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Imipenem and Cilastatin

Pronunciation

Pronunciation

(i mi PEN em & sye la STAT in)

Index Terms

  • Cilastatin and Imipenem
  • Imipemide
  • Imipenem/Cilastatin
  • Primaxin I.M. [DSC]

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)]; imipenem 500 mg and cilastatin 500 mg [contains sodium 37.5 mg (1.6 mEq)]

Brand Names: U.S.

  • Primaxin I.V.

Pharmacologic Category

  • Antibiotic, Carbapenem

Pharmacology

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.

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, Propionibacterium 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, Propionibacterium 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: Unlabeled

Hepatic abscess; neutropenic fever; melioidosis

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.

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]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Dosage based on imipenem content:

Non-CNS infections: IV: Infants ≥3 months, Children, and Adolescents: 15 to 25 mg/kg every 6 hours

Maximum dosage: 4,000 mg/day

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.

Cystic fibrosis exacerbations: IV: Infants, Children, and Adolescents: Up to 100 mg/kg/day divided every 6 hours (Strandvik 1988; Zobell 2012); maximum dose: 4 g daily has been used (Zobell 2012). Note: Efficacy in exacerbations may be limited due to rapid development of resistance (Zobell 2012).

Dosing: Renal Impairment

Adults:

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

Usual dosing regimen of 500 mg every 6 hours:

CrCl ≥90 mL/minute: No dosage adjustment 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.

Usual dosing regimen of 1,000 mg every 8 hours:

CrCl ≥90 mL/minute: No dosage adjustment 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.

Usual dosing regimen of 1,000 mg every 6 hours:

CrCl ≥90 mL/minute: No dosage adjustment 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 IV dosage regimen based on creatinine clearance (mL/minute/1.73 m2) and body weight ≥70 kg (Note: The manufacturer labeling recommends further proportionate dose reductions for patients <70 kg, but does not provide specific dosing recommendations):

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

Fully susceptible organisms: Maximum dosage: 500 mg every 8 hours

Less susceptible organisms (primarily some Pseudomonas strains): Maximum dosage: 500 mg every 6 hours

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

Fully susceptible organisms: Maximum dosage: 500 mg every 12 hours

Less susceptible organisms (primarily some Pseudomonas strains): Maximum dosage: 500 mg every 8 hours

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

Fully susceptible organisms: Maximum dosage: 250 mg every 12 hours

Less susceptible organisms (primarily some Pseudomonas strains): Maximum dosage: 500 mg every 12 hours

Note: 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; seizure risk may increase with higher dosing.

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Use the dosing recommendation (for US labeling) for patients with a CrCl ≥15 to <30 mL/minute; administer dose after dialysis session and at intervals timed from the end of that dialysis session or 250 to 500 mg every 12 hours (Heintz 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): 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 appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 8 hours

CVVHD: Loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 6 to 8 hours

CVVHDF: Loading dose of 1 g followed by either 250 mg every 6 hours or 500 mg every 6 hours

Note: Data suggest that 500 mg every 8 to 12 hours may provide sufficient time above MIC to cover organisms with MIC values ≤2 mg/L; however, a higher dose of 500 mg every 6 hours is recommended for resistant organisms (particularly Pseudomonas spp) with MIC ≥4 mg/L or deep-seated infections (Fish 2005).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Reconstitution

Reconstitute vials with approximately 10 mL of NS, D5W, D10W, 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.

Compatibility

See Trissel’s IV Compatibility Database

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. 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% (Limited to important or life-threatening): Acute renal failure, agranulocytosis, back pain (thoracic spinal), basophilia, bilirubinuria, bone marrow depression, brain disease, candidiasis, casts in urine, change in prothrombin time, Clostridium difficile associated diarrhea, confusion, cyanosis, decreased serum sodium, dental discoloration, drug fever, dyskinesia, erythema multiforme, hallucination, hearing loss, heartburn, hematuria, hemolytic anemia, hemorrhagic colitis, hepatic failure, hepatitis (including fulminant onset), hyperchloremia, hypersensitivity, hyperventilation, hypotension, increased blood urea nitrogen, increased lactate dehydrogenase, increased serum potassium, increased urinary urobilinogen, injection site infection, jaundice, leukocytosis, leukocyturia, leukopenia, lymphocytosis, myoclonus, neutropenia, pancytopenia, positive direct Coombs' test, pseudomembranous colitis, pseudomonas infection (resistant P. aeruginosa), psychiatric disturbances, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis

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 Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Due to pregnancy induced physiologic changes, some pharmacokinetic parameters of imipenem/cilastatin may be altered. Pregnant women have a larger volume of distribution resulting in lower serum peak levels than for the same dose in nonpregnant women. Clearance is also increased.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, or diarrhea. Have patient report immediately to prescriber severe dizziness, passing out, seizures, confusion, chills, pharyngitis, bruising, bleeding, severe loss of strength and energy, mood changes, urinary retention, change in amount of urine passed, signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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