Imipenem and Cilastatin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution: Imipenem 250 mg and cilastatin 250 mg; imipenem 500 mg and cilastatin 500 mg

Primaxin® I.V.: Imipenem 250 mg and cilastatin 250 mg [contains sodium 18.8 mg (0.8 mEq)] [DSC]; imipenem 500 mg and cilastatin 500 mg [contains sodium 37.5 mg (1.6 mEq)]

Pharmacology

Mechanism of Action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested. Cilastatin prevents renal metabolism of imipenem by competitive inhibition of dehydropeptidase along the brush border of the renal tubules.

Pharmacokinetics/Pharmacodynamics

Metabolism

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

Excretion

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

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 (Freij 1985)

Infants and Children: Imipenem: 1.2 hours (Blumer 1996)

Adults: ~60 minutes

Protein Binding

Imipenem: ~20%; cilastatin: ~40%

Use: Labeled Indications

Bacterial septicemia: Treatment of septicemia caused by Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing), Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species, Enterobacter species, Bacteroides species (including Bacteroides fragilis).

Bone and joint infections: Treatment of bone and joint infections caused by E. faecalis, S. aureus (penicillinase-producing), Staphylococcus epidermidis, Enterobacter species, P. aeruginosa.

Endocarditis: Treatment of endocarditis caused by S. aureus (penicillinase-producing).

Gynecologic infections: 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, Cutibacterium species.

Intra-abdominal infections: Treatment of 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, Bifidobacterium species.

Lower respiratory tract infections: Treatment of lower respiratory tract infections caused by S. aureus (penicillinase-producing), 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, 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, Peptostreptococcus species.

Urinary tract infections (complicated and uncomplicated): Treatment of 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, P. aeruginosa.

Limitations of use: Not indicated in patients with meningitis because safety and efficacy have not been established; not recommend in pediatric patients with CNS infections because of the risk of seizures.

Use: Off Label

Burkholderia pseudomallei (melioidosis)b

Data from a randomized, comparative treatment study support the use of imipenem/cilastatin in the treatment of severe melioidosis Simpson 1999. Additional trials may be necessary to further define the role of imipenem/cilastatin in this condition.

Neutropenic fevera

In a meta-analysis of twelve randomized controlled trials evaluating the treatment of neutropenic fever, the use of imipenem and cilastatin as monotherapy was shown to be effective Paul 2006.

Based on the Infectious Diseases Society of America (IDSA) guidelines for the use of antimicrobial agents in neutropenic patients with cancer, imipenem-cilastatin, among other anti-pseudomonal beta-lactam antibiotics, may be used for the initial empiric treatment of high-risk patients who require hospitalization.

Nontuberculous mycobacterial diseaseyes

Based on the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) Guidelines for the Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Disease, imipenem/cilastatin, as part of a multidrug regimen, is effective and recommended for the treatment of nontuberculous mycobacterial disease attributed to Mycobacteria abscessus, M. fortuitum, M. chelonae, M. mucogenicum, or M. smegmatis.

Skin and soft tissue necrotizing infectionsyes

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), imipenem and cilastatin, in combination with an agent effective against methicillin-resistant S. aureus (MRSA) (eg, vancomycin, linezolid, daptomycin), is an effective and recommended empiric treatment for polymicrobial [mixed] necrotizing infections of the skin, fascia, and muscle.

Surgical-site infectionyes

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), imipenem/cilastatin is an effective and recommended option for treatment of surgical-site infections occurring after intestinal or genitourinary tract surgery. Systemic antibacterials are not routinely indicated for surgical-site infections, but may be beneficial (in conjunction with suture removal plus incision and drainage) in patients with significant systemic response (eg, temperature >38.5°C, heart rate >110 beats per minute, erythema/induration extending >5 cm from incision, WBC >12,000/mm³).

Contraindications

Hypersensitivity to imipenem/cilastatin or any component of the formulation

Documentation of allergenic cross-reactivity for carbapenems, penicillins, and cephalosporins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Doses based on imipenem content.

Usual dosage range: IV:

Susceptible bacterial species: 500 mg every 6 hours or 1,000 mg every 8 hours (maximum dose: 4,000 mg/day)

Intermediate susceptibility bacterial species: 1,000 mg every 6 hours (maximum dose: 4,000 mg/day)

Indication-specific dosing:

Burkholderia pseudomallei (melioidosis) (off-label use): IV: Initial: 20 mg/kg every 8 hours for at least 10 days (White 2003) or 25 mg/kg (up to 1 g) every 6 hours for at least 10 days (Currie 2003); continue parenteral therapy until clinical improvement then switch to oral therapy if tolerated and/or appropriate. Additional data may be necessary to further define the role of imipenem/cilastatin in this condition.

Intra-abdominal infections, complicated: IV: 500 mg every 6 hours or 1 g every 8 hours for 4 to 7 days (provided source controlled). Note: Not recommended for mild to moderate, community-acquired intra-abdominal infections due to risk of toxicity and the development of resistant organisms (Solomkin 2010).

Neutropenic fever (off-label use): IV: 500 mg every 6 hours (Paul 2006)

Nontuberculous mycobacterial disease (off-label use): IV: M. abscessus skin, soft tissue, or bone infections: 500 mg every 6 to 12 hours; use in combination with other antibacterial agents (ATS/IDSA [Griffith 2007]).

Pneumonia, hospital acquired or ventilator-associated (off-label dose): IV: 500 mg every 6 hours for 7 days; may consider shorter or longer duration depending on rate of clinical improvement. When used as empiric therapy, use in combination with an agent active against MRSA (unless coverage of MSSA only is appropriate) with or without an additional antipseudomonal agent (dependent on patient and institution-specific risk factors). Note: May need to decrease dose in patients weighing less than 70 kg to prevent seizures (Kalil 2016).

Skin and soft tissue necrotizing infections (off-label use): IV: 1 g every 6 to 8 hours in combination with an agent effective against MRSA (eg, vancomycin, linezolid, daptomycin) for empiric therapy of polymicrobial [mixed] infections. Continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014]).

Surgical-site infection (intestinal or genitourinary tract surgery) (off-label use): IV: 500 mg every 6 hours (IDSA [Stevens 2014]).

Urinary tract infection, complicated (including pyelonephritis): IV: 500 mg every 6 hours for 10 to 14 days; when used for empiric therapy, use alone or in combination with other appropriate agents. Note: Reserved for critically ill patients or patients with risk factor(s) for multidrug-resistant (MDR) pathogens, including extended-spectrum beta-lactamase (ESBL)–producing organisms (Hooton 2018).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dosage recommendations are based on imipenem component.

General dosing, susceptible infection; severe infections (Red Book [AAP 2018]): Infants, Children, and Adolescents: IV: 60 to 100 mg/kg/day divided every 6 hours; maximum daily dose: 4,000 mg/day

Burkholderia pseudomallei (melioidosis): Infants, Children, and Adolescents: IV: Initial: 60 to 100 mg/kg/day divided every 6 to 8 hours for at least 10 days; maximum daily dose: 4,000 mg/day; continue parenteral therapy until clinical improvement, then switch to oral therapy if tolerated and/or appropriate (Currie 2003; White 2003)

Febrile neutropenia, empiric therapy: Limited data available: Children and Adolescents: IV: 60 mg/kg/day divided every 6 hours (Caselli 2012; Erbey 2009; Riikonen 1991); some centers use doses as high as 100 mg/kg/day; maximum daily dose: 4,000 mg/day

Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 60 to 100 mg/kg/day divided every 6 hours; maximum dose: 500 mg (Solomkin 2010)

Non-tuberculosis mycobacterium, cystic fibrosis: Infants, Children, and Adolescents: IV: 15 to 20 mg/kg/dose every 12 hours; maximum dose: 1,000 mg/dose (USCFF/ECFS [Floto 2016])

Peritonitis (peritoneal dialysis): Infants, Children, and Adolescents: Intraperitoneal: Continuous: Loading dose: 250 mg per liter of dialysate; maintenance dose: 50 mg per liter (ISPD [Warady 2012])

Pulmonary exacerbation, cystic fibrosis: Infants, Children, and Adolescents: IV: 100 mg/kg/day divided every 6 hours; maximum daily dose: 4,000 mg/day; efficacy may be limited due to rapid development of resistance (Döring 2000; Zobell 2012)

Reconstitution

Reconstitute vials with approximately 10 mL of NS, D5W, D5NS, D5¹/₂NS, or D5¹/₄NS. Shake well and transfer to 100 mL of an appropriate infusion solution; repeat transfer with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. Agitate resulting mixture until clear. Solutions range from colorless to yellow.

Administration

IV: For IV infusion only; do not administer IV push. Infuse doses ≤500 mg over 20 to 30 minutes; infuse doses >500 mg over 40 to 60 minutes. If nausea and/or vomiting occur during administration, decrease the rate of IV infusion.

Dietary Considerations

Some products may contain sodium.

Storage

Store intact vials at <25°C (77°F). Reconstituted solution is stable for 4 hours at room temperature or 24 hours when refrigerated at 5°C (41°F). Do not freeze.

Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

CycloSPORINE (Systemic): May enhance the neurotoxic effect of Imipenem. Imipenem may decrease the serum concentration of CycloSPORINE (Systemic). Imipenem may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Imipenem. Specifically, the risk of seizures may be increased. Management: Avoid concomitant use of these agents unless the prospective benefits of therapy outweigh the risks. Consider therapy modification

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Probenecid: May increase the serum concentration of Imipenem. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Consider therapy modification

Test Interactions

Interferes with urinary glucose determination using Clinitest®; positive Coombs' [direct]

Adverse Reactions

>10%

Hematologic & oncologic: Decreased hematocrit (infants and children 3 months to 12 years: 18%; neonates and infants <3 months: 2%), decreased hemoglobin (infants and children 3 months to 12 years: 15%), eosinophilia (neonates, infants, and children to 12 years: 9% to 13%), thrombocythemia (infants and children 3 months to 12 years: 13%; neonates and infants <3 months: 4%)

Hepatic: Increased serum AST (infants and children 3 months to 12 years: 18%; neonates and infants <3 months: 6%), increased serum ALT (infants and children 3 months to 12 years: 11%; neonates and infants <3 months: 3%)

1% to 10%:

Cardiovascular: Phlebitis (2% to 3%), tachycardia (neonates and infants ≤3 months: 2%; adults <1%)

Central nervous system: Seizure (neonates and infants ≤3 months: 6%; adults <1%)

Dermatologic: Skin rash (≤2%)

Gastrointestinal: Diarrhea (neonates, infants, and children to 12 years: 3% to 4%; adults 2%), nausea (2%), oral candidiasis (neonates and infants ≤3 months: 2%), vomiting (≤1% to 2%), gastroenteritis (≤1%)

Genitourinary: Proteinuria (infants and children 3 months to 12 years: 8%), urine discoloration (≤1%), oliguria (neonates and infants ≤3 months: 2%; adults <1%)

Hematologic & oncologic: Neutropenia (infants and children 3 months to 12 years: 3%; adults <1%), decreased platelet count (neonates and infants <3 months: 2%), increased hematocrit (neonates and infants <3 months: 1%)

Hepatic: Increased serum alkaline phosphatase (neonates and infants <3 months: 3%), increased serum bilirubin (neonates and infants <3 months: 3%), decreased serum bilirubin (neonates and infants <3 months: 1%)

Local: Irritation at injection site (infants, children, and adolescents 3 months to 16 years: 1%)

Renal: Increased serum creatinine (neonates and infants <3 months: 5%)

<1%, postmarketing and/or case reports: Abdominal pain, acute renal failure, agitation, agranulocytosis, anaphylaxis, angioedema, back pain (thoracic spinal), basophilia, bilirubinuria, bone marrow depression, brain disease, candidiasis, casts in urine, change in prothrombin time, chest discomfort, Clostridioides (formerly Clostridium) difficile-associated diarrhea, confusion, cyanosis, decreased serum sodium, dental discoloration, dizziness, drowsiness, drug fever, dysgeusia, dyskinesia, dyspnea, erythema at injection site, erythema multiforme, fever, flushing, glossitis, hallucination, headache, hearing loss, heartburn, hematuria, hemolytic anemia, hemorrhagic colitis, hepatic failure, hepatitis (including fulminant onset), hyperchloremia, hyperhidrosis, hypersensitivity, hyperventilation, hypotension, increased blood urea nitrogen, increased lactate dehydrogenase, increased monocytes, increased serum potassium, increased urinary urobilinogen, induration at injection site, injection site infection, jaundice, leukocytosis, leukocyturia, leukopenia, lymphocytosis, myoclonus, neutropenia, pain at injection site, palpitations, pancytopenia, paresthesia, polyarthralgia, polyuria, positive direct Coombs' test, pruritus, pruritus vulvae, pseudomembranous colitis, pseudomonas infection (resistant P. aeruginosa), psychiatric disturbances, sialorrhea, skin changes (texture), sore throat, Stevens-Johnson syndrome, thrombocytopenia, tinnitus, tongue changes (papillar hypertrophy), tongue discoloration, toxic epidermal necrolysis, tremor, urticaria, vertigo, weakness

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states and seizures (myoclonic); use caution with CNS disorders (eg, brain lesions and history of seizures) and adjust dose in renal impairment to avoid drug accumulation, which may increase seizure risk. However, there have been reports of adverse CNS effects in patients who had no recognized or documented underlying CNS disorder or compromised renal function.
• Hypersensitivity reactions: Serious hypersensitivity/anaphylactic reactions have been reported, including fatalities; may be more common in patients with a history of sensitivity to multiple allergens. Patients with a history of penicillin hypersensitivity may experience severe hypersensitivity reactions when treated with other beta-lactams; carefully inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. Serious anaphylactic reactions require immediate discontinuation and supportive care as clinically indicated.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with moderate to severe renal dysfunction. Increased seizure risk has been reported in patients with significant renal dysfunction. Do not use in patients with CrCl ≤15 mL/minute unless hemodialysis is instituted within 48 hours. For patients on hemodialysis, use is recommended only when the benefit outweighs the potential risk of seizures.

Concurrent drug therapy issues:

• Valproic acid and derivatives: Carbapenems, including imipenem, may decrease the serum concentration of divalproex sodium/valproic acid increasing the risk of breakthrough seizures. Concurrent use of carbapenem antibiotics with divalproex sodium/valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional antiseizure medication.
• Drug-drug interactions: Additional potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Not recommended in pediatric CNS infections due to seizure potential. Not recommended in pediatric patients <30 kg with impaired renal function (no data available).

Monitoring Parameters

Periodic renal, hepatic, and hematologic function tests; monitor for signs of anaphylaxis during first dose

Pregnancy

Pregnancy Considerations

Imipenem and cilastatin cross the placenta (Cho 1988; Heikkilä 1992)

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of imipenem/cilastatin may be altered (Heikkilä 1992).

Imipenem is not one of the preferred antibiotics for the management of cystic fibrosis in pregnant females; however, it may be used when a safer alternative is not available (Panchaud 2016).

Patient Education

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Fatigue
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness
• Passing out
• Seizures
• Confusion
• Injection site irritation
• Clostridioides (formerly Clostridium) difficile-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.