IMIPENEM-CILASTATIN SODIUM (Generic for PRIMAXIN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Tuberculosis patients*
-Directly observed therapy (DOT) is recommended for all children as well as adolescents and adults living with HIV.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution and Dilution
-Do not use diluents containing benzyl alcohol for reconstitution when administering to neonates due to toxicity.
-Reconstitute the vial with 10 mL of a compatible solution, including 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, and 5% Dextrose with 0.225% or 0.45% Sodium Chloride Injection.
-Shake well.
-Further dilution is required prior to administration. Do not administer the reconstituted suspension by direct intravenous infusion.
-Transfer the reconstituted suspension to an age-appropriate amount of a compatible infusion solution (Max: 100 mL). Maximum concentration for final administration is 5 mg/mL.
-Repeat transfer of the resulting suspension with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution and agitate the resulting mixture until clear.
-Storage: Reconstituted solutions maintain potency for 4 hours at room temperature or 24 hours under refrigeration. Do not freeze.

Intermittent IV Infusion:
-Infusion rate is dependent on the dose. Infuse doses of 500 mg or less over 20 to 30 minutes. Infuse doses more than 500 mg over 40 to 60 minutes.
-The infusion rate may be slowed in patients who develop nausea during the infusion.
-Storage: Discard unused portion of the infusion solution when applicable.

In a retrospective cohort study of 5,566 infants < 3 months old, the rates of overall laboratory adverse reactions (increased creatinine, hyperbilirubinemia, and increased liver enzymes) were higher with meropenem compared with imipenem (odds ratio (OR) 1.41; 95% CI: 1.28 to 1.55); however, the probability of severe adverse reactions such as death or the combined outcome of death or seizure was significantly lower in infants treated with meropenem compared with those treated with imipenem (OR 0.68; 95% CI: 0.5 to 0.88 and OR 0.77; 95% CI: 0.62 to 0.95, respectively).

Diarrhea (3% to 3.9%), vomiting (1.1%), and gastroenteritis (1.1%) were among the most frequent adverse reactions reported in pediatric patients receiving imipenem in clinical trials. Although not reported in pediatric patients, nausea was reported in 2% of adults in clinical trials. If nausea is experienced during administration, the infusion rate may be slowed. Other gastrointestinal adverse reactions reported in less than 0.2% of adult patients in clinical trials include hemorrhagic colitis, abdominal pain, glossitis, tongue papillar hypertrophy, pyrosis (heartburn), pharyngeal pain, and hypersalivation. Tooth discoloration, tongue discoloration, and taste perversion (dysgeusia) were reported during postmarketing surveillance.

A local injection site reaction can occur after IV administration of imipenem. Phlebitis (2.2%) and irritation at the IV site (1.1%) were reported in pediatric patients receiving imipenem in clinical trials. Erythema at the injection site (0.4%) and vein induration (0.2%) were also reported in adult patients.

Imipenem has been associated with adverse CNS reactions, including confusion, myoclonia, and seizures. Seizures have been reported in 5.9% of pediatric patients 3 months of age and younger receiving imipenem in clinical trials. In a retrospective cohort study of 5,566 infants younger than 3 months old, the rate of seizures was 7.8% (180/2,310) in patients who received imipenem compared with 5.4% (187/3,479) in patients who received meropenem (p less than 0.001); however, on multivariate analysis, the probability of seizure occurrence was similar between the 2 treatment groups (odds ratio 0.96; 95% CI: 0.68 to 1.32). Seizures are more likely to occur in patients with a history of a CNS disorder, a history of seizures, significant renal impairment, and in cases in which the recommended dosage is exceeded; however, seizures have also occurred in patients with none of these risk factors. In addition, imipenem is not recommended for the treatment of CNS infections in pediatric patients because of the increased seizure risk. Additive CNS toxicity also has occurred in patients receiving imipenem in combination with other drugs. Although not reported in pediatric patients, dizziness (0.3%) and drowsiness (0.2%) were reported in adult patients in clinical trials. Additional adverse reactions reported in less than 0.2% of adult patients in clinical trials include encephalopathy, paresthesias, vertigo, and headache. Tremor, psychic disturbances, hallucinations, agitation, and dyskinesia were reported during postmarketing surveillance.

Elevated hepatic enzymes, including elevated AST and ALT, were reported in pediatric patients receiving imipenem in clinical trials. Hyperbilirubinemia, decreased bilirubin, and increased alkaline phosphatase were also reported. Other adverse reactions reported in adult patients in clinical trials or during postmarketing surveillance include hepatitis (including fulminant hepatitis), hepatic failure, jaundice, and elevated LDH.

Hematologic adverse reactions reported in pediatric patients during imipenem clinical trials include eosinophilia, neutropenia, thrombocytopenia, thrombocytosis, decreased hemoglobin, decreased hematocrit, and increased hematocrit. Other hematologic adverse reactions noted in adults during clinical trials or during postmarketing surveillance include pancytopenia, bone marrow depression, leukopenia, hemolytic anemia, positive Coombs test, agranulocytosis, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils, and decreased erythrocytes.

Urinary and renal adverse reactions reported in pediatric patients during imipenem clinical trials include oliguria (2.2%), anuria (2.2%), urine discoloration (1.1%), increased serum creatinine, and the presence of urine protein (proteinuria). Other adverse reactions reported in less than 0.2% of adult patients in clinical trials or during postmarketing surveillance include acute renal failure (unspecified), increased BUN (azotemia), polyuria, and abnormalities in the urinalysis (presence of red blood cells, white blood cells, casts, bilirubin, and urobilinogen).

Rash (unspecified) was reported in 1.5% to 2.2% of pediatric patients receiving imipenem in clinical trials. Although not reported in pediatric patients, pruritus (0.3%) and urticaria (0.2%) were reported in adults. Other adverse reactions reported in less than 0.2% of adult patients during clinical trials include erythema multiforme, angioneurotic edema (angioedema), flushing, cyanosis, hyperhidrosis, skin texture changes, and pruritus vulvae. Stevens-Johnson syndrome and toxic epidermal necrolysis were reported during postmarketing surveillance. Anaphylactoid reactions have been reported with beta-lactam therapy.

Imipenem has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2 to 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days.

Sinus tachycardia was reported in 1.5% of pediatric patients receiving imipenem in clinical trials. Other cardiovascular adverse reactions reported in adult patients in clinical trials include hypotension (0.4%) and palpitations (less than 0.2%).

Although not reported in pediatric patients, fever was reported in 0.5% of adult patients receiving imipenem in clinical trials. Other generalized adverse reactions reported in less than 0.2% of adult patients in clinical trials include polyarthralgia/arthralgia, asthenia, and weakness. Drug fever was reported during postmarketing surveillance.

Hearing loss and tinnitus have been reported in less than 0.2% of adult patients during imipenem clinical trials.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis (less than 0.2%) has been reported with imipenem. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Oral candidiasis was reported in 1.5% of pediatric patients during clinical trials. Infused vein infection was reported in less than 0.2% of adult patients during IV infusion.

Respiratory and related adverse reactions reported in less than 0.2% of adult patients during imipenem clinical trials include chest discomfort/chest pain (unspecified), dyspnea, hyperventilation, and thoracic spine pain.

Electrolyte abnormalities reported in adult patients receiving imipenem in clinical trials include hyponatremia, hyperkalemia, and hyperchloremia.

Imipenem; cilastatin is contraindicated in patients with a carbapenem hypersensitivity. Imipenem-cilastatin should be used cautiously in patients with penicillin hypersensitivity, cephalosporin hypersensitivity, or sensitivity to other beta-lactams (e.g., aztreonam, loracarbef). Although imipenem has been used safely in these patients, imipenem is structurally similar to the penicillins and cephalosporins, causing these patients to be more susceptible to hypersensitivity reactions.

Use imipenem cautiously in patients with brain lesions, a history of seizure disorder, or other neurological disease or condition that may lower the seizure threshold, such as head trauma. In addition, the manufacturer warns against use of imipenem in pediatric patients with CNS infections due to the increased risk of seizures. This risk of imipenem-induced seizures increases when imipenem is given at doses higher than recommended. Imipenem also should be used cautiously in patients receiving drugs when potential CNS effects may be additive.

Due to a lack of data and increased risk of toxicity, the FDA-approved labeling recommends against the use of imipenem in pediatric patients weighing less than 30 kg with renal impairment. Patients with impaired renal function are known to be at increased risk for toxicity, specifically seizures. Adult patients with a CrCl <= 30 mL/minute are particularly at risk; the threshold for increased risk in pediatric patients is not known. Pediatric patients with renal impairment resulting in CrCl <= 50 mL/minute require adjustments of their imipenem dose. The FDA-approved labeling recommends that adult patients with renal failure (CrCl < 15 mL/minute) should not receive imipenem unless hemodialysis is instituted within 48 hours. For patients receiving dialysis, imipenem therapy should only be continued if the benefit outweighs the risk.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including imipenem; cilastatin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Imipenem; cilastatin use may result in laboratory test interference. A false-positive reaction for glucose in the urine has been observed in patients receiving imipenem and using copper-reduction tests (e.g., Benedict's solution, Fehling's solution, and Clinitest tablets). This reaction, however, has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix). Additionally, a positive Coombs' test has been observed during imipenem; cilastatin use.

Description: Imipenem is a beta-lactam antibiotic and was the first drug to be classified as a carbapenem antibiotic. Cilastatin is added as an inhibitor of dehydropeptidase-1, an enzyme found in the renal tubule border that metabolizes imipenem. Without cilastatin, imipenem is rapidly metabolized and causes toxicity to the proximal tubule. Cilastatin itself has no antibacterial activity. Imipenem possesses several traits that make it an effective antibiotic compared to some more narrow spectrum beta-lactams including more efficient penetration through the bacterial cell wall, resistance to bacterial enzymes, and affinity for all bacterial penicillin-binding proteins (PBPs). Overuse can lead to the development of resistance; therefore, imipenem should be used judiciously. The combination of imipenem; cilastatin is used to treat severe or resistant infections, especially those that are polymicrobial, such as complicated intra-abdominal infections. Imipenem is also used for the treatment of patients with febrile neutropenia and is considered a first-line therapy. Seizures are one of the most serious adverse reactions reported with imipenem and have been reported particularly in patients with CNS disorders (e.g., meningitis, brain lesions, or history of seizures) and in patients with impaired renal function; imipenem dosages should be reduced in patients with renal impairment. Imipenem is not indicated for patients with CNS infections due to the risk of seizures. Imipenem is FDA-approved for use in pediatric patients as young as neonates.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter calcoaceticus, Acinetobacter sp., Aeromonas hydrophila, Alcaligenes sp., Bacillus sp., Bacteroides fragilis, Bacteroides intermedius, Bacteroides sp., Bacteroides thetaiotaomicron, Bifidobacterium sp., Capnocytophaga sp., Citrobacter sp., Clostridium perfringens, Clostridium sp., Enterobacter cloacae, Enterobacter sp., Enterococcus faecalis, Escherichia coli, Eubacterium sp., Fusobacterium sp., Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella sp., Listeria monocytogenes, Morganella morganii, Neisseria gonorrhoeae, Nocardia sp., Pantoea agglomerans, Parabacteroides distasonis, Pasteurella sp., Peptococcus sp., Peptostreptococcus sp., Prevotella bivia, Prevotella disiens, Prevotella melaninogenica, Propionibacterium sp., Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Serratia sp., Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae (group B streptococci), Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus sp. (Group C), Streptococcus sp. (Group G), Veillonella sp., Viridans streptococci
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of intraabdominal infections, including peritonitis, appendicitis, intraabdominal abscess, and peritoneal dialysis-related peritonitis*:
-for the treatment of complicated community-acquired, healthcare-acquired, or hospital-acquired intraabdominal infections with adequate source control:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours for 7 to 10 days.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours for 7 to 10 days.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms). Treat for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
-for the treatment of uncomplicated intraabdominal infections:
Intravenous dosage:
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 4 g/day). Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of peritoneal dialysis-related peritonitis*:
Continuous Intraperitoneal dosage*:
Infants, Children, and Adolescents: 250 mg/L intraperitoneal loading dose, followed by 50 mg/L in each dialysate exchange. Treat for 14 to 21 days.

For the treatment of pulmonary exacerbations in patients with cystic fibrosis*:
Intravenous dosage:
Children and Adolescents: 25 mg/kg/dose IV every 6 hours (Max: 1 g/dose). Imipenem has improved clinical outcomes in small, observational studies in CF patients with acute pulmonary exacerbations; however, a high rate of emergence to Pseudomonas has been observed. The Cystic Fibrosis Foundation recommends a carbapenem as the beta-lactam choice for patients with a cephalosporin sensitivity or multidrug-resistant organisms.

For the empiric treatment of febrile neutropenia*:
Intravenous dosage:
Infants, Children, and Adolescents: 15 to 25 mg/kg/dose IV every 6 hours; consider renal function, concomitant drugs, and clinical status when determining the dose. Imipenem, a carbapenem antibiotic, has been successfully used for the empiric treatment of febrile neutropenia in children. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent (i.e., aminoglycoside, aztreonam) is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

For the treatment of melioidosis* due to Burkholderia pseudomallei:
Intravenous dosage:
Infants, Children, and Adolescents: 60 to 100 mg/kg/day IV in divided doses (25 mg/kg/dose every 6 hours or 20 mg/kg/dose every 8 hours; Max: 1 g/dose) for at least 10 to 14 days and clinical improvement is achieved. After intensive IV therapy, follow with at least 3 months of eradication therapy with oral agents (e.g. trimethoprim/sulfamethoxazole 8 mg/40 mg/kg/dose PO every 12 hours [Max: 320 mg/1,600 mg/dose] +/- doxycycline 2 mg/kg/dose PO every 12 hours [Max: 100 mg/dose]).

For the treatment of anthrax*:
-for the treatment of cutaneous anthrax* without aerosol exposure or signs and symptoms of meningitis:
Intravenous dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for 7 to 10 days or until clinical criteria for stability are met; may consider step-down to oral therapy.
-for the treatment of cutaneous anthrax* with aerosol exposure and without signs and symptoms of meningitis:
Intravenous dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 8 hours for 7 to 10 days or until clinical criteria for stability are met; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course.
-for the treatment of systemic anthrax* without aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy:
Intravenous dosage:
Neonates 32 weeks gestation and older: 25 mg/kg/dose IV every 8 hours for at least 14 days; may consider step-down to oral therapy.
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy.
-for the treatment of systemic anthrax* with aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy:
Intravenous dosage:
Neonates 32 weeks gestation and older: 25 mg/kg/dose IV every 8 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy.
Immunocompromised Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.

For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia:
-for the treatment of nonspecific lower respiratory tract infections:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. The FDA-approved dosage is 25 mg/kg/dose IV every 12 hours for neonates weighing 1.5 kg or more.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. The FDA-approved dosage 25 mg/kg/dose IV every 8 hours for neonates weighing 1.5 kg or more.
Infants 1 to 2 months weighing 1.5 kg or more: 25 mg/kg/dose IV every 6 hours.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms and 4 g/day for moderately susceptible organisms).
-for the treatment of community-acquired pneumonia:
Intravenous dosage:
Adolescents: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms and 4 g/day for moderately susceptible organisms) for 5 to 7 days. In persons living with HIV, imipenem; cilastatin is recommended as part of combination therapy for hospitalized patients at risk for P. aeruginosa.

For the treatment of bone and joint infections, including osteomyelitis and infectious arthritis:
-for the treatment of osteomyelitis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms). Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 3 to 4 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
-for the treatment of infectious arthritis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms). Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 2 to 3 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.

For the treatment of skin and skin structure infections, including cellulitis, erysipelas, necrotizing infections, and pyomyositis:
-for the treatment of unspecified skin infections due to a susceptible bacterial species:
Intravenous dosage:
Neonates 7 days and younger: 25 mg/kg/dose IV every 12 hours.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose (Max: 500 mg/dose) IV every 6 hours.
-for the treatment of unspecified skin infections due to bacterial species with intermediate susceptibility:
Intravenous dosage:
Neonates 7 days and younger: 25 mg/kg/dose IV every 12 hours.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours.
-for the treatment of severe nonpurulent skin infections, such as cellulitis and erysipelas:
Intravenous dosage:
Neonates 7 days and younger: 25 mg/kg/dose IV every 12 hours for 5 to 14 days.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours for 5 to 14 days.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours for 5 to 14 days.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for 5 to 14 days.
-for the treatment of necrotizing infections of the skin, fascia, and muscle:
Intravenous dosage:
Neonates 7 days and younger: 25 mg/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.
-for the treatment of pyomyositis:
Intravenous dosage:
Neonates 7 days and younger: 25 mg/kg/dose IV every 12 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.

For the treatment of gynecologic infections:
Intravenous dosage:
Children and Adolescents: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms and 4 g/day for moderately susceptible organisms).

For the treatment of bacteremia and sepsis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from guideline scope.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from guideline scope.
Infants 1 to 2 months: 25 mg/kg/dose IV every 6 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms). Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.

For the treatment of endocarditis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. The FDA-approved dosage is 25 mg/kg/dose IV every 12 hours for neonates weighing 1.5 kg or more.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. The FDA-approved dosage is 25 mg/kg/dose IV every 8 hours for neonates weighing 1.5 kg or more.
Infants 1 to 2 months weighing 1.5 kg or more: 25 mg/kg/dose IV every 6 hours.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms).

For the treatment of urinary tract infection (UTI):
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 12 hours. The FDA-approved dosage is 25 mg/kg/dose IV every 12 hours for neonates weighing 1.5 kg or more.
Neonates older than 7 days: 25 mg/kg/dose IV every 8 hours. The FDA-approved dosage is 25 mg/kg/dose IV every 8 hours for neonates weighing 1.5 kg or more.
Infants 1 to 2 months weighing 1.5 kg or more: 25 mg/kg/dose IV every 6 hours.
Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms).

For the treatment of drug-resistant tuberculosis infection* paired with clavulanic acid as part of combination therapy:
Intravenous dosage:
Infants, Children, and Adolescents: 15 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours.

For the treatment of severe or complicated extensively drug-resistant typhoid fever*:
Intravenous dosage:
Infants, Children, and Adolescents: 20 to 60 mg/kg/day divided every 6 to 8 hours (Max: 1 g/dose) for 10 to 14 days. Consider adding azithromycin for patients who do not improve.

Maximum Dosage Limits:
-Neonates
0 to 7 days: 50 mg/kg/day IV.
older than 7 days : 75 mg/kg/day IV.
-Infants
100 mg/kg/day IV.
-Children
1 to 11 years: 100 mg/kg/day IV (Max: 4 g/day).
12 years: 100 mg/kg/day IV (Max: 4 g/day).
-Adolescents
100 mg/kg/day IV (Max: 4 g/day).

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
The manufacturer does not recommend imipenem use in children weighing less than 30 kg with renal impairment due to a lack of data. Other experts recommend the following adjustments based on a usual dosage of 15 to 25 mg/kg/dose IV every 6 hours. Monitor patients carefully for signs of toxicity.
CrCl more than 50 mL/minute/1.73 m2: no dosage adjustment necessary.
CrCl 30 to 50 mL/minute/1.73 m2: 7 to 13 mg/kg/dose IV every 8 hours.
CrCl 10 to 29 mL/minute/1.73 m2: 7.5 to 12.5 mg/kg/dose IV every 12 hours.
CrCl less than 10 mL/minute/1.73 m2: 7.5 to 12.5 mg/kg/dose IV every 24 hours.
NOTE: For adults with CrCl less than 15 mL/minute, the manufacturer recommends against use unless hemodialysis can be instituted within 48 hours. Patients with renal dysfunction are at higher risk for toxicity.

Intermittent hemodialysis
7.5 to 12.5 mg/kg/dose IV every 24 hours given after hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Imipenem, a carbapenem beta-lactam antibiotic, is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. PBPs are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Imipenem binds to all PBP subtypes but has highest affinity for PBP-2 and PBP 1B. At PBP-3, where cephalosporins bind, imipenem has minimal activity. Antimicrobial activity of imipenem is a result of binding to PBP-1A, PBP-1B, and PBP-2. Because little activity is exerted at PBP-3 (the protein responsible for bacterial septum formation), long, filamentous forms are not produced after imipenem exposure. PBP-2 is responsible for maintaining the rod-like shape. Binding of imipenem to PBP-2 causes bacteria to form spheroplasts or ellipsoidal cells without filament formation. Binding to PBP-1, which is responsible for formation of the cell wall, causes these cells to lyse rapidly. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Prevention of the autolysin response to beta-lactam antibiotic exposure through loss of autolytic activity (mutation) or inactivation of autolysin (low-medium pH) by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in bacteriostatic activity. Imipenem also has greater ability to penetrate the outer membrane of gram-negative bacteria than do the other beta-lactam antibiotics.

Beta-lactams, including imipenem, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above the MIC). This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Carbapenems require free drug concentrations to exceed the MIC for 20% of the dosing interval for bacteriostatic activity and 40% of the dosing interval for maximal bactericidal activity. Cephalosporins require free drug concentrations to be above the MIC for 35% to 40% of the dosing interval for bacteriostatic activity and 60% to 70% of the dosing interval for bactericidal activity. Penicillins require free drug concentrations to exceed the MIC for 30% of the dosing interval to achieve bacteriostatic activity and 50% of the dosing interval to achieve bactericidal activity. Carbapenems also are reported to have a post-antibiotic effect (PAE). PAE is defined as the suppression of bacterial growth that continues after the antibiotic concentration falls below the bacterial MIC. PAE has been reported to be 1.3 to 4 hours with imipenem, 4 to 5 hours with meropenem, and 1.5 hours with ertapenem.

Cilastatin is a reversible, competitive inhibitor of dehydropeptidase-1 (DHP-1), an enzyme found in the brush border of the proximal tubular cells of the kidneys that breaks down imipenem to inactive metabolites. By inhibiting this enzyme, cilastatin prevents the renal metabolism of imipenem, which results in an increase in urinary concentrations of imipenem from 15% to 20% up to 60% to 70% and minimizes the nephrotoxicity observed when imipenem is administered alone. Cilastatin has no antimicrobial activity, nor does it interfere with imipenem's actions.

The susceptibility interpretive criteria for imipenem; cilastatin are delineated by pathogen. The MICs for Enterobacterales are defined as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more (based on a dosage regimen of 500 mg IV every 6 hours or 1 g IV every 8 hours). The MICs for Acinetobacter sp. are defined as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more (based on a dosage of 500 mg IV every 6 hours). The MICs for P. aeruginosa are defined as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more (based on a dosage of 500 mg IV every 6 hours or 1 g IV every 8 hours). The MICs for other non-Enterobacterales, anaerobes, B. mallei, B. pseudomallei, Aggregatibacter sp., Bacillus sp. (excluding B. anthracis) and related genera including Brevibacillus, Cohnella, Lysinibacillus, Paenibacillus, and Sporolactobacillus are defined as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more. The MICs for S. pneumoniae are defined as susceptible at 0.12 mcg/mL or less, intermediate at 0.25 to 0.5 mcg/mL, and resistant at 1 mcg/mL or more. For non-meningitis S. pneumoniae isolates, a penicillin MIC of 0.06 mcg/mL or less can be used to predict imipenem; cilastatin susceptibility. The MICs for H. influenzae and H. parainfluenzae are defined as susceptible at 4 mcg/mL or less. The MICs are defined for Lactobacillus sp., Cardiobacterium sp., E. corrodens, Kingella sp., Abiotrophia sp., and Granulicatella sp. as susceptible at 0.5 mcg/mL or less, intermediate at 1 mcg/mL, and resistant at 2 mcg/mL or more. The MICs are defined for Pediococcus sp. and E. rhusiopathiae as susceptible at 0.5 mcg/mL or less. The MICs are defined for Aeromonas sp. and Vibrio sp. as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. A Streptococcus sp. beta-hemolytic group organism that is susceptible to penicillin can be considered susceptible to imipenem; cilastatin. Considering site of infection and appropriate imipenem; cilastatin dosing, oxacillin-susceptible Staphylococcus sp. can be considered susceptible to imipenem.

Imipenem has a high degree of stability in the presence of beta-lactamases, including both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram-negative bacteria that may be inherently resistant to many beta-lactam antibiotics (e.g., P. aeruginosa, Serratia sp., and Enterobacter sp.).

Pharmacokinetics: Imipenem; cilastatin is administered intravenously. Approximately 20% of imipenem and 40% of cilastatin are protein bound. Imipenem is distributed into most body tissues and fluids including heart valve, bone, uterus, ovary, intestine, saliva, sputum, bile, as well as peritoneal, pleural, and wound fluids. However, imipenem achieves low concentrations within the CSF, and it is not indicated in the treatment of meningitis. The mean volume of distribution (Vd) in adults is 0.23 to 0.31 L/kg.

When administered alone, imipenem is rapidly metabolized in the brush border of the proximal renal tubule by dehydropeptidase 1 (DHP-1); therefore, imipenem must be administered with cilastatin, a DHP-1 inhibitor, to prevent renal metabolism and proximal tubular toxicity. Cilastatin is metabolized in the kidneys to N-acetylcilastatin, which is also an inhibitor of DHP-1. When coadministered with cilastatin, up to 70% of an imipenem dose is excreted unchanged in the urine within 10 hours. In adults, urine concentrations of imipenem more than 10 mcg/mL are seen for up to 8 hours after a 500 mg IV dose. The remainder is eliminated primarily via metabolic inactivation by nonrenal mechanisms. No accumulation of imipenem or cilastatin in the blood is noted with IV doses given every 6 hours in patients with normal renal function. In adults, renal clearance of imipenem resembles creatinine clearance; however, in children, it exceeds creatinine clearance suggesting significant tubular secretion in younger patients. The elimination half-lives of imipenem and cilastatin are approximately 60 minutes in adult patients with normal renal function.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Imipenem is rapidly distributed to body tissues. Peak concentrations are achieved after a 20 minute infusion.


-Special Populations
Pediatrics
Neonates
The elimination half-life of imipenem is longest in premature neonates and decreases with increasing age. The imipenem elimination half-life is approximately 2.5 hours and 1.5 to 2 hours in premature and term neonates, respectively. The volume of distribution is approximately 0.5 L/kg in premature neonates and 0.35 to 0.4 L/kg in term neonates. One pharmacokinetic study of 41 premature neonates (gestational age 29 +/- 3.2 weeks) during the first week of life demonstrated no imipenem accumulation after doses of 10 to 25 mg/kg/dose IV every 12 hours; however, significant accumulation of cilastatin occurred. The mean imipenem half-life was 2.5 hours, but the mean cilastatin half-life was 9.1 hours. The clinical significance of cilastatin accumulation in this population is not known.

Infants and Children
The elimination half-life of imipenem in infants and children is approximately 1 to 1.2 hours, which is similar to what has been reported in adults. The volume of distribution is approximately 0.65 L/kg, which is larger than that reported in adults (0.25 L/kg).

Renal Impairment
Pharmacokinetic data are unavailable in pediatric patients with renal impairment; the FDA-approved product labeling recommends against use in pediatric patients with renal impairment weighing less than 30 kg because of a lack of data. Imipenem is substantially eliminated by the kidneys, and dose adjustments are recommended in adults with renal impairment.

Hemodialysis
Both imipenem and cilastatin are removed by hemodialysis.

Continuous Venovenous Hemodialysis (CVVHD)
Data in pediatric patients are not available. In a study of 6 critically ill adults receiving CVVHD at a fixed blood flow rate of 60 mL/minute, fixed dialysate flow rate of 20 mL/minute, and drainage flow rate of 1 to 3 mL/minute, the imipenem half-life was 2.79 +/- 0.3 hours and the cilastatin half-life was 6.67 +/- 0.93 hours. The authors concluded that extending the dosage interval to every 12 hours would provide appropriate blood concentrations of imipenem; cilastatin (the dose used in the study was 500 mg IV).