intra-abdominal infections:
  • For 4 to 7 days, take 500 mg every 6 hours or 1 g every 8 hours.

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• Off-label use in Neutropenic fever:
  • 500 mg every 6 hours

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• Off-label use in Nontuberculous mycobacterial disease (M. abscessus skin, soft tissue, or bone infections)
  • 500 mg intravenously every 6 to 12 hours, along with additional antibiotics.

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• Off-label dose in hospital-acquired or ventilator-associated Pneumonia:
  • 500 mg intravenous every 6 hours for 7 days. The duration may be shortened or prolonged depending on the clinical status of the patient.

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• Off-label use in Skin and soft tissue necrotizing infections:
  • 1 gm intravenous every 6 to 8 hours (in combination with an agent effective against MRSA for empiric therapy of polymicrobial [mixed] infections. Continue until the patient is afebrile for 48 to 72 hours, has clinically improved and does not need any further debridement

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• Off-label use in intestinal or genitourinary tract surgery Surgical-site infection:
  • 500 mg intravenous every 6 hours

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• Complicated Urinary tract infection including pyelonephritis:
  • every six hours intravenously for ten to fourteen days, 500 mg

Note: Patients who are critically unwell or who have risk factors for multidrug-resistant (MDR) pathogens, such as extended-spectrum beta-lactamase (ESBL)-producing organisms, should only receive imipenem.

Imipenem/ cilastatin Dose in Children

Note: The component of imipenem is the basis for dosage recommendations.

General dosing in severe infections for susceptible infections:

• Infants, Children, and Adolescents:
  • A maximum daily dose of 4 gms/day, or 60 to 100 mg/kg/day divided every 6 hours, is recommended.

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Imipenem/cilastatin dosing based on the susceptible organisms

• Melioidosis of Burkholderia pseudomallei:
  • Infants, Children, and Adolescents:
    • For at least 10 days, administer 60 to 100 mg/kg/day intravenously divided every 6 to 8 hours, up to a maximum daily dose of 4 g/day.
    • Therapy should be continued until clinical improvement after which oral therapy may be started.

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• Empiric therapy of Febrile neutropenia:
  • Children and Adolescents:
    • IV: The maximum daily dose should not exceed 4 gms/day, or 60 mg/kg/day intravenously divided every 6 hours.

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• Complicated Intra-abdominal infection:
  • Infants, Children, and Adolescents:
    • IV: A maximum dose of 500 mg/dose, split between doses of 60 to 100 mg/kg/day every 6 hours. .

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• Non-tuberculosis mycobacterium in patients with cystic fibrosis:
  • Infants, Children, and Adolescents:
    • maximum dose of 1 gm/dose, administered intravenously every 12 hours at 15 to 20 mg/kg/dose.

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• Peritoneal dialysis of Peritonitis:
  • Infants, Children, and Adolescents:
    • A Loading dose of 250 mg per liter of dialysate.
    • Maintenance dose of 50 mg per liter.

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• Pulmonary exacerbation in cystic fibrosis:
  • Infants, Children, and Adolescents:
    • A maximum daily dose of 4 grammes per day (100 mg/kg/day intravenously divided every 6 hours) is allowed.

Pregnancy Risk Factor C

• Imipenem crosses the placenta and may be used in pregnancy if other alternative agents are not available.

Use of imipenem or cilastatin during breastfeeding

• Imipenem can be found in breast milk, but it is not recommended for lactating women. 
• If there are no other agents, it may be used. Before initiating treatment, it is important to weigh the risks and benefits of imipenem for the mother as well as the benefits to infants. 
• The risks of imipenem inhalation are low because oral bioavailability can be very low.

Imipenem/ cilastatin Dose in Kidney Disease:

For calculating renal dosage, the Cockroft-gault formula should be used.

Dose adjustment in patients requiring 500 mg every 6 hours:

• patient with CrCl of more than 90 mL/minute: No dose adjustment is required
• patient with CrCl 60 to 90 mL/minute: 400 mg every 6 hours
• patient with CrCl 30 to 60 mL/minute: 300 mg every 6 hours
• patient with CrCl 15 to 30 mL/minute: 200 mg every 6 hours
• CrCl <15 mL/minute: Don't administer imipenem and cilastatin unless the patient is hemodialysed within 48 hours

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Patients requiring imipenem dose of 1,000 mg every 8 hours:

• patient with CrCl ≥90 mL/minute: No dose adjustment is required
• patient with CrCl 60 to 90 mL/minute: 500 mg every 6 hours
• patient with CrCl 30 to 60 mL/minute: 500 mg every 8 hours
• patient with CrCl 15 to 30 mL/minute: 500 mg every 12 hours
• CrCl <15 mL/minute: Don't administer imipenem and cilastatin unless the patient is hemodialysed within 48 hours

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Patients requiring imipenem dose of 1,000 mg every 6 hours:

• patient with CrCl ≥90 mL/minute: No dose adjustment is required
• patient with CrCl 60 to 90 mL/minute: 750 mg every 8 hours
• patient with CrCl 30 to 60 mL/minute: 500 mg every 6 hours
• patient with CrCl 15 to 30 mL/minute: 500 mg every 12 hours
• CrCl <15 mL/minute: Don't administer imipenem and cilastatin unless the patient is hemodialysed within 48 hours

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Alternative dosing (Canadian labeling):

Adjust the dose based on the creatinine clearance (mL/minute/1.73 m ) and body weight of more than 70 kgs:

• CrCl 31 to 70 mL/minute/1.73 m2 (mild renal impairment):
  • The maximum dose is 500 mg every 8 hours for fully susceptible organisms.
  • The maximum dose is 500 mg every 6 hours for less susceptible organisms (pseudomonas)
• CrCl 21 to 30 mL/minute/1.73 m2 (moderate renal impairment):
  • The maximum dose is 500 mg every 12 hours for fully susceptible organisms.
  • The maximum dose is 500 mg every 8 hours for less susceptible organisms (pseudomonas)
• CrCl 0 to 20 mL/minute/1.73 m2 (severe renal impairment):
  • The maximum dose is 250 mg every 12 hours for fully susceptible organisms.
  • The maximum dose is 500 mg every 12 hours for less susceptible organisms (pseudomonas)
• Patients with End-stage renal disease (ESRD) on intermittent (thrice weekly) hemodialysis (IHD):
  • Administer dose after dialysis session and at intervals timed from the end of that dialysis session or 250 to 500 mg every 12 hours.
• Continuous renal replacement therapy (CRRT):
  • CVVH:
    • A loading dose of 1 gm followed by either 250 mg four times a day or
    • 500 mg every thrice daily
  • CVVHD:
    • A Loading dose of 1 gm followed by either 250 mg four times a day or
    • 500 mg every 6 to 8 hours
  • CVVHDF:
    • A Loading dose of 1 gm followed by either 250 mg four times a day or
    • 500 mg four times a day

Note:

• Higher doses like 500 mg every 8 to 12 hours may provide sufficient time above MIC to cover organisms with MIC values less than 2 mg/L.
• A higher dose of 500 mg every 6 hours is recommended for resistant organisms (particularly Pseudomonas spp) with MIC of more than 4 mg/L or deep-seated infections

Imipenem/ cilastatin Dose in Liver Disease:

The manufacturer has not recommended any dose adjustment in patients with liver disease.

Common Side Effects of imipenem/cilastatin:

• Hematologic & oncologic:
  • Decreased hematocrit
  • Decreased hemoglobin
  • Eosinophilia
  • Thrombocythemia
• Hepatic:
  • Increased serum AST & ALT

Less Common Side Effects of imipenem/ cilastatin:

• Cardiovascular:
  • Phlebitis
  • Tachycardia
• Central nervous system:
  • Seizure
• Dermatologic:
  • Skin rash
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Oral candidiasis
  • Vomiting
• Genitourinary:
  • Proteinuria
  • Urine discoloration
  • Oliguria
• Hematologic & oncologic:
  • Neutropenia
  • Decreased platelet count
  • Increased hematocrit
• Hepatic:
  • Increased serum alkaline phosphatase
  • Increased serum bilirubin
• Local:
  • Irritation at the injection site
• Renal:
  • Increased serum creatinine

Contraindications to Imipenem/ cilastatin include:

• Allergy or sensitivity to imipenem/cilastatin, or any component of this formulation
• Patients who are allergic to other carbapenems.PenicillinCephalosporins and cephalosporins can be used with caution, as cross-sensitivity is not common.

Warnings and Precautions

• Neurological effects
  • Neurological adverse effects have been reported from imipenem and carbapenems, including confusional states and myoclonic seizures.
  • Patients suffering from neurological diseases such as epilepsy or brain tumors should be cautious about taking the drug.
  • Due to the possibility of medication accumulation, patients with kidney disease are more likely to experience neurological side effects.
• Hypersensitivity reactions
  • Sometimes, severe hypersensitivity and anaphylactic reactions can occur which may lead to death.
• Superinfection
  • Long-term use of imipenem for more than two months may lead to fungal or bacterial overinfections, such as C. difficile-associated diarrhea(CDAD) or pseudomembranous collitis.
• Renal impairment
  • Patients with severe renal impairment may experience serious neurological adverse drug reactions if they accumulate the drug.
  • Patients with a GFR below 15 ml/min are not advised to use this medication.
  • Patients on hemodialysis might be advised to use the drug with caution.

Imipenem and cilastatin: Drug Interaction

Monitoring Parameters:

Monitor for signs of anaphylaxis during first dose

• Periodically monitor CBS, renal, and liver function tests.

​​​​​​​How to administer Imipenem and cilastatin?

• Imipenem should be administered as an intravenous infusion.
• It should not be given as an intravenous push.
• Doses less the 500 mg should be infused over 20 to 30 minutes.
• Doses more than 500 mg should be infused over 40 to 60 minutes.
• If the patient starts to feel queasy or sick, the rate of the infusion should be reduced.

Mechanism Of Action Of Imipenem/ cilastatin:

• Imipenem binds to one of the PBPs to prevent the development of bacterial cell walls (penicillin binding proteins).
• The lysis is produced by the autolytic enzymes.
• The dehydropeptidase at the renal tubule boundary is inhibited by cilostatin, which stops imipenem from being metabolised in the kidneys.

Imipenem is 20% Protein bound while cilastatin is 40% bound to protein. Imipenem is metabolized in the kidneys by dehydropeptidase I, the enzyme which is inhibited by cilastatin, thus prolonging its half-life. Half-life elimination ranges from 1 hour to 1.2 and 2.4 hours in adults, children, and neonates respectively, and is prolonged in patients with  renal impairment: It is primarily excreted via urine (70% as unchanged drug).

International Brands of Imipenem/ cilastatin

• Amanam
• Anipen
• Arzobema
• Bacquire
• Bacqure
• Bidinam
• Bionam
• Cilanem
• Cilapenem
• Cispenam
• Imcitin
• Imenam
• Imicila
• Alvogen
• Imiclast
• Iminem
• Iminen
• Imipen
• Imivex
• Inem
• Minem
• Nemcis
• Nimedine
• Pelascap
• Pelastin IV
• Penam
• Premax
• Prepenem
• Primax
• Primaxin
• Sianem
• Supernem
• Supranem
• Tenacid
• Tienam
• Tiesilan
• Timipen
• Tipem
• Vexpinem
• Xerxes
• Zienam

Imipenem/ cilastatin Brands in Pakistan: