Imipenem Cilastatin (Tienam) is a broad-spectrum antibiotic of the carbapenem class of β-lactams. It is used in the treatment of serious hospital-acquired infections that are resistant to first-line antibiotics like penicillins, macrolides, and other narrow-spectrum antibiotics. Imipenem Cilastatin is also available as a triple combination with relebactam as Recarbrio. The triple combination has a 128 fold reduced MIC compared to the dual combination.

Imipenem Cilastatin Uses:

• Bacterial septicemia:

  • It is used in the treatment of septicemia caused by:
    • Enterococcus faecalis,
    • Staphylococcus aureus (penicillinase-producing),
    • Escherichia coli,
    • Klebsiella species,
    • Pseudomonas aeruginosa,
    • Serratia species,
    • Enterobacter species, and
    • Bacteroides species including Bacteroides fragilis.

• Bone and joint infections:

  • it is also used in the treatment of bone and joint infections caused by:
    • E. faecalis,
    • S. aureus which produces penicillinase,
    • Staphylococcus epidermidis,
    • Enterobacter species, and
    • P. aeruginosa.

• Endocarditis:

  • It is used in the management of endocarditis caused by S. aureus which produces penicillinase.

• Gynecologic infections:

  • It is also used in treatment of gynecologic infections caused by:
    • E. faecalis,
    • S. aureus (penicillinase-producing),
    • 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, and
    • Cutibacterium species.

• Intra-abdominal infections:

  • it is used in regimens treatment for intra-abdominal infections caused by:
    • E. faecalis,
    • S. aureus (penicillinase-producing),
    • 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, and
    • Bifidobacterium species.

• Lower respiratory tract infections:

  • It is also used in the treatment of lower respiratory tract infections caused by:
    • S. aureus which produces penicillinase,
    • E. coli, Klebsiella species,
    • Enterobacter species,
    • Haemophilus influenzae,
    • Haemophilus parainfluenzae,
    • Acinetobacter species, and
    • Serratia marcescens.

• Skin and skin structure infections:

  • It can also be used in the management of  skin and skin structure infections caused by:
    • E. faecalis,
    • S. aureus (penicillinase-producing),
    • 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, and
    • Peptostreptococcus species.

• Complicated and uncomplicated urinary tract infections:

  • It is used to treat uncomplicated and complicated urinary tract infections caused by:
    • E. faecalis,
    • S. aureus (penicillinase-producing),
    • E. coli,
    • Klebsiella species,
    • Enterobacter species,
    • P. vulgaris,
    • Providencia rettgeri,
    • M. morganii, and
    • P. aeruginosa.
  • However, there is some limitation to its use. It is not indicated in patients with meningitis because safety and efficacy have not yet been established.
  • It is not recommended in pediatric patients with CNS infections because of the risk of seizures.

• Off Label Use of Imipenem and cilastatin in Adults:

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

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Imipenem Cilastatin (Tienam) Dose in Adults:

Imipenem Cilastatin (Tienam) Usual dosage range: IV:

• Susceptible bacterial species:

  • 500 mg every 6 hours or 1,000 mg every 8 hours with a maximum dose of 4,000 mg/day.

• Intermediate susceptibility bacterial species:

  • 1,000 mg every 6 hours with a maximum dose of 4,000 mg/day.

Indication-specific dosing:

Imipenem Cilastatin (Tienam) Dose in the treatment of Burkholderia pseudomallei (melioidosis) (off-label):

• It is initially given intravenously as 20 mg/kg every 8 hours for at least 10 days or 25 mg/kg (up to 1 g) every 6 hours for at least 10 days.
• The parenteral therapy is given until clinical improvement is observed then switched to oral therapy if tolerated and appropriate.
• Additional data may be necessary to further define the role of imipenem/cilastatin in such conditions.

Imipenem Cilastatin (Tienam) Dose in the treatment of complicated Intra-abdominal infections:

• It is given intravenously as 500 mg every 6 hours or 1 g every 8 hours for 4 to 7 days provided the source of contamination is being removed.
• It is noteworthy that it is not recommended for mild to moderate, and community-acquired intra-abdominal infections due to the risk of toxicity and the development of resistant organisms.

Imipenem Cilastatin (Tienam) Dose in the treatment of Neutropenic fever (off-label):

• IV: 500 mg every 6 hours.

Imipenem Cilastatin (Tienam) Dose in the treatment of Nontuberculous mycobacterial disease (off-label):

• IV: It can also be given in M. abscessus skin, soft tissue, or bone infections as 500 mg every 6 to 12 hours. And is used in combination with other antibacterial agents.

Imipenem Cilastatin (Tienam) Dose in the treatment of hospital-acquired or ventilator-associated pneumonia (off-label dose):

• IV: 500 mg every 6 hours for 7 days.
• The duration of therapy is dependent on clinical improvement. When used as empirical therapy, it is given in combination with an agent active against MRSA (unless coverage of MSSA only is appropriate) with or without an additional antipseudomonal agent which is dependent on patient and institution-specific risk factors.
• It should be noted that a reduction in a dose can be indicated to prevent seizures.

Imipenem Cilastatin (Tienam) Dose in the treatment of Skin and soft tissue necrotizing infections (off-label):

• IV: it is given as 1 g every 6 to 8 hours in combination with an agent effective against MRSA like vancomycin, linezolid, and daptomycin for empirical therapy of polymicrobial infections.
• The regimen is continued until further debridement is not necessary, the patient has clinically improved, and the patient is afebrile for 48 to 72 hours.

Imipenem Cilastatin (Tienam) Dose in the treatment of Surgical-site infection (intestinal or genitourinary tract surgery) (off-label):

• IV: 500 mg every 6 hours.

Imipenem Cilastatin (Tienam) Dose in the treatment of complicated urinary tract infection (including pyelonephritis):

• IV: It is administered as 500 mg every 6 hours for 10 to 14 days.
• When it is used for empirical therapy, then give it alone or in combination with other appropriate agents.
• It is reserved for critically ill patients or patients with risk factors for multidrug-resistant (MDR) pathogens, including extended-spectrum beta-lactamase (ESBL)–producing organisms.

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Imipenem Cilastatin (Tienam) Dose in Childrens:

Note: Dosage recommendations are based on the imipenem component.

Imipenem Cilastatin (Tienam) General dosing Guidelines in severe susceptible infections:

• Infants, Children, and Adolescents:

  • IV: 60 to 100 mg/kg/day divided every 6 hours with a maximum daily dose of 4,000 mg/day

Imipenem Cilastatin (Tienam) Dose in the treatment of Burkholderia pseudomallei (melioidosis):

• Infants, Children, and Adolescents:

  • IV: Initially it is administered as 60 to 100 mg/kg/day divided every 6 to 8 hours for at least 10 days with a maximum daily dose of 4,000 mg/day.
  • Parenteral therapy should be continued until clinical improvement, then switch to oral therapy if tolerated or appropriate.

Imipenem Cilastatin (Tienam) Dose in the treatment of Febrile neutropenia as empiric therapy: Limited data available:

• Children and Adolescents:

  • IV: 60 mg/kg/day divided every 6 hours.
  • Some centers use doses as high as 100 mg/kg/day.
  • The maximum daily dose is 4,000 mg/day

Imipenem Cilastatin (Tienam) Dose in the treatment of complicated Intra-abdominal infection:

• Infants, Children, and Adolescents:

  • IV: 60 to 100 mg/kg/day divided every 6 hours with a maximum dose up to 500 mg.

Imipenem Cilastatin (Tienam) Dose in the treatment of Non-tuberculosis mycobacterium in patients with cystic fibrosis:

• Infants, Children, and Adolescents:

  • IV: it is given as 15 to 20 mg/kg/dose every 12 hours with maximum dose up to 1,000 mg/dose.

Imipenem Cilastatin (Tienam) Dose in the treatment of Peritonitis (peritoneal dialysis):

• Infants, Children, and Adolescents:

  • Intraperitoneal: It is given as a continuous loading dose of 250 mg per liter of dialysate and the maintenance dose is 50 mg per liter.

Imipenem Cilastatin (Tienam) Dose in the treatment of Pulmonary exacerbation in patients with cystic fibrosis:

• Infants, Children, and Adolescents:

  • IV: 100 mg/kg/day divided every 6 hours with a maximum daily dose of 4,000 mg/day.
  • The efficacy can be limited due to the rapid development of resistance.

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Imipenem Cilastatin Pregnancy Category: C

• Cilastatin and imipenem can easily cross the placenta.
• Some pharmacokinetic parameters for imipenem/cilastatin have been altered by pregnancy-induced physiological changes
• Cystic fibrosis is not something that Imipenem should be used for in pregnant women. It can be used if a safer alternative is unavailable.

Use of imipenem or cilastatin during breastfeeding

• Breast milk contains imipenem.
• According to literature, when deciding whether to breastfeed during therapy, one should consider the risks to infants, the benefits to the mother, and the benefits to the mother.
• Cystic fibrosis is a condition that affects lactating women and imipenem should not be used. However, it may be used if there is no alternative.
• Poor oral bioavailability means that breastfeeding infants will be exposed to less.

 

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Imipenem Cilastatin (Tienam) Dose in Kidney Disease:

• US labeling (estimation of renal function for the purpose of dosing adjustment should be done using the Cockcroft-Gault formula):

  • The usual dosing regimen of 500 mg every 6 hours:

    • CrCl ≥90 mL/minute:
      • No dosage adjustment is necessary.
    • CrCl ≥60 to <90 mL/minute:
      • 400 mg every 6 hours
    • CrCl ≥30 to <60 mL/minute:
      • 300 mg every 6 hours
    • CrCl ≥15 to <30 mL/minute:
      • 200 mg every 6 hours
    • CrCl <15 mL/minute:
      • Do not administer imipenem and cilastatin unless hemodialysis is instituted within 48 hours.

  • The usual dosing regimen of 1,000 mg every 8 hours:

    • CrCl ≥90 mL/minute:
      • No dosage adjustment is necessary.
    • CrCl ≥60 to <90 mL/minute:
      • 500 mg every 6 hours
    • CrCl ≥30 to <60 mL/minute:
      • 500 mg every 8 hours
    • CrCl ≥15 to <30 mL/minute:
      • 500 mg every 12 hours
    • CrCl <15 mL/minute:
      • Do not administer imipenem and cilastatin unless hemodialysis is instituted within 48 hours.

  • The usual dosing regimen of 1,000 mg every 6 hours:

    • CrCl ≥90 mL/minute:
      • No dosage adjustment is necessary.
    • CrCl ≥60 to <90 mL/minute:
      • 750 mg every 8 hours
    • CrCl ≥30 to <60 mL/minute:
      • 500 mg every 6 hours
    • CrCl ≥15 to <30 mL/minute:
      • 500 mg every 12 hours
    • CrCl <15 mL/minute:
      • Do not administer imipenem and cilastatin unless hemodialysis is instituted within 48 hours.
• Canadian labeling:
  • Reduced intravenous dose based on creatinine clearance (mL/minute/1.73 m²) and body weight of more than 70 kg.
  • The literature recommends further proportionate dose reductions for patients less than 70 kg but does not provide specific dosing recommendations.

  • Mild renal impairment (CrCl 31 to 70 mL/minute/1.73 m²):

    • Fully susceptible organisms:
      • The maximum dosage is 500 mg every 8 hours
    • Less susceptible organisms (primarily some Pseudomonas strains):
      • The maximum dosage is 500 mg every 6 hours

  • Moderate renal impairment (CrCl 21 to 30 mL/minute/1.73 m²):

    • Fully susceptible organisms:
      • The maximum dose is 500 mg every 12 hours
    • Less susceptible organisms (primarily some Pseudomonas strains):
      • The maximum dose is 500 mg every 8 hours.

  • Severe renal impairment (CrCl 0 to 20 mL/minute/1.73 m²):

    • Fully susceptible organisms:
      • The maximum dosage is 250 mg every 12 hours.
    • Less susceptible organisms (primarily some Pseudomonas strains):
      • The maximum dosage is 500 mg every 12 hours.
    • It should be noted that patients with CrCl 6 to 20 mL/minute/1.73 m² should receive 250 mg every 12 hours or 3.5 mg/kg whichever is lower, every 12 hours for most pathogens. The seizure risk may increase with higher dosing.

  • End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):

    • The dosing recommendation (for US labeling) for patients with a CrCl ≥15 to <30 mL/minute should be used.
    • Give the dose after the dialysis session and at intervals timed from the end of that dialysis session or 250 to 500 mg every 12 hours.
    • The dosages are dependent on the assumption of 3 times per week.

  • Continuous renal replacement therapy (CRRT):

    • Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate.
    • Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough if indicated.
    • The following are general recommendations only which are based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function, and should not supersede clinical judgment:
    • CVVH:
      • A Loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 8 hours.
    • CVVHD:
      • A loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 6 to 8 hours.
    • CVVHDF:
      • A loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 6 hours.

The data suggest that 500 mg every 8 to 12 hours may provide sufficient time above MIC to cover organisms with MIC values of less than 2 mg/L. However, a higher dose of 500 mg every 6 hours is recommended for resistant organisms particularly for Pseudomonas spp, with MIC  of more than 4 mg/L or deep-seated infections.

Dose in Liver Disease:

No specific dose reductions are indicated in hepatic impairment.

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Common Side Effects of Imipenem Cilastatin (Tienam):

• Hematologic & Oncologic:

  • Decreased Hematocrit
  • Decreased Hemoglobin
  • Eosinophilia
  • Thrombocythemia

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT

Less Common Side Effects of Imipenem Cilastatin (Tienam):

• Cardiovascular:

  • Phlebitis
  • Tachycardia

• Central Nervous System:

  • Seizure

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Oral Candidiasis
  • Vomiting
  • Gastroenteritis

• Genitourinary:

  • Proteinuria
  • Urine Discoloration
  • Oliguria

• Hematologic & Oncologic:

  • Neutropenia
  • Decreased Platelet Count
  • Increased Hematocrit

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Increased Serum Bilirubin
  • Decreased Serum Bilirubin

• Local:

  • Irritation At Injection Site

• Renal:

  • Increased Serum Creatinine

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Contraindications to Imipenem Cilastatin (Tienam):

• Hypersensitivity to imipenem/cilastatin, or any component thereof, is a serious contraindication.
• It is difficult to say with certainty that cross-reactions occur due to the limited evidence on cross-reactivity between penicillins and carbapenems. 
• However, cross-reactions can still occur due to the biophysical similarities of compounds.

Warnings and precautions

• CNS effects

  • CNS adverse effects have been linked to Carbapenems, including confusional states or myoclonic seizures. 
  • CNS disorders such as brain lesions or history of seizures should be avoided. To avoid drug accumulation and increase seizure risk, adjust the dose for renal impairment.
  • There have been instances of adverse CNS effects reported in patients with no underlying CNS disorder or impaired renal function.

• Hypersensitivity reactions

  • There have been cases of severe hypersensitivity and anaphylactic reactions, with some even leading to death. 
  • Patients with a history involving multiple allergens may experience it more frequently.
  • Penicillin hypersensitivity patients may have severe reactions to beta-lactams if they are treated with penicillins.
  •  You should ask about any previous hypersensitivity reactions to penicillins or cephalosporins, beta-lactams, or other allergens.
  • Anaphylactic reactions that are severe require immediate discontinuation. Supportive care is required as clinically indicated.

• Superinfection

  • Extended use can lead to fungal or bacterial overinfections, such as C. difficile-associated diarrhea (CDAD), and pseudomembranous collitis. After 2 months of post-antibiotic treatment, CDAD was observed.

• Renal impairment

  • Patients with impaired renal function should be cautious. Patients with severe or moderate renal impairment will require dose adjustment.
  • Patients with severe renal dysfunction have been shown to be at greater risk of seizure.
  • Patients with CrCl >=15 mg/minute should not be used unless hemodialysis is initiated within 48 hours.
  • Patients on hemodialysis should only use it if the potential for seizures is outweighed by the benefits.

 

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Monitoring parameters:

• Periodic renal, hepatic, and hematologic function tests.
• Monitor for signs of anaphylaxis during the first dose.

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How to administer Imipenem Cilastatin (Tienam)?

• It is administered intravenously only.
• Do not administer IV push.
• Infuse doses of less than 500 mg over 20 to 30 minutes and doses more than 500 mg over 40 to 60 minutes.
• If nausea or vomiting occurs during administration, decrease the rate of IV infusion.

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Mechanism of action of Imipenem Cilastatin (Tienam):

• It blocks bacterial cell wall synthesis through binding to one or several penicillin-binding protein (PBPs).
• This in turn inhibits the final step of peptidoglycan transpeptidation in bacterial cell walls and thus, inhibits cell wall biosynthesis.
• Bacteria eventually lyse because of the continuing activity of cell wall hydrolases (autolysins, murein hydrolases), while cell wall assembly becomes stopped.
• Cilastatin inhibits the renal metabolism of imipenem through competitive inhibition of dehydropeptidase at the brush border of renal tubules.  

Protein binding:

• Imipenem: ~20%.
• cilastatin: ~40%

Metabolism:

• Imipenem is metabolized in the kidney by dehydropeptidase I. cilastatin prevents imipenem metabolism by this enzyme.

Half-life elimination:

• IV: Both drugs: Prolonged with renal impairment.
  • Neonates: Imipenem: 1.7 to 2.4 hours. Cilastatin: 3.9 to 6.3 hours.
  • Infants and Children: Imipenem: 1.2 hours.
  • Adults: ~60 minutes

Excretion:

• Both drugs: Urine (~70% as unchanged drug)

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International Brand Names of Imipenem Cilastatin:

• Primaxin I.V.
• Imipenem and Cilastatin for Injection
• Imipenem and Cilastatin for Injection, USP
• Primaxin
• RANImipenem-Cilastatin
• Amanam
• Anipen
• Arzobema
• Bacquire
• Bacqure
• Bidinam
• Bionam
• Cilanem
• Cilapenem
• Cispenam
• Imcitin
• Imenam
• Imicila Alvogen
• Imiclast
• Iminem
• Iminen
• Imipen
• Imivex
• Inem
• Junte
• Minem
• Nemcis
• Nimedine
• Pelascap
• Pelastin IV
• Penam
• Plastin
• Premax
• Prepenem
• Primax
• Primaxin
• Primaxin IV
• Sianem
• Supernem
• Supranem
• Talispenem
• Tenacid
• Tienam
• Tiesilan
• Timipen
• Tipem
• Vexpinem
• Xerxes
• Zienam

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Imipenem Cilastatin Brand Names in Pakistan:

Imipenem Cilastatin Injection 500 Mg in Pakistan
Prepenem	Highnoon Laboratories Ltd.
Stanem	Cirin Pharmaceuticals (Pvt) Ltd.

 

Imipenem Cilastatin Injection 250 Mg in Pakistan
Tienam	OBS

Imipenem Cilastatin Injection 500 Mg in Pakistan

• Tienam: OBS