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 utilised to treat septicemia brought on 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:

  • Additionally, it is utilised to treat bone and joint infections brought on by:
    • E. faecalis,
    • S. aureus which produces penicillinase,
    • Staphylococcus epidermidis,
    • Enterobacter species, and
    • P. aeruginosa.

• Endocarditis:

  • It is used to treat endocarditis brought on by S. aureus, a penicillinase-producing bacteria.

• Gynecologic infections:

  • Infections of the gynaecological system brought on 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 a component of regimens used to treat intra-abdominal infections brought on 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:

  • Additionally, it is utilised to treat lower respiratory tract infections brought on 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 may also be utilised to treat infections of the skin and skin structures brought on 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:

  • Treatment for simple and complex urinary tract infections brought on by:
    • E. faecalis,
    • S. aureus (penicillinase-producing),
    • E. coli,
    • Klebsiella species,
    • Enterobacter species,
    • P. vulgaris,
    • Providencia rettgeri,
    • M. morganii, and
    • P. aeruginosa.
  • Its use is, however, subject to various restrictions. Meningitis sufferers should not use it because its safety and effectiveness have not yet been shown.
  • The possibility of seizures makes it contraindicated in young patients with CNS infections.

• 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

Imipenem Cilastatin (Tienam) Dose in Adults:

Imipenem Cilastatin (Tienam) Usual dosage range: IV:

• Susceptible bacterial species:

  • 4,000 mg/day is the maximum daily dose, which is 500 mg every six hours or 1,000 mg every eight hours.

• Intermediate susceptibility bacterial species:

  • 4,000 mg per day is the maximum dose, which is 1,000 mg every six hours.

Indication-specific dosing:

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

• An intravenous dose of 20 mg/kg every eight hours for at least ten days or 25 mg/kg (up to 1 g) every six hours for at least ten days is initially administered.
• If tolerable and appropriate, parenteral medication is continued until clinical improvement is seen before switching to oral therapy.
• To more clearly describe the function of imipenem/cilastatin in such circumstances, more information might be required.

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

• If the source of contamination is being eliminated, it is administered intravenously as 500 mg every six hours or 1 g every eight hours for four to seven days.
• It is notable that due to the danger of toxicity and the emergence of resistance organisms, it is not advised for mild to moderate community-acquired intra-abdominal infections.

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 administered as 500 mg every 6 to 12 hours for M. abscessus skin, soft tissue, or bone infections. and is combined with additional antibacterial agents.

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

• IV: 7 days of taking 500 mg every 6 hours.
• Depending on how well a patient is doing, the therapy may last longer. Depending on the patient and institution-specific risk factors, it may or may not be given in addition to an antibiotic active against MRSA when used as empirical therapy (unless coverage of MSSA exclusively is appropriate).
• It should be noted that a dose reduction may be necessary to stop seizures.

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

• IV: For empirical treatment of polymicrobial infections, it is administered as 1 g every 6 to 8 hours in combination with a medication effective against MRSA, such as vancomycin, linezolid, and daptomycin.
• The treatment plan is maintained until the patient has shown clinical improvement, no additional debridement is required, and the patient has been 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: For 10 to 14 days, 500 mg are given every six hours.
• Give it alone or in combination with other suitable medications when it is used for empirical therapy.
• It is only used in patients who are severely ill or who have conditions that put them at risk for bacteria that are multidrug-resistant (MDR), such as
• those that produce extended-spectrum beta-lactamases (ESBLs).

Imipenem Cilastatin (Tienam) Dose in Children:

Note: The imipenem component is used to determine dosage recommendations.

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

• Infants, Children, and Adolescents:

  • IV: A maximum daily dose of 4,000 mg/day, split into doses of 60 to 100 mg/kg/day every 6 hours, is used.

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

• Infants, Children, and Adolescents:

  • IV: For the first 10 days, it is given in doses of 60 to 100 mg/kg/day, divided every 6 to 8 hours, with a daily dose cap of 4,000 mg.
  • If acceptable or necessary, oral therapy should be substituted for parenteral therapy after continuing parenteral therapy until clinical improvement.

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.
  • In some facilities, daily doses can reach 100 mg/kg.
  • The daily dose cap is set at 4,000 mg.

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: Every 12 hours, it is administered in doses of 15 to 20 mg/kg with a maximum dose of 1,000 mg.

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 into six equal doses, with a daily dose cap of 4,000 mg.
  • Due to the quick emergence of resistance, the effectiveness may be restricted.

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.

Imipenem Cilastatin (Tienam) Dose in Kidney Disease:

• U.S. labels (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:
      • Dosage adjustment not 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:
      • Ipenem and cilastatin shouldn't be given until hemodialysis is started within 48 hours.

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

    • CrCl ≥90 mL/minute:
      • Dosage adjustment not 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:
      • Ipenem and cilastatin shouldn't be given until hemodialysis is started 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:
      • Ipenem and cilastatin shouldn't be given until hemodialysis is started within 48 hours.
• Canadian labeling:
  • Reduced intravenous dose based on body weight more than 70 kg and creatinine clearance of mL/min/1.73 m2.
  • For patients weighing less than 70 kg, the literature suggests further proportionate dose reductions, but it makes no recommendations regarding particular dosing.

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

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

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

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

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

    • Fully susceptible organisms:
      • 250 mg every 12 hours is maximum dose
    • Less susceptible organisms (primarily some Pseudomonas strains):
      • 500 mg every 12 hours is maximum dose
    • It should be emphasised that for the majority of infections, patients with CrCl 6 to 20 mL/minute/1.73 m2 should get 250 mg every 12 hours or 3.5 mg/kg every 12 hours, whichever is lower. With higher dosages, the risk of seizures could increase.

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

    • Use the dose advice (for US labelling) for patients with a CrCl between 15 and 30 mL/minute.
    • Give the dose 250 to 500 mg every 12 hours, after the dialysis treatment and at intervals timed from the end of that dialysis session.
    • The dosages are predicated on a weekly frequency of three.

  • Continuous renal replacement therapy (CRRT):

    • The technique of renal replacement, the type of filter, and the flow rate all have a significant impact on drug clearance.
    • Close monitoring of the pharmacologic response, warning indicators of drug accumulation, and drug concentrations in respect to the target trough are all necessary for proper dosing.
    • Only general suggestions based on little residual renal function and dialysate flow/ultrafiltration rates of 1 to 2 L/hour are provided below; clinical judgement should always be used.:
    • CVVH:
      • 1 g loading dosage, followed by either 250 or 500 mg every 6 or 8 hours.
    • CVVHD:
      • 1 g as a loading dosage, then either 250 mg every six hours or 500 mg every six to eight hours.
    • CVVHDF:
      • 1g as a loading dosage, then either 250 or 500 mg every six hours after that.

According to the results, 500 mg per 8 to 12 hours may be enough to keep an organism's MIC above 2 mg/L for a significant amount of time. For resistant organisms, notably Pseudomonas spp., with MICs of more than 4 mg/L or deep-seated infections, a larger dose of 500 mg every 6 hours is advised.

Dose in Liver Disease:

No specific dose reductions are indicated in hepatic impairment.

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

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 cases of negative CNS effects being observed in people who had neither a CNS illness nor a renal impairment.

• 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.
  •  Ask about any prior allergic reactions to beta-lactams, penicillins, cephalosporins, or other substances.
  • Severe anaphylactic reactions call for immediate cessation. Clinical evidence indicates that supportive care is necessary.

• Superinfection

  • Extended use may result in fungal or bacterial overinfections, such as pseudomembranous collitis and C. difficile-associated diarrhoea (CDAD).
  • CDAD was noticed two months after the end of the antibiotic treatment.

• Renal impairment

  • Renal impairment patients need to exercise caution. A dose adjustment will be necessary for patients with severe or moderate renal impairment.
  • Seizure risk has been linked to patients with severe renal impairment.
  • It is not recommended to use patients with CrCl >=15 mg/min unless hemodialysis is started within 48 hours.
  • Hemodialysis patients should only take it if the advantages outweigh the risk of seizures.

Monitoring parameters:

• Periodic checks on the liver, haematology, and kidneys.
• During the initial dose, keep an eye out for any anaphylactic symptoms.

How to administer Imipenem Cilastatin (Tienam)?

• It is administered intravenously only.
• Give IV pushes without pushing.
• Less than 500 mg should be infused over 20 to 30 minutes, while more than 500 mg should be infused over 40 to 60 minutes.
• Reduce the IV infusion rate if nausea or vomiting develop during administration.

Mechanism of action of Imipenem Cilastatin (Tienam):

• By interacting with one or more penicillin-binding proteins, it prevents the formation of bacterial cell walls (PBPs).
• Cell wall production is then inhibited as a result of this blocking the last stage of peptidoglycan transpeptidation in bacterial cell walls.
• Bacteria eventually lyse as a result of cell wall hydrolases' (autolysins, murein hydrolases) ongoing activity, while cell wall synthesis stops.
• Through competitive inhibition of dehydropeptidase at the brush boundary of renal tubules, cilostatin prevents imipenem's renal metabolism.

Protein binding:

• Imipenem: ~20%.
• cilastatin: ~40%

Metabolism:

• Dehydropeptidase I breaks down imipenem in the kidney, however cilastatin stops this from happening.

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)

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

Imipenem Cilastatin Brand Names in Pakistan:

Imipenem Cilastatin Injection 500 Mg in Pakistan

• Tienam: OBS