Imipenem/Cilastatin

Class: Carbapenems
Chemical Name: [5R-[5α,6α(R*)]]-6-(1-Hydroxyethyl)-3-[[2-(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylic acid monohydrate mixt. with [R-[R*,S*-(Z)]]-7-[(2-Amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl) carbonyl]amino]-2-heptenoic acid monosodium salt
Molecular Formula: C₁₂H₁₇N₃O₄S•H₂
CAS Number: 92309-29-0
Brands: Primaxin I.M.

Medically reviewed by Drugs.com. Last updated on June 30, 2020.

Introduction

Antibacterial; fixed combination of imipenem (a carbapenem β-lactam antibiotic)² ⁴ ⁵ ⁶ ¹⁴⁸ ¹⁹⁶ ¹⁹⁷ ¹⁹⁸ and cilastatin¹ ³⁵ (prevents renal metabolism of imipenem by dehydropeptidase I [DHP I]).¹ ² ¹⁰¹ ¹¹³ ¹²⁵ ¹³⁷ ¹⁴⁰ ¹⁴¹ ¹⁴⁵ ¹⁴⁸ ¹⁹⁶ ¹⁹⁸

Uses for Imipenem/Cilastatin

Bone and Joint Infections

Treatment of serious bone and joint infections caused by susceptible Staphylococcus aureus (penicillinase-producing strains), S. epidermidis, Enterobacter, or Pseudomonas aeruginosa.¹ ¹⁴⁶ ¹⁶⁴ ¹⁶⁷ ¹⁸² ²⁵⁶

Endocarditis

Treatment of endocarditis caused by susceptible S. aureus (penicillinase-producing strains).¹ ¹⁴⁶ ¹⁸⁶ Not considered a preferred or alternative drug for staphylococcal endocarditis.^a ^b

Should not be used for treatment of enterococcal endocarditis.¹⁰³ ¹⁹⁸ ¹⁹⁹ ²¹⁰

Gynecologic Infections

Treatment of gynecologic infections (including mixed aerobic-anaerobic infections) caused by susceptible Enterococcus faecalis, S. aureus (penicillinase-producing strains), S. epidermidis, S. agalactiae (group B streptococci), Enterobacter, E. coli, Gardnerella vaginalis, Klebsiella, Proteus, Bacteroides (including B. fragilis), Bifidobacterium, Peptococcus, Peptostreptococcus, and Propionibacterium.¹ ¹⁴⁶ ¹⁷⁶ ¹⁷⁸

Intra-abdominal Infections

Treatment of intra-abdominal infections (including mixed aerobic-anaerobic infections) caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains), S. epidermidis, Citrobacter, Enterobacter, E. coli, Klebsiella, Morganella morganii, Proteus, Ps. aeruginosa, Bacteroides (including B. fragilis), Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Peptococcus, Peptostreptococcus, or Propionibacterium.¹ ¹⁶⁴ ¹⁷² ¹⁷⁹ ²⁵⁶ .

Respiratory Tract Infections

Treatment of lower respiratory tract infections caused by susceptible S. aureus (penicillinase-producing strains), S. pneumoniae, Haemophilus influenzae, H. parainfluenzae, Acinetobacter, Enterobacter, E. coli, Klebsiella, or Serratia marcescens.¹ ¹⁶⁴ ¹⁶⁷ ¹⁷⁰ ¹⁷² ¹⁸³ ²⁵⁶

Treatment of pneumonia and bronchitis (as an exacerbation of COPD) caused by susceptible S. pneumoniae.²⁵⁶ Indicated for polymicrobial infections when S. pneumoniae may be involved, but not usually indicated for monobacterial pneumococcal infections.¹ Not considered a drug of first choice for empiric treatment of community-acquired pneumonia (CAP);¹⁴⁷ ¹⁹³ usually reserved for use in patients with pneumonia who are at risk for Ps. aeruginosa and when anaerobes may be involved.¹⁴⁷ ¹⁹³ ²⁶¹

Has been used for treatment of Legionella pneumophila† respiratory tract infections.¹⁵² ¹⁵⁴ ¹⁷¹ ²¹⁵ Other anti-infectives (e.g., a macrolide or a fluoroquinolone with or without rifampin) generally preferred.⁷⁶ ²⁶¹ ³⁰⁴

Septicemia

Treatment of septicemia caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains), Enterobacter, E. coli, Klebsiella, Ps. aeruginosa, Serratia, or Bacteroides (including B. fragilis).¹ ¹⁴⁶ ¹⁶⁴ ¹⁶⁷ ¹⁷⁰ ¹⁷² ¹⁸¹ ²⁶¹

Skin and Skin Structure Infections

Treatment of serious skin and skin structure infections caused by susceptible S. aureus (penicillinase-producing strains), S. epidermidis, E. faecalis, Acinetobacter, Citrobacter, Enterobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, P. rettgeri, Ps. aeruginosa, or Serratia.¹ ¹⁴⁶ ¹⁶⁴ ¹⁶⁷ ¹⁷⁰ ¹⁷² ¹⁷⁹ ¹⁸⁴

Treatment of serious skin and skin structure infections caused by susceptible Bacteroides (including B. fragilis), Fusobacterium, Peptococcus, or Peptostreptococcus.¹ ¹⁷⁹ ¹⁸⁴

Urinary Tract Infections (UTIs)

Treatment of complicated and uncomplicated UTIs caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains) , Enterobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, Providencia rettgeri, or Ps. aeruginosa.¹ ¹⁴⁶ ¹⁵⁸ ¹⁶⁴ ¹⁶⁷ ¹⁶⁸ ¹⁷⁰ ¹⁷² ¹⁷³ ¹⁸⁰ ²⁶¹

Actinomycosis

Has been used for treatment of thoracic actinomycosis†.²⁹¹ Not considered a drug of choice; penicillin G generally preferred for initial treatment of all forms of actinomycosis, including thoracic, abdominal, CNS, and cervicofacial infections.⁷⁶ ²⁶¹ ²⁹²

Bacillus Infections

Treatment of invasive infections caused by Bacillus cereus†.⁷⁶ ²⁶¹ Vancomycin considered drug of choice; carbapenems (imipenem or meropenem) or clindamycin are alternatives.²⁶¹

Burkholderia Infections

Treatment of localized or septicemic melioidosis†,²⁶¹ ²⁸⁰ ²⁸¹ ²⁸² ²⁸³ ²⁸⁴ a potentially life-threatening disease caused by Burkholderia pseudomallei.²⁸⁰ ²⁸² ²⁸³ A drug of choice.²⁶¹ ²⁸⁰ ²⁸¹ ²⁸² ²⁸³ ²⁸⁴ ²⁸⁵ B. pseudomallei is difficult to eradicate (relapse of melioidosis is common).²⁸⁰ ²⁸¹ ²⁸³ ²⁸⁵

Alternative for treatment of glanders† caused by B. mallei.²⁶¹

Alternative for treatment of infections caused by B. cepacia†.²⁶¹

Campylobacter Infections

Treatment of systemic infections caused by Campylobacter fetus†;²⁶¹ ²⁸⁶ a drug of choice.²⁶¹ ²⁸⁶

Capnocytophaga Infections

Treatment of infections caused by Capnocytophaga canimorsus†.²⁶¹

Optimum regimens for treatment of infections caused by Capnocytophaga have not been identified; some clinicians recommend use of penicillin G²⁶¹ ²⁹⁰ or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem or meropenem), vancomycin, a fluoroquinolone, or clindamycin.²⁶¹

Nocardia Infections

Treatment of infections caused by Nocardia†, including pulmonary nocardiosis caused by N. asteroides and primary cutaneous nocardiosis.²⁶¹ ²⁹³ ²⁹⁴ ²⁹⁵ Co-trimoxazole considered drug of first choice for Nocardia infections;⁷⁶ ¹⁴⁷ ²⁶¹ alternatives include a sulfonamide (e.g., sulfisoxazole) with or without minocycline or amikacin; a tetracycline (e.g., doxycycline, minocycline); a carbapenem (imipenem or meropenem) with or without amikacin; amoxicillin and clavulanate; cycloserine; or linezolid.⁷⁶ ¹⁴⁷ ²⁶¹

Rhodococcus Infections

Treatment of infections caused by Rhodococcus equi†; used in conjunction with vancomycin.²⁶¹ Optimum regimens have not been identified;²⁹⁸ combination regimens usually are recommended, including vancomycin given with a fluoroquinolone, rifampin, a carbapenem (imipenem or meropenem), or amikacin.²⁶¹ ²⁹⁷ ²⁹⁸ ²⁹⁹

Empiric Therapy in Febrile Neutropenic Patients

Empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.²⁶⁵ ²⁶⁶ ²⁶⁷ ²⁶⁸ ²⁶⁹ ²⁷⁰ ²⁷¹ Used alone or in conjunction with other anti-infectives.²⁶⁸ ²⁶⁹ ²⁷¹

Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.¹⁴ Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.¹⁴

Imipenem/Cilastatin Dosage and Administration

Administration

Administer by intermittent IV infusion¹ and by deep IM injection.²⁵⁶

IM route should only be used for mild to moderately severe infections;²⁵⁶ ²⁵⁷ ²⁵⁸ ²⁵⁹ it is not intended for use in severe and/or life-threatening infections (e.g., sepsis, endocarditis) or in patients with major physiologic impairment (e.g., shock).²⁵⁶ Patients for whom IM therapy is being considered should be selected carefully²⁵⁶ ²⁵⁷ ²⁵⁸ ²⁵⁹ since some reported treatment failures and/or recurrences may have been related to the route of administration.²⁵⁷ ²⁵⁸ ²⁵⁹

The IM suspension should not be given IV.²⁵⁶

ADD-Vantage vials should be used only for IV infusion.¹

For solution and drug compatibility information, see Compatibility under Stability.

IV Infusion

Imipenem solutions for IV infusion should have concentrations ≤5 mg/mL since physical and chemical stability of the drug may be adversely affected at higher concentrations.²¹⁹

If an aminoglycoside is administered concomitantly, the drugs should not be admixed but may be administered from separate containers through the same IV tubing.²¹⁹

Reconstitution and Dilution

Reconstitute infusion bottles containing 250 mg of imipenem and 250 mg of cilastatin or 500 mg of imipenem and 500 mg of cilastatin with 100 mL of a compatible IV solution¹ to provide solutions containing 2.5 or 5 mg/mL of each drug, respectively.²¹⁹ Shake until a clear solution is obtained.¹

Alternatively, vials containing 250 mg of imipenem and 250 mg of cilastatin or 500 mg of imipenem and 500 mg of cilastatin may be initially suspended with a portion of a compatible IV solution and then the resulting suspension of drug added to the remaining IV solution to a volume of 100 mL.¹ A suggested procedure for preparing an initial suspension is to add approximately 10 mL from a 100-mL container of the IV solution to the vial of drug.¹ The resulting initial suspension should be shaken well and then transferred to the IV solution container.¹ To ensure complete transfer of the vial contents, an additional 10 mL from the IV solution container should be added to the vial and transferred back to the IV solution container.¹

ADD-Vantage vials should be reconstituted according to the manufacturer’s directions with the diluent provided.¹

Rate of Administration

The rate of IV infusion depends on the dose.¹ ¹⁶⁴ If nausea and/or vomiting occur during administration, the rate of IV infusion may be decreased.¹ ¹⁶⁴

In adults, each 125-, 250- or 500-mg dose of imipenem should be infused over 20–30 minutes and each 1-g dose should be infused over 40–60 minutes.¹ ¹⁶⁴

In pediatric patients, doses of ≤500 mg should be given by IV infusion over 15–30 minutes and doses >500 mg should be given by IV infusion over 40–60 minutes.¹

IM Administration

IM suspensions are administered by deep IM injection into a large muscle mass (such as the gluteal muscle or lateral aspect of the thigh) with a 21-gauge, 2-inch needle.²⁵⁶ Use aspiration to avoid inadvertent injection into a blood vessel.²⁵⁶

Reconstitution and Dilution

IM injections are reconstituted with lidocaine hydrochloride 1% injection (without epinephrine).²⁵⁶ Add 2 or 3 mL of the diluent to a vial containing 500 or 750 mg of imipenem, respectively.²⁵⁶ The vial should be agitated well to form a suspension and the entire contents of the vial withdrawn for IM injection.²⁵⁶

Dosage

Available as fixed-combination containing imipenem monohydrate and cilastatin sodium; dosage generally expressed in terms of the imipenem content (as anhydrous imipenem).¹ ³⁵ ²⁵⁶

To minimize risk of seizures, closely adhere to dosage recommendations, especially in patients with factors known to predispose to seizure activity; dosage adjustment recommended for patients with advanced age and/or renal impairment.¹ Anticonvulsant therapy should be continued in patients with existing seizure disorders.¹ (See CNS Effects under Cautions.)

Duration of therapy depends on type and severity of infection.²⁵⁶ Safety and efficacy of the IM route for >14 days have not been established.²⁵⁶

Pediatric Patients

General Dosage for Neonates

IV

Neonates <1 week of age weighing ≥1.5 kg: 25 mg/kg every 12 hours.¹

Neonates 1–4 weeks of age weighing ≥1.5 kg: 25 mg/kg every 8 hours.¹

General Dosage for Infants and Children

IV

Children 1–3 months of age weighing ≥1.5 kg: 25 mg every 6 hours.¹

Children ≥3 months of age: 15–25 mg/kg every 6 hours.¹

Mild to Moderately Severe Infections

Gynecologic, Lower Respiratory Tract, or Skin and Skin Structure Infections

Children ≥12 years of age: 500 or 750 mg every 12 hours.²⁵⁶

Intra-abdominal Infections

Children ≥12 years of age: 750 mg every 12 hours.²⁵⁶

Adults

Recommended IV adult dosages are for adults weighing ≥70 kg.¹ Modification of dosage is recommended for patients weighing <70 kg.¹ (See Adults with Low Body Weight under Dosage and Administration.)

Mild Infections

Fully Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 250 mg every 6 hours (1 g daily).¹

Moderately Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).¹

Moderately Severe Infections

Fully Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 500 mg every 8 hours (1.5 g daily) or 500 mg every 6 hours (2 g daily).¹

Moderately Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily) or 1 g every 8 hours (3 g daily).¹

Severe, Life-threatening Infections

Fully Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).¹

Moderately Susceptible Aerobic or Anaerobic Bacteria

Adults weighing ≥70 kg: 1 g every 6 hours (4 g daily) or 1 g every 8 hours (3 g daily).¹

Urinary Tract Infections (UTIs)

Uncomplicated UTIs

Adults weighing ≥70 kg: 250 mg every 6 hours (1 g daily)¹ .

Complicated UTIs

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).¹

Mild to Moderately Severe Infections

Gynecologic, Lower Respiratory Tract, or Skin and Skin Structure Infections

500 or 750 mg every 12 hours.²⁵⁶

Intra-abdominal Infections

750 mg every 12 hours.²⁵⁶

Empiric Therapy in Febrile Neutropenic Patients†

IV

500 mg every 6 hours (1 g daily).²⁶⁵ ²⁶⁶ ²⁶⁸

Prescribing Limits

Pediatric Patients

IV

2 g daily in those with infections caused by fully susceptible bacteria or 4 g daily in those with infections caused by moderately susceptible bacteria (e.g., some strains of Ps. aeruginosa).¹ Higher dosage (up to 90 mg/kg daily in older children) has been used in some cystic fibrosis patients.¹

Adults

IV

50 mg/kg daily or 4 g daily, whichever is lower.¹

IM

1.5 g daily.²⁵⁶

Special Populations

Renal Impairment

Infections in Adults

IV

Dosage adjustments recommended in adults with Cl_cr <70 mL/minute per 1.73 m².¹ Serum creatinine concentrations alone may not be sufficiently accurate to assess the degree of renal impairment; dosage preferably should be based on the patient’s measured or estimated Cl_cr.¹ ²⁵⁶

Manufacturer makes the following recommendations for dosage in adults with Cl_cr <70 mL/minute per 1.73 m² and/or body weight <70 kg.¹ (See Table 1.)

Table 1. Reduced Intravenous Dosage of Imipenem and Cilastatin Sodium IV in Adult Patients with Impaired Renal Function and/or Body Weight < 70 kg
	If Total Recommended Daily Dose is:
	1 g/day	1.5 g/day	2 g/day
	and creatinine clearance (mL/min/1.73 m²) is:
	≥71	41–70	21–40	6–20	≥71	41–70	21–40	6–20	≥71	41–70	21–40	6–20
and Body Weight (kg) is:	then the reduced dosage regiment (mg) is:
≥70	250 q6h	250 q8h	250 q12h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h	500 q6h	500 q8h	250 q6h	250 q12h
60	250 q8h	125 q6h	250 q12h	125 q12h	250 q6h	250 q8h	250 q8h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h
50	125 q6h	125 q6h	125 q8h	125 q12h	250 q6h	250 q8h	250 q12h	250 q12h	250 q6h	250 q6h	250 q8h	250 q12h
40	125 q6h	125 q8h	125 q12h	125 q12h	250 q8h	125 q6h	125 q8h	125 q12h	250 q6h	250 q8h	250 q12h	250 q12h
30	125 q8h	125 q8h	125 q12h	125 q12h	125 q6h	125 q8h	125 q8h	125 q12h	250 q8h	125 q6h	125 q8h	125 q12h

Table 1. Renal Impairment Dosage (contd.)
	If Total Recommended Daily Dose is:
	3 g/day	4 g/day
	and creatinine clearance (mL/min/1.73 m²) is:
	≥71	41–70	21–40	6–20	≥71	41–70	21–40	6–20
and Body Weight (kg) is:	then the reduced dosage regiment (mg) is:
≥70	1000 q8h	500 q6h	500 q8h	500 q12h	1000 q6h	750 q8h	500 q6h	500 q12h
60	750 q8h	500 q8h	500 q8h	500 q12h	1000 q8h	750 q8h	500 q8h	500 q12h
50	500 q6h	500 q8h	250 q6h	250 q12h	750 q8h	500 q6h	500 q8h	500 q12h
40	500 q8h	250 q6h	250 q8h	250 q12h	500 q6h	500 q8h	250 q6h	250 q12h
30	250 q6h	250 q8h	250 q8h	250 q12h	500 q8h	250 q6h	250 q8h	250 q12h

Imipenem should be used in patients undergoing hemodialysis only when potential benefits outweigh the potential risk of drug-induced seizures.¹ ²¹⁹ If used IV in hemodialysis patients, a supplemental dose of the drug should be given after each dialysis period¹ ¹²⁰ ¹²⁶ ¹⁴⁰ and at 12-hour intervals thereafter.¹ In addition, patients should be monitored closely for adverse CNS effects (e.g., confusion, myoclonic activity, seizures), especially those with CNS disease.¹

Patients with Cl_cr ≤5 mL/minute per 1.73² should not receive imipenem and cilastatin sodium IV unless hemodialysis is instituted within 48 hours.¹

IM

IM route should not be used in patients with Cl_cr <20 mL/minute per 1.73 m².²⁵⁶

Infections in Pediatric Patients

IV

Not recommended in pediatric patients weighing <30 kg with impaired renal function.¹

Adults with Low Body Weight

Dosage adjustment recommended when IV imipenem used in adults with body weight <70 kg.¹ IV dosage recommended for these adults is the same as that recommended for adults with renal impairment.¹ (See Tables.)

Geriatric Patients

No dosage adjustments except those related to renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Cautions for Imipenem/Cilastatin

Contraindications

Hypersensitivity to any ingredient in the formulation.¹ ²⁵⁶
IM injections are prepared using lidocaine hydrochloride and are contraindicated in patients with known hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block.²⁵⁶

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible organism.¹ ²⁵⁶ Careful observation of the patient is essential.¹ ²⁵⁶ Institute appropriate therapy if superinfection occurs.¹ ²⁵⁶

Treatment with anti-infectives may permit overgrowth of clostridia.¹ ²⁵⁶ ³⁰⁵ ³⁰⁶ ³⁰⁷ ³⁰⁸ ³⁰⁹ Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.¹ ²⁵⁶

Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.¹ ²⁵⁶ ³⁰⁵ ³⁰⁶ ³⁰⁷ ³⁰⁸ ³⁰⁹ Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe.¹ ²⁵⁶ ³⁰⁵ ³⁰⁶ ³⁰⁷ ³⁰⁸ ³⁰⁹

CNS Effects

Seizures and other CNS effects (e.g., confusional states, myoclonic activity) have occurred.¹ ²⁵⁶ Reported most frequently in those with CNS disorders (e.g., brain lesions, history of seizures) and/or renal impairment, but also reported in patients with no recognized or documented underlying CNS disorder or renal impairment.¹ ²⁵⁶

Do not exceed recommended dosage, especially in those with known factors that predispose to seizures.¹ ²⁵⁶ Anticonvulsant therapy should be continued in those with known seizure disorders.¹ ²⁵⁶

Patients with Cl_cr ≤20 mL/minute per 1.73 m₂ (even if undergoing hemodialysis) are at increased risk of seizures if recommended doses are exceeded.¹ For patients undergoing hemodialysis, IV imipenem should be used only if benefits outweigh the potential risk of seizures.¹

If focal tremors, myoclonus, or seizures occur, evaluate the patient neurologically, initiate anticonvulsant therapy if necessary, and determine whether imipenem dosage should be decreased or the drug discontinued.¹ ²⁵⁶

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) reported with β-lactams.¹ ²⁵⁶

If hypersensitivity occurs, discontinue imipenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).¹ ²⁵⁶

Cross-Hypersensitivity

Partial cross-allergenicity among β-lactam antibiotics, including penicillins, cephalosporins, and other β-lactams.¹ ²⁵⁶

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to imipenem, cephalosporins, penicillins, or other drugs.¹ ²⁵⁶

General Precautions

Laboratory Monitoring

Periodically assess organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy.¹ ²⁵⁶

Sodium Content

IV preparations contain approximately 1.6 mEq (37.5 mg) of sodium per 500 mg of imipenem;¹ IM preparations contain approximately 1.4 mEq (32 mg) of sodium per 500 mg of imipenem.¹

Ps. aeruginosa Infections

Because resistant strains of Ps. aeruginosa have emerged during imipenem and cilastatin therapy,¹³⁷ ¹⁵³ ¹⁵⁷ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁷¹ ¹⁷³ ¹⁸³ ¹⁹¹ ¹⁹⁸ ²²² ²⁴⁰ most clinicians recommend that an aminoglycoside be used concomitantly whenever the drug is used in the treatment of serious infections known or suspected to be caused by Ps. aeruginosa.¹³⁷ ¹⁴⁶ ¹⁵³ ¹⁵⁷ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁷³ ¹⁷⁴ ¹⁸³ ¹⁹¹ ¹⁹⁶ ¹⁹⁸ ²¹⁰ ²⁴⁰

Meningitis and Other CNS Infections

Safety and efficacy for treatment of meningitis has not been established.¹ High incidence of seizures reported in children 3 months to 12 years of age who received the drug for empiric treatment of bacterial meningitis.²⁴²

Specific Populations

Pregnancy

Category C.¹ ²⁵⁶

Lactation

Imipenem distributed into milk.²¹⁹ Use with caution.¹ ²⁵⁶

Pediatric Use

Safety and efficacy of IM imipenem and cilastatin have not been established in children <12 years of age.²⁵⁶

Adverse effects reported with IV imipenem in neonates and children are similar to those reported in adults.¹ Seizures have been reported in neonates and children ≤3 months of age; a high incidence of seizures reported in children 3 months to 12 years of age who received the drug for empiric treatment of bacterial meningitis.¹ ²⁴² Because of the risk of seizures, imipenem should not be used in pediatric patients with CNS infections.¹

Data are insufficient to date regarding use of imipenem in pediatric patients with impaired renal function who weigh <30 kg; the drug should not be used in these children.¹

Imipenem solutions that have been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates or children ≤3 months of age.¹ ²⁷² ²⁷³ Although a causal relationship not established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.²⁷² ²⁷³

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹ ²⁵⁶

Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.¹ ²⁵⁶ Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.¹ ²⁵⁶

No dosage adjustments except those related to renal function.¹ ²⁵⁶ (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Half-lives of both imipenem and cilastatin prolonged in patients with impaired renal function.¹²⁰ ¹²⁶ ¹⁸⁵

Patients with renal impairment are at increased risk for adverse CNS effects (e.g., seizures), especially if usual dosage is exceeded.¹ Do not use in patients undergoing hemodialysis unless benefits outweigh the possible risk of drug-induced seizures.¹ ²¹⁹ Patients with Cl_cr ≤5 mL/minute per 1.73 m² should not receive IV imipenem and cilastatin IV unless hemodialysis is instituted within 48 hours.¹ If used IV in hemodialysis patients, a supplemental dose of the drug should be given after each dialysis period¹ ¹²⁰ ¹²⁶ ¹⁴⁰ and at 12-hour intervals thereafter.¹ In addition, patients should be monitored closely for adverse CNS effects (e.g., confusion, myoclonic activity, seizures), especially those with CNS disease.¹

Dosage adjustment recommended in adults with Cl_cr ≤70 mL/minute.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, diarrhea, vomiting); CNS effects; eosinophilia; local reactions (phlebitis/thrombophlebitis).¹ ²⁵⁶

Interactions for Imipenem/Cilastatin

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Aminoglycosides	In vitro evidence of additive or synergistic antibacterial effects against E. faecalis, S. aureus, and Listeria monocytogenes¹³ ¹⁹ ¹⁰³ ¹⁰⁶ ¹⁰⁹ ¹³⁹
β-Lactam anti-infectives	In vitro evidence of antagonism with other β-lactam anti-infectives against Enterobacteriaceae and Ps. aeruginosa³ ¹³ ⁵⁴ ¹⁰² ¹⁰⁷ ¹¹¹ ¹³⁷ ¹⁹⁸ ²⁴⁰ ²⁴⁴ ²⁴⁷	Clinical importance unclear; probably should not be used in conjunction with other β-lactam anti-infectives⁵⁴ ¹⁰² ²¹⁰ ²⁴⁰
Chloramphenicol	In vitro evidence of antagonism with chloramphenicol against K. pneumoniae¹⁰⁴ ¹¹¹	If used concomitantly, consider administering chloramphenicol a few hours after imipenem¹⁰⁴
Co-trimoxazole	In vitro evidence of synergistic antibacterial effect against Nocardia asteroides¹⁰⁸	Clinical importance unclear¹⁰⁸
Ganciclovir	Seizures reported with concomitant use¹ ²⁵³ ²⁵⁴	Use concomitantly only when potential benefits outweigh the possible risks¹ ²⁵³ ²⁵⁴
Probenecid	Increased cilastatin concentrations and prolonged half-life¹²⁵ ¹⁴⁰	Concomitant use not recommended¹ ²⁵⁶
Tests for glucose	Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution¹³²	Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)¹³²

Imipenem/Cilastatin Pharmacokinetics

Absorption

Bioavailability

Neither imipenem nor cilastatin appreciably absorbed from GI tract; must be given parenterally.¹²⁵ ¹⁴³

Imipenem incompletely absorbed following IM administration;²¹⁷ ²⁵⁶ peak plasma concentrations of imipenem attained within 2 hours and peak plasma concentrations of cilastatin attained within 1 hour.²⁵⁶ Bioavailabilities of imipenem and cilastatin following IM administration range from 60–75 and 95–100%, respectively.²¹⁷ ²⁵⁶

Following IV administration, plasma imipenem concentrations during the first 2 hours exceed those attained following IM administration of the same doses; however, plasma imipenem concentrations achieved 4–6 hours after an IM dose exceed those after an IV dose and persist longer.²⁵⁶

Distribution

Extent

Following IV administration, imipenem distributed into saliva, ²⁰⁸ sputum, ¹ ²⁰⁸ ²¹⁵ aqueous humor, ¹ ²¹⁵ bone, ¹ ¹⁸² ²⁰⁸ ²¹⁵ bile, ¹ ²¹⁵ reproductive organs, ¹ myometrium, ²¹⁵ endometrium, ²¹⁵ heart valve, ²¹⁵ intestine, ²¹⁵ and pleural, ¹ interstitial, ¹ blister, ¹⁴² and wound²⁰⁸ ²¹⁵ fluids.

Only low imipenem concentrations distribute into CSF following IV administration.¹ ¹¹⁷ ¹⁸⁸ ²⁰⁵

Both imipenem and cilastatin cross the placenta and are distributed into cord blood and amniotic fluid.²⁰⁹ ²⁵¹ Imipenem is distributed into milk.²¹⁹

Plasma Protein Binding

Imipenem is 13–21%¹ ¹²⁵ ²⁵⁶ and cilastatin is approximately 40%¹ ²⁵⁶ bound to serum proteins.

Elimination

Metabolism

If imipenem is administered alone, the drug is partially hydrolyzed in kidneys by dehydropeptidase I (DHP I) to a microbiologically inactive metabolite.¹ ¹¹³ ¹²⁵ ¹⁴⁰ ¹⁴³ ¹⁴⁸ ²⁵⁶ Concurrent administration of cilastatin prevents metabolism of imipenem by DHP I.¹ ² ¹¹³ ¹¹⁸ ¹²⁰ ¹²⁵ ¹³⁷ ¹⁴⁰ ¹⁴¹ ¹⁴⁸ ¹⁹⁶ ¹⁹⁷ ¹⁹⁸ ²⁵⁶

Imipenem also is metabolized to some extent by a nonrenal mechanism unrelated to DHP I² ¹¹⁵ ¹⁴⁰ ²⁰⁴ to an inactive metabolite identical to that formed by renal DHP I, this nonspecific hydrolysis is unaffected by concurrent administration of cilastatin.² ¹⁴⁰ ²⁰⁴

Cilastatin is partially metabolized in the kidneys to N-acetylcilastatin, ² ¹²⁵ ¹⁴⁰ ¹⁴⁸ which also is an effective inhibitor of DHP I.²

Elimination Route

Imipenem, cilastatin, and their metabolites eliminated principally in urine.² ¹¹⁵ ¹²³ ¹²⁵ ¹⁴⁰ ¹⁴⁸

Half-life

In adults with normal renal function, distribution half-life of IV imipenem averages 0.23–0.31 hours¹¹⁴ ¹²² ¹²⁴ and elimination half-life averages 0.85–1.35 hours.¹ ¹¹⁴ ¹²² ¹²⁴ ¹²⁵ ¹⁴⁰ ¹⁴³ IV cilastatin has an elimination half-life of 0.83–1.1 hours in adults with normal renal function¹ ¹¹⁴ ¹¹⁶ ¹²⁵ ¹⁴⁰

Elimination half-life of IV imipenem averages 1–1.3 hours in children¹⁴⁴ and 1.5–2.6 hours in neonates.¹¹⁷ ¹¹⁸ Elimination half-life of IV cilastatin is 3.1–8.8 hours in neonates.¹¹⁷ ¹¹⁸

The elimination half-life of imipenem following IM administration of imipenem and cilastatin suspension is 2–3 hours.²⁵⁶

Special Populations

Serum half-lives of both imipenem and cilastatin are prolonged in patients with impaired renal function; half-life of cilastatin is prolonged to a greater extent than that of imipenem.¹²⁰ ¹²⁶ ¹⁸⁵

In healthy geriatric adults, mean plasma half-lives of imipenem and cilastatin are similar to half-lives expected in individuals with slight renal impairment.¹

Stability

Storage

Parenteral

Powder for Injection

<25°C.¹ ²⁵⁶

Solutions and suspensions may darken (i.e., IV solutions may turn deep yellow or IM suspensions may turn light tan) with time;¹ ²⁵⁶ this color change does not indicate loss of potency.¹ ²⁵⁶ However, IV solutions of the drug should be discarded if they become brown.²¹⁹

IV solutions prepared using 100 mL of 0.9% sodium chloride injection; 5 or 10% dextrose; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride; 0.15% potassium chloride in 5% dextrose; or 5 or 10% mannitol are stable for 4 hours at room temperature or 24 hours when refrigerated at 5°C.¹

Reconstituted ADD-Vantage vials are stable for 4 hours at room temperature.¹

IM suspensions prepared using lidocaine hydrochloride 1% injection (without epinephrine) should be used within 1 hour of reconstitution.²⁵⁶

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Incompatible
Dextrose 5% with potassium chloride 0.15%¹
Dextrose 5% in Ringer’s injection, lactated^HID
Dextrose 5% in sodium chloride 0.225, 0.45, or 0.9%¹ ^HID
Dextrose 10% in water¹ ^HID
Mannitol 2.5, 5, or 10% in water¹ ^HID
Normosol M in dextrose 5%^HID
Ringer’s injection, lactated^HID
Sodium bicarbonate 5%^HID
Sodium lactate 1/6 M^HID
Variable
Dextrose 5% in water^HID
Sodium chloride 0.9%^HID

Drug Compatibility

Y-Site CompatibilityHID
Compatible
Acyclovir sodium
Amifostine
Anidulafungin
Aztreonam
Caspofungin acetate
Cisatracurium besylate
Diltiazem HCl
Docetaxel
Famotidine
Fludarabine phosphate
Foscarnet sodium
Granisetron HCl
Idarubicin HCl
Insulin, regular
Linezolid
Melphalan HCl
Methotrexate sodium
Ondansetron HCl
Propofol
Remifentanil HCl
Tacrolimus
Teniposide
Thiotepa
Tigecycline
Vasopressin
Vinorelbine tartrate
Zidovudine
Incompatible
Allopurinol sodium
Amiodarone HCl
Amphotericin B cholesteryl sulfate complex
Azithromycin
Etoposide phosphate
Fluconazole
Gallium nitrate
Gemcitabine HCl
Lorazepam
Meperidine HCl
Midazolam HCl
Milrinone lactate
Sargramostim
Sodium bicarbonate
Variable
Filgrastim
Telavancin HCl

Actions and Spectrum

Fixed combination of imipenem monohydrate and the sodium salt of cilastatin.¹ ³⁵ ²⁵⁶ Imipenem is carbapenem antibiotic² ⁴ ⁵ ⁶ ¹⁴⁸ ¹⁹⁶ ¹⁹⁷ ¹⁹⁸ structurally and pharmacologically related to meropenem and ertapenem.¹ ² ³ Cilastatin is a specific and reversible inhibitor of dehydropeptidase I (DHP I).¹ ² ¹⁰¹ ¹²⁵ ¹⁴⁰ ¹⁴¹ ¹⁴⁵ ¹⁴⁸ ¹⁹⁶ ¹⁹⁸ ²⁵⁶
Concomitant use of cilastatin prevents in vivo metabolism of imipenem by DHP I and results in urinary concentrations of active imipenem that are higher than could be obtained following use of the antibiotic alone.¹ ² ¹¹³ ¹²⁵ ¹³⁷ ¹⁴⁰ ¹⁴¹ ¹⁴⁸ ¹⁹⁶ ¹⁹⁸ ²⁵⁶
Usually bactericidal in action.¹ ²⁵⁶
Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.¹ ²⁵⁶
Spectrum of activity includes many gram-positive and -negative aerobic bacteria and some gram-positive and -negative anaerobic bacteria.¹ ²⁵⁶ Stable in the presence of a variety of β-lactamases (including penicillinases, cephalosporinases, and extended-spectrum β-lactamases).¹ ²⁵⁶
Gram-positive aerobes: active in vitro and in clinical infections against Enterococcus faecalis, Staphylococcus aureus (including penicillinase-producing strains), S. epidermidis, Streptococcus agalactiae (group B streptococci), S. pneumoniae, and S. pyogenes (group A β-hemolytic streptococci).¹ ²⁵⁶ Also active in vitro against S, saprophyticus, groups C and G streptococci, viridans streptococci, Bacillus, Listeria monocytogenes, and Nocardia.¹ ²⁵⁶ Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.¹ ²⁵⁶
Gram-negative aerobes: active in vitro and in clinical infections against Acinetobacter, Citrobacter, Enterobacter, Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, H. parainfluenzae, Klebsiella, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, and Serratia (including S. marcescens).¹ ²⁵⁶ Also active in vitro against Aeromonas hydrophila, Alcaligenes, Capnocytophaga, H. ducreyi, Neisseria gonorrhoeae, Pasteurella, and P. stuartii.¹ ²⁵⁶
Anaerobes: active in vitro and in clinical infections against Bacteroides (including B. fragilis), Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Peptococcus, Peptostreptococcus, and Propionibacterium.¹ ²⁵⁶ Also active in vitro against Prevotella bivia, P. disiens, P. melaninogenica, and Veillonella.¹

Advice to Patients

Importance of informing clinicians of other medical conditions, including history of seizures.¹
Importance of discontinuing therapy and informing clinician if an allergic or hypersensitivity reaction occurs.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of informing patient of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Imipenem and Cilastatin Sodium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, for IM use only	500 mg (of anhydrous imipenem) and 500 mg (of cilastatin)	Primaxin I.M.	Merck
		750 mg (of anhydrous imipenem) and 750 mg (of cilastatin)	Primaxin I.M.	Merck
	For injection, for IV infusion	250 mg (of anhydrous imipenem) and 250 mg (of cilastatin)	Primaxin I.V. (available in infusion bottles and vials)	Merck
			Primaxin ADD-Vantage	Merck
		500 mg (of anhydrous imipenem) and 500 mg (of cilastatin)	Primaxin I.V. (available in infusion bottles and vials)	Merck
			Primaxin ADD-Vantage	Merck

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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51. Michael PR, Alford RH, McGee ZA. Superior activity of N-formimidoyl thienamycin against gentamicin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1981; 20:702-4. (IDIS 141487)

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53. Conrad DA, Scribner RK, Weber AH et al. In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum. Antimicrob Agents Chemother. 1985; 28:58-63. http://www.ncbi.nlm.nih.gov/pubmed/3929681?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176310&blobtype=pdf

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