Imipenem/ Cilastatin

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Intra-abdominal infections: Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species, Clostridium species, Eubacteria species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis, Fusobacterium species
• Lower respiratory tract infections: Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella species, Serratia marcescens
• Gynaecologic infections: Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains) and Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species, Escherichia coli, Gardnerella vaginalis, Klebsiella species, Proteus species, Bifidobacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis
• Septicaemia: Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species, Bacteroides species including B. fragilis
• Genito-urinary tract infections (complicated and uncomplicated): Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa
• Bone and joint infections: Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa
• Skin and soft tissue infections: Enterococcus faecalis, Staphylococcus aureus (penicillinase producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species
• Endocarditis: Staphylococcus aureus (penicillinase-producing strains)
• Mixed infections caused by susceptible strains of aerobic and anaerobic bacteria
• Wound sepsis prophylaxis after colorectal surgery

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to any other carbapenem antibacterial agent
• Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins)
• Meningitis
• Pregnancy
• Breastfeeding

• Renal impairment
  - Adults: eGFR <70ml/min/1.73m² 
  - Paediatrics: eGFR <50ml/min/1.73m² 
• Hepatic impairment
  - Pre-existing hepatic disorders
• Patients with a history of sensitivity to multiple allergens
• Limited susceptibility of specific pathogens associated with certain infections, such as bacterial skin and soft tissue infections
• Meningitis
• Central nervous system disorders
  - Brain lesions
  - History of seizures
• Known seizure disorders
• Children with known risk factors for seizures, or coadministered with agents that lower the seizure threshold
• Controlled sodium diet
• Coadministration with valproic acid
• Coadministration with agents that inhibit peristalsis

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• General dosing range
• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages 
• Indications and dosages registered in other jurisdictions

Infections caused by: Some gram-positive aerobes such as Enterococcus faecalis, Staphylococcus aureus (Methicillin-susceptible), Staphylococcus coagulase negative (Methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans group; Some gram-negative aerobes such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Serratia marcescens; Some gram-positive anaerobes such as Clostridium perfringens, Peptostreptococcus spp.; Some gram-negative anaerobes such as Bacteroides fragilis, Bacteroides fragilis group, Fusobacterium spp., Porphyromonas asaccharolytica, Prevotella spp., Veillonella spp.; Nocardia sp., Extended spectrum beta-lactamase producing Klebsiella

General dosing range 

• IV: 500/500mg, 6hrly OR 1000/1000mg, 8hrly

- Bacterial species with intermediate susceptibility

• IV: 1000/1000mg, 6hrly

---

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guidelines indications and dosages

Febrile neutropenia
- If fever develops after 48hrs of admission

• IV: 500/500mg, 6hrly; If neutrophil count increases to >0.5X10⁹/L: Treatment duration: Continue for 2 days after fever has settled; If neutrophil count remains ≤0.5X10⁹/L: Treatment duration: Continue for 7 days after fever has settled  
  (STG, Adult 2019)

Hospital-acquired pneumonia
- With prior intravenous antibiotic use within 90 days and ventilator-associated pneumonia (VAP)

• IV: 1000/1000mg, 8hrly; Treatment duration: 10 days
  (STG, Adult 2019)

---

South African registered indications and dosages

Intra-abdominal infections
Lower respiratory tract infections
Gynaecological infections
Septicaemia
Genito-urinary tract infections (complicated and uncomplicated)
Bone and joint infections
Skin and soft tissue infections
Endocarditis
Mixed infections caused by susceptible strains of aerobic and anaerobic bacteria 

Refer to the table below for dosage information in patients with normal renal function (CrCl >70ml/min/1,73 m²) and a body mass of ≥70kg

Type or severity of infection	Fully susceptible organisms including gram-positive and gram-negative aerobes and anaerobes	Moderately susceptible organisms, primarily some strains of P. aeruginosa
Mild	IV: 250/250mg, 6hrly; Max: 1000/1000mg/24hrs	IV: 500/500mg, 6hrly; Max: 2000/2000mg/24hrs
Moderate	IV: 500/500mg, 8hrly; Max: 1500/1500mg/24hrs OR IV: 500/500mg, 6hrly; Max: 2000/2000mg/24hrs	IV: 500/500mg, 6hrly; Max: 2000/2000mg/24hrs OR IV: 1000/1000mg, 8hrly; Max: 3000/3000mg/24hrs
Severe, life-threatening conditions only	IV: 500/500mg, 6hrly; Max: 2000/2000mg/24hrs	IV: 1000/1000mg, 8hrly; Max: 3000/3000mg/24hrs OR IV: 1000/1000mg, 6hrly; Max: 4000/4000mg/24hrs
Uncomplicated urinary tract infections	IV: 250/250mg, 6hrly; Max: 1000/1000mg/24hrs
Complicated urinary tract infections	IV: 500/500mg, 6hrly; Max: 2000/2000mg/24hrs

---

For the treatment of moderate infections, 1g, 12hrly, may also be used. In infections due to less susceptible organisms, the daily dosage of imipenem/ cilastatin may be increased to a max dose of 4g/day or 50mg/kg/day, whichever is lower

---

Cystic fibrosis patients, with normal renal function, however, have been treated with imipenem/cilastatin at doses up to 90mg/kg/day in divided doses, not exceeding 4 g/day

---

Imipenem/ cilastatin should be given by intravenous infusion over 20-30mins for doses ≤500mg and over 40-60mins for doses >500mg. The rate of infusion may be slowed in patients who develop nausea during the infusion

---

Wound sepsis prophylaxis after colorectal surgery

• IV: 1000/1000mg, on induction of anaesthesia; Then: 1000/1000mg, 3hrs after induction; Then: 500/500mg, 8hrs after induction; Then: 500/500mg, 16hrs after induction

---

The prophylactic use of imipenem/ cilastatin in patients with a CrCl clearance ≤70ml/min/1.73m² is not recommended due to lack of safety data

---

Imipenem/cilastatin has been used successfully as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis

---

See additional prescribing points for administration directions

---

Indications and dosages registered in other jurisdictions

Complicated intra-abdominal infections
Severe pneumonia, including hospital and ventilator-associated pneumonia
Intra- and post-partum infections
Complicated urinary tract infections
Complicated skin and soft tissue infections
Management of neutropenic patients with fever that is suspected to be due to a bacterial infection
Bacteraemia that occurs in association with, or is suspected to be associated with, any of the above infections

• IV: 500/500mg, 6hrly; OR 1000/1000mg, 8hrly; OR 1000/1000mg, 6hrly; Max: 4000/4000mg/24hrs 

---

The daily dose of imipenem/ cilastatin should be based on the type of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s) and the patient's renal function

---

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (such as in neutropenic patients with a fever) should be treated with 1000/1000mg, 6hrly

---

Each dose of ≤500/500mg should be given by intravenous infusion over 20-30min. Each dose >500/500mg should be infused over 40-60min. In patients who develop nausea during the infusion, the rate of infusion may be slowed

See additional prescribing points

Paed. forms avail. in SA and covered in this monograph: inj

Paed. dosages below include:

• General dosing range
• South African registered indications and dosages 
• Indications and dosages registered in other jurisdictions

Infections caused by: Some gram-positive aerobes such as Enterococcus faecalis, Staphylococcus aureus (Methicillin-susceptible), Staphylococcus coagulase negative (Methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans group; Some gram-negative aerobes such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Serratia marcescens; Some gram-positive anaerobes such as Clostridium perfringens, Peptostreptococcus spp.; Some gram-negative anaerobes such as Bacteroides fragilis, Bacteroides fragilis group, Fusobacterium spp., Porphyromonas asaccharolytica, Prevotella spp., Veillonella spp.; Nocardia sp., Extended spectrum beta-lactamase producing Klebsiella

General dosing range

Younger than 7 days and ≥1.5kg

• IV: 25/25mg/kg/dose, 12hrly

Between 1-4 weeks and ≥1.5kg

• IV: 25/25mg/kg/dose, 8hrly

Between 4 weeks-3 months and ≥1.5kg

• IV: 25/25mg/kg/dose, 6hrly

≥3 months

• IV: 15/15-25/25mg/kg/dose, 6hrly; Max: 4g/24hrs

---

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African registered indications and dosages

Intra-abdominal infections
Lower respiratory tract infections
Gynaecological infections
Septicaemia
Genito-urinary tract infections (complicated and uncomplicated)
Bone and joint infections
Skin and soft tissue infections
Endocarditis
Mixed infections caused by susceptible strains of aerobic and anaerobic bacteria 

Younger than 3 months

• Not recommended for use

3 months and older

<40kg

• IV: 15/15mg, 6hrly; Max: 2000/2000mg/24hrs

≥40kg

• See adult dosage

---

Experience of use of imipenem/ cilastatin in children is limited

---

See additional prescribing points for administration directions

---

Indications and dosages registered in other jurisdictions

Complicated intra-abdominal infections
Severe pneumonia, including hospital and ventilator-associated pneumonia
Intra- and post-partum infections
Complicated urinary tract infections
Complicated skin and soft tissue infections
Management of neutropenic patients with fever that is suspected to be due to a bacterial infection
Bacteraemia that occurs in association with, or is suspected to be associated with, any of the above infections

Younger than 1 year

• Not established for use

≥1 year

• IV: 15/15-25/25mg/kg/dose, 6hrly

---

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 25/25mg/kg, 6hrly

---

Adolescents

• See adult dosage

Pregnancy

South African recommendations

• Contraindicated
• Safety and efficacy during pregnancy has not been established. Studies in pregnant monkeys have shown reproductive toxicity; the potential risk for humans is unknown
• The use of imipenem/cilastatin is not recommended during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Imipenem/cilastatin is excreted in breast milk. If the use of imipenem/cilastatin is deemed essential, the patient should stop nursing her baby

Fertility

South African recommendations

• There are no data available regarding potential effects of imipenem/cilastatin treatment on male or female fertility

Adult

• eGFR ≥70ml/min/1.73m²: No dose adjustment needed
• eGFR <70ml/min/1.73m²: Caution; dose adjustment recommended
• Prophylactic use (wound sepsis in adults after colorectal surgery): eGFR ≤70ml/min/1.73m²: Use not recommended
• When necessary, loading doses should be fully administered without adjustment. Only maintenance doses should be adjusted according to the changes in renal function
• Restrict use for culture-based (fully susceptible/ sensitive organisms) antimicrobial indication (avoid in empirical therapy with pre-existing renal impairment)

Type of organism	Recommended dose
eGFR ≥30-69 ml/min/1.73m2
Fully susceptible organisms	Max: 500mg, 8hrly
Less susceptible organisms (Pseudomonas)	Max: 500mg, 6hrly
eGFR ≥20-29 ml/min/1.73m2
Fully susceptible organisms	Max: 500mg, 12hrly
Less susceptible organisms (Pseudomonas)	Max: 500mg, 8hrly
eGFR ≤19 ml/min/1.73m2
Fully susceptible organisms	Max: 250mg, 12hrly
Less susceptible organisms (Pseudomonas)	Max: 500mg, 12hry
End stage renal disease on intermittent haemodialysis (IHD)
250-500mg, 12hrly Administer dose after dialysis session and at intervals timed from the end of that dialysis session eGFR<15ml/min/1.73m2 should not receive imipenem/cilastatin unless haemodialysis is instituted within 48hrs

Paediatric

• Children with renal function (eGFR ≥50ml/min/1.73m²): No dose adjustment recommended
• Children with renal function (eGFR <50ml/min/1.73m²): Caution; dose adjustment recommended
• When necessary, loading doses should be fully administered without adjustment. Only maintenance doses should be adjusted according to the changes in renal function

eGFR (ml/min/1.73 m2)	Recommended dose
≥30-49	7.5-12mg/kg/dose, 8hrly
≥20-29	7.5-12.5mg/kg/dose, 12hrly
≥11-19	7.5 to 12.5mg/kg/dose, 24hrly
End stage renal disease (≤10)	Use is not recommended

• Caution; no dose adjustment recommended

• No dose adjustment recommended

Central Nervous System Disorders

• Psychic disturbances
• Hallucinations
• Confusional state
• Seizures
• Myoclonic activity
• Dizziness
• Somnolence
• Encephalopathy
• Paraesthesia
• Focal tremor
• Aggravation of myasthenia gravis
• Headache
• Agitation
• Dyskinesia
• Asthenia

Cardiovascular Disorders

• Cyanosis
• Tachycardia
• Palpitations
• Thrombophlebitis
• Hypotension
• Flushing
• Chest discomfort

Respiratory Disorders

• Dyspnoea
• Hyperventilation
• Pharyngeal pain

Gastrointestinal Disorders

• Diarrhoea
• Pseudomembranous colitis
• Gastroenteritis
• Nausea and vomiting (more frequently in granulocytopenic patients than in non-granulocytopenic patients)
• Staining of teeth and/or tongue
• Haemorrhagic colitis
• Abdominal pain
• Heartburn
• Glossitis
• Tongue papilla hypertrophy 
• Increased salivation

Hepatobiliary Disorders

• Hepatic failure
• Hepatitis
• Fulminant hepatitis
• Increased serum transaminases
• Increased serum alkaline phosphatase
• Increased serum bilirubin

Genitourinary Disorders

• Acute renal failure
• Oliguria
• Anuria
• Polyuria
• Urine discolouration
• Pruritus vulvae

Musculoskeletal Disorders

• Polyarthralgia
• Thoracic spine pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Exanthematous
• Urticaria
• Pruritus
• Toxic epidermal necrolysis
• Angioedema
• Stevens-Johnson syndrome
• Erythema multiforme 
• Exfoliative dermatitis
• Hyperhidrosis
• Skin texture changes

Immune, Blood and Lymphatic System Disorders

• Candidiasis
• Eosinophilia
• Pancytopenia
• Neutropenia
• Leucopenia
• Thrombocytopenia
• Thrombocytosis
• Agranulocytosis
• Haemolytic anaemia
• Bone marrow depression
• Anaphylactic reactions
• Prolonged prothrombin time
• Decreased haemoglobin
• Elevations in serum creatinine
• Elevations in blood urea nitrogen

Sensory Disorders

• Hearing loss
• Taste perversion
• Vertigo
• Tinnitus

• Ganciclovir
• Valproic acid
• Oral anticoagulants
• Warfarin
• Probenecid
• Agents that inhibit peristalsis

Other interactions

• Coombs test

None routine. Specific cases may require

• Renal function
• Hepatic function
• International Normalised Ratio (INR)
• Haematologic function tests

Additional observations

• Signs of anaphylaxis (during first dose)

Administration directions

Reconstitution

• Contents of each vial must be transferred to 100ml of an appropriate infusion solution, such as 0.9% sodium chloride
• In exceptional circumstances where 0.9% sodium chloride cannot be used for clinical reasons, 5% glucose may be used
• A suggested procedure is to add approximately 10ml of the appropriate infusion solution to the vial
• Shake well and transfer the resulting mixture to the infusion solution container
• CAUTION: THE MIXTURE IS NOT FOR DIRECT INFUSION
• Repeat with an additional 10ml of infusion solution to ensure complete transfer of vial contents to the infusion solution
• The resulting mixture should be agitated until clear
• The concentration of the reconstituted solution following the above procedure is approximately 5mg/ml for both imipenem and cilastatin
• Variations of colour, from colourless to yellow, do not affect the potency of the product

After reconstitution

• Diluted solutions should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous infusion should not exceed 2hrs

Imipenem also referred to as N-formimidoyl-thienamycin, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya. Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs). Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolises and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Spectrum of activity: Some gram-positive aerobes such as Enterococcus faecalis, Staphylococcus aureus (Methicillin-susceptible), Staphylococcus coagulase negative (Methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans group; Some gram-negative aerobes such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Serratia marcescens; Some gram-positive anaerobes such as Clostridium perfringens, Peptostreptococcus spp.; Some gram-negative anaerobes such as Bacteroides fragilis, Bacteroides fragilis group, Fusobacterium spp., Porphyromonas asaccharolytica, Prevotella spp., Veillonella spp.; Nocardia sp., Extended spectrum beta-lactamase producing Klebsiella

COMBINATION PREPARATIONS

Imipenem/ Cilastatin 

Injection (per vial) 500mg/500mg

• Actapen 500 (Teva Pharmaceuticals)
• Cilapen (Ranbaxy)
• Imcil (Austell Lab)
• Imipenem/Cilastatin 500mg/500mg Fresenius (Fresenius Kabi SA)
• Sepencil (Pharma Dynamics)
• Tienam (MSD) originator