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Imipenem and Cilastatin

Imipenem and cilastatin sodium is a fixed combination of imipenem monohydrate (a semisynthetic carbapenem b-lactam antibiotic) and cilastatin sodium, 1, 35 which prevents renal metabolism of imipenem by dehydropeptidase I (DHP I).

Uses

Imipenem and cilastatin sodium solution is used IV in the treatment of serious infections caused by susceptible organisms including lower respiratory tract, skin and skin structure, intra-abdominal, gynecologic, or bone and joint infections. The drug also is used IV in the treatment of serious complicated or uncomplicated urinary tract infections, septicemia, or endocarditis caused by susceptible organisms. If IM therapy is considered appropriate, imipenem and cilastatin sodium for injectable suspension can be used IM in the treatment of serious but mild to moderately severe infections caused by susceptible organisms including lower respiratory tract, skin and skin structure, intra-abdominal, and gynecologic infections. The drug has been used IM for mild-to-moderate urinary tract infections (UTIs) caused by susceptible organisms, although recurrences occasionally have occurred, particularly in those with a history of chronic infection. Treatment failures and/or recurrences also have been reported when the drug was administered IM in the treatment of other infections and may have been related to the route of administration in some cases. Therefore, while it is not always possible to predict outcome, patients for whom IM therapy with the drug is being considered should be selected carefully; IM imipenem and cilastatin sodium therapy 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).

Imipenem and Cilastatin

IM therapy with the drug also may be useful for prolonged anti-infective therapy after an initial IV course. Because of its wide spectrum of activity, one of the principal uses of IV imipenem and cilastatin sodium is the treatment of polymicrobial bacterial infections. The drug is especially useful for empiric IV therapy of serious nosocomial infections that may include both gram-positive and gram-negative aerobic bacteria as well as anaerobic bacteria. IV imipenem and cilastatin sodium generally should not be used for the treatment of monobacterial infections when an anti-infective agent with a narrower spectrum of activity would be effective when used alone or for the treatment of most community-acquired infections caused by organisms susceptible to other anti-infective agents. IV imipenem and cilastatin sodium has been effective in the treatment of monobacterial and polymicrobial bacterial infections that failed to respond to other anti-infective agents, including cephalosporins, penicillins, and/or aminoglycosides.Imipenem and cilastatin sodium should not be used for perioperative prophylaxis. In addition, the manufacturer states that the drug should not be used in the treatment of CNS infections because safety and efficacy of the drug in these infections have not been definitely established. Prior to initiation of imipenem and cilastatin sodium therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. Imipenem and cilastatin sodium therapy may be started pending results of susceptibility tests, but generally should be discontinued if the organism is found to be resistant to the drug. Because resistant strains of Pseudomonas aeruginosa have developed during therapy with imipenem and cilastatin sodium, concomitant therapy with an aminoglycoside is recommended and in vitro susceptibility tests should probably be performed periodically when the drug is used in the treatment of infections caused by this organism.

Gram-positive Aerobic Bacterial Infections

Infections Caused by Aerobic Gram-positive Cocci

Imipenem and cilastatin sodium has been used IV in the treatment of serious lower respiratory tract infections caused by susceptible penicillinase-producing Staphylococcus aureus); serious complicated or uncomplicated urinary tract infections or septicemia caused by susceptible enterococci or penicillinase-producing S. aureus; serious skin and skin structure, bone and joint, or intra-abdominal infections caused by susceptible S. epidermidis, enterococci, or penicillinase-producing S. aureus; serious gynecologic infections caused by susceptible S. epidermidis, group B streptococci, enterococci, or penicillinase-producing S. aureus; or endocarditis caused by penicillinase-producing S. aureus. However, imipenem and cilastatin sodium generally is not considered an initial drug of choice for these infections. Imipenem and cilastatin sodium has also been used IV in the treatment of polymicrobial infections in which Streptococcus pneumoniae, S. pyogenes (group A b-hemolytic streptococci), or nonpenicillinase-producing S. aureus is one of the causative organisms, but other anti-infective agents with a narrower spectrum of activity (e.g., natural penicillins) are indicated for the treatment of monobacterial infections caused by these gram-positive aerobic cocci. Imipenem and cilastatin sodium has been used IM in the treatment of serious lower respiratory tract infections of mild to moderate severity caused by susceptible Streptococcus pneumoniae; serious intra-abdominal infections of mild to moderate severity caused by susceptible Enterococcus faecalis (formerly Streptococcus faecalis) or S. viridans group organisms; serious skin and skin structure infections of mild to moderate severity caused by susceptible S. aureus (including penicillinase-producing S. aureus), S. pyogenes, or group D streptococci (including E. faecalis); or serious gynecologic infections of mild-to-moderate severity caused by susceptible group D streptococci (including E. faecalis). Imipenem and cilastatin sodium usually is effective when used in the treatment of infections caused by penicillinase-producing S. aureus and has been effective when used alone IV in a limited number of patients for the treatment of endocarditis caused by penicillinase-producing S. aureus. However, penicillinase-resistant penicillins are generally the drugs of choice for the treatment of infections caused by susceptible penicillinase-producing staphylococci. Imipenem and cilastatin sodium has been used IV in the treatment of a limited number of infections caused by methicillin-resistant staphylococci (MRSA); however, the efficacy of the drug in these infections and adequate in vitro methods for determining susceptibility of MRSA to imipenem have not been established. Although imipenem and cilastatin sodium may be effective in the treatment of some enterococcal infections (e.g., skin and skin structure infections), the drug should not be used in the treatment of enterococcal endocarditis. Imipenem and cilastatin sodium has been effective when used alone IV in a limited number of patients for the treatment of enterococcal endocarditis; however, imipenem is not bactericidal against enterococci and the drug has been less effective than penicillin G used in conjunction with an aminoglycoside in the treatment of E. faecalis (formerly S. faecalis) endocarditis in animal models.

Bacillus Infections

Some clinicians suggest that imipenem and cilastatin sodium can be used for the treatment of invasive infections caused by Bacillus cereus. Individuals with B. cereus food poisoning usually require only supportive care (oral rehydration or, occasionally IV fluid and electrolyte replacement for those with severe dehydration); however, patients with invasive disease require anti-infective therapy and prompt removal of potentially infected foreign bodies (e.g., indwelling intravascular catheters, implanted devices). Some clinicians consider vancomycin the drug of choice for invasive B. cereus infections and recommend carbapenems (imipenem or meropenem) or clindamycin as alternatives.

Nocardia Infections

Imipenem and cilastatin sodium has been effective when used for the treatment of infections caused by Nocardia, including pulmonary nocardiosis caused by N. asteroides and primary cutaneous nocardiosis. Many clinicians suggest that co-trimoxazole is the drug of first choice for Nocardia infections. Other recommended regimens for Nocardia 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. In patients with CNS or disseminated disease or overwhelming infection, concomitant amikacin may be indicated during the first 4-12 weeks or until the patients improves clinically.

Rhodococcus Infections

Imipenem and cilastatin sodium used in conjunction with vancomycin is one of several regimens recommended for the treatment of infections caused by Rhodococcus equi. R. equi has been identified as a cause of pulmonary infections (e.g., lung abscess) in immunocompromised individuals such as patients with human immunodeficiency virus (HIV) infection and solid organ transplant recipients. While optimum regimens for the treatment of these infections have not been identified, combination regimens usually are recommended. Some clinicians suggest that R. equi infections be treated with a regimen of vancomycin given with a fluoroquinolone, rifampin, a carbapenem (imipenem or meropenem), or amikacin.

Gram-negative Aerobic Bacterial Infections

Infections Caused by Enterobacteriaceae

Imipenem and cilastatin sodium is used IV in the treatment of serious lower respiratory tract infections or septicemia caused by susceptible Enterobacter, Escherichia coli, Klebsiella, or Serratia marcescens; serious complicated or uncomplicated urinary tract infections caused by susceptible Enterobacter, E. coli, Klebsiella, Morganella morganii, Proteus vulgaris, or Providencia rettgeri; or serious bone and joint infections caused by susceptible Enterobacter. The drug is also used IV in the treatment of serious intra-abdominal infections caused by susceptible Citrobacter, Enterobacter, E. coli, Klebsiella, M. morganii, or Proteus; serious gynecologic infections caused by susceptible Enterobacter, E. coli, Klebsiella, or Proteus; or serious skin and skin structure infections caused by susceptible Citrobacter, Enterobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, P. rettgeri, or Serratia. Imipenem and cilastatin sodium is used IM in the treatment of serious intra-abdominal or gynecologic infections of mild-to-moderate severity caused by susceptible E. coli or K. pneumoniae or serious skin and skin structure infections of mild-to-moderate severity caused by susceptible Citrobacter, E. coli, Enterobacter cloacae, or K. pneumoniae. Imipenem and cilastatin sodium has generally been effective when used alone IV in the treatment of serious infections caused by susceptible Enterobacteriaceae. Although some clinicians recommend that an aminoglycoside be used concomitantly if the drug is used IV for empiric therapy of nosocomial gram-negative bacteremia in seriously ill patients, other clinicians state that imipenem and cilastatin sodium can generally be used alone IV for these infections unless there is a possibility that Pseudomonas aeruginosa may be present.

Pseudomonas aeruginosa Infections

Imipenem and cilastatin sodium is used IM or IV in the treatment of intra-abdominal or skin and skin structure infections, and is used IV in the treatment of serious complicated or uncomplicated urinary tract infections,septicemia, or bone and joint infections caused by susceptible Pseudomonas aeruginosa. Because resistant strains of Ps. aeruginosa have emerged during imipenem and cilastatin sodium therapy, most clinicians state that an aminoglycoside should be used concomitantly whenever the drug is used in the treatment of serious infections known or suspected to be caused by Ps. aeruginosa. Clinical improvement has been observed in some patients when imipenem and cilastatin sodium was used IV for the treatment of acute exacerbations of bronchopulmonary Ps. aeruginosa infections in patients with cystic fibrosis; however, as with other anti-infective agents, a bacteriologic cure is rarely obtained and should not be expected in these patients.

Acinetobacter Infections

Imipenem and cilastatin sodium is used in the treatment of serious infections caused by Acinetobacter; it is administered IV in the treatment of lower respiratory tract infections and IM or IV in the treatment of skin and skin structure infections caused by these organisms. Some clinicians suggest that carbapenems (imipenem or meropenem) are drugs of choice for the treatment of Acinetobacter infections and recommend concomitant use of an aminoglycoside (amikacin, gentamicin, tobramycin) in severe infections.

Campylobacter Infections

Some clinicians suggest that imipenem and cilastatin sodium is a drug of choice for the treatment of systemic infections caused by Campylobacter fetus. Campylobacter are spiral or curved, motile, microaerophilic gram-negative bacilli. Most Campylobacter infections reported in the US are caused by C. jejuni and involve mild to moderate gastroenteritis, although complications can occur as the result of local invasion of the organism (e.g., GI hemorrhage, proctitis, pancreatitis) and systemic infection has been reported. While relatively rare in the US, C. fetus infection usually involves systemic disease, including bacteremia, sepsis, and meningitis, especially in neonates and debilitated hosts. Erythromycin or azithromycin usually is considered the drug of choice for the treatment of gastroenteritis or locally invasive infections caused by C. jejuni when such therapy is considered necessary; systemic infections caused by C. jejuni or C. fetus usually require parenteral therapy. Some clinicians suggest that the treatment of choice for C. fetus infection is a carbapenem antibiotic (imipenem or meropenem) and that gentamicin can be used as an alternative.

Melioidosis

Imipenem and cilastatin sodium has been used effectively for the treatment of localized or septicemic melioidosis, a potentially life-threatening disease caused by Burkholderia pseudomallei (formerly Ps. pseudomallei). B. pseudomallei is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents. Some clinicians suggest that drugs of choice for the treatment of melioidosis are imipenem or ceftazidime. Other drugs that have been recommended as alternative agents for the treatment of melioidosis include IV amoxicillin and clavulanate potassium (not commercially available in the US), IV meropenem, oral amoxicillin and clavulanate potassium, or a 3-drug regimen of chloramphenicol, doxycycline, and co-trimoxazole. B. pseudomallei is difficult to eradicate, and relapse of melioidosis commonly occurs. Therefore, anti-infective therapy usually is continued for 6 weeks to 6 months or, alternatively, a parenteral anti-infective (e.g., ceftazidime) is given for at least 1-2 weeks followed by an oral anti-infective (e.g., amoxicillin and clavulanate potassium) given for at least 3-6 months.

Actinomycosis

Imipenem and cilastatin sodium has been effective when used in a limited number of patients for the treatment of thoracic actinomycosis. However, IV penicillin G or ampicillin usually are the drugs of choice for the treatment of all forms of actinomycosis, including thoracic, abdominal, CNS, and cervicofacial infections.

Capnocytophaga Infections

Some clinicians suggest that imipenem and cilastatin sodium can be used in the treatment of infections caused by Capnocytophaga canimorsus (formerly CDC group DF-2). C. canimorsus is a gram-negative bacilli that can cause life-threatening septicemia, meningitis, and/or endocarditis and often is associated with disseminated intravascular coagulation; Capnocytophagainfection usually occurs as the result of a dog bite or other close contact with a dog. The optimum regimen for the treatment of infections caused by Capnocytophaga has not been identified, but some clinicians recommend use of penicillin G or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem or meropenem), vancomycin, a fluoroquinolone, or clindamycin.

Legionella Infections

Imipenem and cilastatin sodium has been effective when used in a few patients for the treatment of Legionella pneumophila respiratory tract infections. However, other anti-infectives (e.g., a macrolide or a fluoroquinolone with or without rifampin) generally are preferred for L. pneumophila infections.

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Imipenem and cilastatin sodium is used either IM or IV in the treatment of infections caused by gram-positive and gram-negative anaerobic bacteria. The drug has been effective IV in the treatment of serious intra-abdominal infections caused by susceptible Bifidobacterium, Clostridium, Peptococcus, Peptostreptococcus, Eubacterium, or Propionibacterium; serious gynecologic infections caused by susceptible Bifidobacterium, Peptococcus, Peptostreptococcus, or Propionibacterium; or serious skin and skin structure infections caused by susceptible Peptococcus or Peptostreptococcus. IV imipenem and cilastatin sodium has also been effective in the treatment of septicemia or serious intra-abdominal, gynecologic, or skin and skin structure infections caused by susceptible Bacteroides, including B. fragilis, and in the treatment of serious intra-abdominal tract or skin and skin structure infections caused by susceptible Fusobacterium. Imipenem and cilastatin sodium is used IM or IV in the treatment of serious intra-abdominal infections of mild-to-moderate severity caused by susceptible Bacteroides (including B. fragilis, B. distasonis, B. thetaiotaomicron), Fusobacterium, Prevotella intermedia (formerly B. intermedius), or Peptostreptococcus; serious skin and skin structure infections of mild-to-moderate severity caused by susceptible Bacteroides, including B. fragilis; or serious gynecologic infections of mild-to-moderate severity caused by susceptible P. intermedia or Peptostreptococcus. Imipenem and cilastatin sodium has been effective when used alone IV in the treatment of mixed aerobic-anaerobic infections such as peritonitis, intra-abdominal abscess, and gynecologic infections. In several controlled studies, IV imipenem and cilastatin sodium alone was at least as effective as gentamicin used in conjunction with clindamycin for the treatment of mixed aerobic-anaerobic bacterial infections. However, further study is needed to establish the relative efficacy and safety of therapy with IV imipenem and cilastatin sodium compared with therapy with an aminoglycoside used in conjunction with clindamycin, metronidazole, or cefoxitin or with other regimens used in the treatment of mixed aerobic-anaerobic bacterial infections.

Respiratory Tract Infections

Imipenem and cilastatin sodium has been used IV in the treatment of serious lower respiratory tract infections (including pneumonia) caused by susceptible penicillinase-producing S. aureus), S. pneumoniae, Enterobacter, E. coli, Klebsiella, or S. marcescens.

Community-acquired Pneumonia

Although imipenem generally is active against S. pneumoniae (including drug-resistant S. pneumoniae), the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) state that the drug is not usually considered a drug of first choice for the empiric treatment of community-acquired pneumonia (CAP). The ATS suggests that use of imipenem in the treatment of CAP be reserved for patients at risk for Ps. aeruginosa infections. Factors that increase the risk of Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an intensive care unit (ICU), structural lung disease (bronchiectasis, cystic fibrosis), corticosteroid therapy (prednisone dosage exceeding 10 mg daily), broad-spectrum anti-infective therapy given for longer than 7 days within the past month, and malnutrition. In CAP patients with risk factors for Ps. aeruginosa, the ATS recommends use of an empiric regimen that includes 2 antipseudomonal agents and also provides coverage for drug-resistant S. pneumoniae and Legionella. These experts suggest that this can be accomplished with a regimen that includes an IV antipseudomonal b-lactam anti-infective (e.g., cefepime, piperacillin and tazobactam, imipenem, meropenem) in conjunction with an IV antipseudomonal fluoroquinolone (e.g., ciprofloxacin) or a regimen that includes one of these IV antipseudomonal b-lactam anti-infectives, an IV aminoglycoside, and either an IV macrolide (e.g., azithromycin) or an IV nonpseudomonal quinolone. If anaerobic bacteria have been identified or are suspected in patients with pulmonary infections, the IDSA recommends use of clindamycin, a b-lactam/b-lactamase inhibitor combination, imipenem, or meropenem.

Empiric Therapy in Febrile Neutropenic Patients

Imipenem and cilastatin sodium has been effective when used alone for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic adults or pediatric patients. Imipenem and cilastatin sodium used alone generally is as effective for empiric therapy in these patients as ceftazidime used alone or ceftazidime used in combination with an aminoglycoside or piperacillin. Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present. The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding usual pathogens in these patients and data regarding their in vitro susceptibility to available anti-infective agents. The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen. No empiric regimen has been identified that would be appropriate for all patients. Regimens that have been recommended for empiric therapy in febrile neutropenic patients with presumed bacterial infections include monotherapy with a third or fourth generation cephalosporin (i.e., ceftazidime, cefepime) or a carbapenem (e.g., imipenem and cilastatin sodium, meropenem); combination therapy consisting of a b-lactam antibiotic (e.g., ceftazidime, ceftriaxone), a carbapenem (e.g., imipenem, meropenem), an extended-spectrum penicillin (e.g., mezlocillin, piperacillin, ticarcillin), or a fixed combination of an extended-spectrum penicillin and a b-lactamase inhibitor (e.g., piperacillin sodium and tazobactam sodium, ticarcillin disodium and clavulanate potassium) given in conjunction with an aminoglycoside (e.g., amikacin, gentamicin, tobramycin); or combination therapy consisting of 2 b-lactam antibiotics (e.g., ceftazidime given with piperacillin). The IDSA recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate) should only be considered in selected adults at low risk for complications who have no focus of bacterial infection and no signs or symptoms of systemic infection other than fever. At health-care facilities where gram-positive bacteria are common causes of serious infection and use of vancomycin in the initial empiric regimen is considered necessary, the IDSA recommends 2- or 3-drug combination therapy that includes vancomycin and either cefepime, ceftazidime, imipenem, or meropenem given with or without an aminoglycoside; vancomycin should be discontinued 24-48 hours later if a susceptible gram-positive bacterial infection is not identified. At health-care facilities where vancomycin is not indicated in the initial empiric regimen, the IDSA recommends monotherapy with a third or fourth generation cephalosporin (ceftazidime, cefepime) or a carbapenem (imipenem, meropenem) for uncomplicated cases; however, for complicated cases or if anti-infective resistance is a problem, combination therapy consisting of an aminoglycoside (amikacin, gentamicin, tobramycin) given in conjunction with an antipseudomonal penicillin (ticarcillin and clavulanate, piperacillin and tazobactam), an antipseudomonal cephalosporin (cefepime, ceftazidime), or a carbapenem (imipenem, meropenem) is recommended. Regardless of the initial regimen selected, patients should be reassessed after 3-5 days of treatment and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient. Published protocols for the treatment of infections in febrile neutropenic patients should be consulted 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.

Dosage and Administration

Reconstitution and Administration

Imipenem and cilastatin sodium is administered by intermittent IV infusion as a solution and by deep IM injection as a suspension. IM administration of the drug should be limited to mild to moderately severe infections.

Intermittent IV Infusion

Piggyback units containing 250 mg of imipenem and 250 mg of cilastatin or those containing 500 mg of imipenem and 500 mg of cilastatin should be reconstituted with 100 mL of a compatible IV solution to provide solutions containing 2.5 or 5 mg/mL of each drug, respectively. ADD-Vantage® vials containing imipenem and cilastatin sodium should be reconstituted according to the manufacturer’s directions with the diluent provided. For IV administration, the manufacturer recommends that an imipenem concentration of 5 mg/mL not be exceeded since the physical and chemical stability of solutions of the drug may be adversely affected at higher concentrations. Alternatively, the contents of 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. 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. The resulting initial suspension should be shaken well and then transferred to the IV solution container. 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. Initial suspensions of the drug should not be infused IV. The resulting solution of imipenem and cilastatin sodium should be agitated until clear, but should not be heated to facilitate dissolution. The rate of IV infusion of imipenem depends on the dose of the drug. Each 125-, 250- or 500-mg dose of imipenem should generally be infused over 20-30 minutes, and each 1-g dose of the drug should generally be infused over 40-60 minutes. If nausea and/or vomiting occur during administration of imipenem, the rate of IV infusion may be decreased. If an aminoglycoside is administered concomitantly with imipenem and cilastatin sodium, the drugs should not be admixed but may be administered from separate containers through the same IV tubing. Imipenem and cilastatin sodium solutions should be inspected visually for particulate matter prior to administration whenever solution and container permit.

IM Injection

Imipenem and cilastatin sodium powder for injectable suspension should be reconstituted with lidocaine hydrochloride 1% injection (without epinephrine). To reconstitute the suspension, 2 or 3 mL of the diluent should be added to the vial labeled as containing 500 or 750 mg of imipenem, respectively. The vial should be agitated well to form a suspension and the entire contents of the vial withdrawn for IM injection. Imipenem and cilastatin sodium for injectable suspension is 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. To avoid inadvertent injection of the suspension into a blood vessel, the plunger of the syringe should be drawn back prior to IM administration to ensure that blood is not aspirated. The IM preparation should not be used IV.

Dosage

Dosage of imipenem and cilastatin sodium is generally expressed in terms of the imipenem content of the fixed combination; dosage of imipenem monohydrate is expressed in terms of anhydrous imipenem. The dosage of imipenem should be given in equally divided doses based on type and severity of infection, susceptibility of the causative organism(s), and the patient’s renal function and body weight.

Adult Dosage

The manufacturer states that recommended usual IV dosages of imipenem and cilastatin sodium are for adults weighing at least 70 kg. Modification of dosage is recommended for patients weighing less than this. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment and Reduced Body Weight.) For the treatment of mild infections, the usual adult IV dosage of imipenem is 250 mg every 6 hours (1 g daily) for infections caused by fully susceptible gram-positive or -negative aerobic or anaerobic bacteria and 500 mg every 6 hours (2 g daily) for infections caused by moderately susceptible bacteria. Adults with moderately severe infections caused by fully susceptible organisms should receive 500 mg of imipenem IV every 6 (2 g daily) or 8 (1. g daily) hours, and adults with moderately severe infections caused by moderately susceptible organisms should receive 500 mg every 6 hours (2 g daily) to 1 g IV every 8 hours (3 g daily). For the treatment of severe, life-threatening infections, adults should receive 500 mg IV every 6 hours (2 g daily) for infections caused by fully susceptible organisms and 1 g IV every 6 (4 g daily) or 8 (3 g daily) hours for infections caused by moderately susceptible organisms. The maximum adult IV dosage of imipenem recommended by the manufacturer is 50 mg/kg daily or 4 g daily, whichever is lower. However, patients older than 12 years of age with cystic fibrosis who had normal renal function have received daily dosages up to 90 mg/kg (maximum daily dosage: 4 g), given in divided doses. The manufacturer states that there is no evidence that higher dosages would be more effective. When IM imipenem is used for treatment of lower respiratory tract, skin and skin structure, or gynecologic infections of mild-to-moderate severity, adults can receive 500 or 750 mg of imipenem IM every 12 hours, depending on the severity of the infection. For the IM treatment of intra-abdominal infections of mild-to-moderate severity, adults can receive 750 mg of imipenem IM every 12 hours. The maximum adult dosage of IM imipenem recommended by the manufacturer is 1.5 g daily. The duration of therapy depends on the type and severity of the infection. Generally, IM imipenem therapy should be continued for at least 2 days after the signs and symptoms of infection have resolved; the safety and efficacy of IM therapy beyond 14 days have not been established.

Urinary Tract Infections

For the treatment of uncomplicated urinary tract infection, the usual adult IV dosage of imipenem is 250 mg every 6 hours (1 g daily) for infections caused by fully susceptible gram-positive or -negative aerobic or anaerobic bacteria or by moderately susceptible bacteria. For the treatment of complicated urinary tract infection, the usual adult IV dosage of imipenem is 500 mg every 6 hours (2 g daily) for infections caused by fully susceptible gram-positive or -negative aerobic or anaerobic bacteria or by moderately susceptible bacteria.

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective therapy in febrile neutropenic patients, IV imipenem and cilastatin sodium has been given in a dosage of 500 mg every 6 hours.

Pediatric Dosage

The usual IV dosage of imipenem and cilastatin sodium for pediatric patients 3 months of age or older for the treatment of infections (other than CNS infections) caused by susceptible bacteria is 15-25 mg/kg every 6 hours. Based on studies in adults, the manufacturer states that the maximum daily dosage of the drug in pediatric patients is 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 Pseudomonas aeruginosa); however, higher dosage (up to 90 mg/kg daily in older children) has been used in some cystic fibrosis patients. The recommended dosage of IV imipenem and cilastatin sodium for the treatment of infections (other than CNS infections) in infants 4 weeks to 3 months of age who weigh at least 1.5 kg is 25 mg/kg every 6 hours. Neonates younger than 1 week of age who weigh at least 1.5 kg can receive an IV dosage of 25 mg/kg every 12 hours and neonates 1-4 weeks of age who weigh at least 1.5 kg can receive an IV dosage of 25 mg/kg every 8 hours. When IV imipenem and cilastatin sodium is used in pediatric patients, doses of 500 mg or less should be given by IV infusion over 15-30 minutes and doses greater than 500 mg should be given by IV infusion over 40-60 minutes.

Dosage in Renal Impairment and Reduced Body Weight

Modification of the usual dosage of imipenem generally is unnecessary in patients with creatinine clearances greater than 70 mL/minute per 1.73 m who weigh at least 70 kg. However, modification of dosage is necessary in those with normal renal function weighing less than 70 kg and in any patient with impaired renal function regardless of body weight. Safety and efficacy of IM imipenem and cilastatin sodium therapy in patients with creatinine clearances less than 20 mL/minute per 1.73 m have not been established. In patients with creatinine clearances of 70 mL/minute per 1.73 m or less and in those weighing less than 70 kg, doses and/or frequency of IV administration of imipenem should be modified in response to the degree of renal impairment, body weight, type and severity of the infection, and susceptibility of the causative organisms. 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 creatinine clearance. The patient’s creatinine clearance (Ccr) can be estimated by using the following formulas: The manufacturer recommends the following reduced IV dosage based on the patient’s creatinine clearance and body weight (see tables above). The manufacturer recommends that patients with creatinine clearances of 6-20 mL/minute per 1.73 m receive 125 or 250 mg of imipenem every 12 hours for infections caused by most susceptible organisms. When the 500-mg IV dose given twice daily (every 12 hours) is used in these patients, there may be an increased risk of seizures. In patients undergoing hemodialysis, IV imipenem and cilastatin sodium therapy is recommended only when the potential benefit from the drug outweighs the potential risk of drug-induced seizures. Patients with creatinine clearances of 5 mL/minute or less per 1.73 2 should not receive imipenem and cilastatin sodium IV unless hemodialysis is instituted within 48 hours. The manufacturer states that IV dosage recommendations and precautions for patients with creatinine clearances of 6-20 mL/minute per 1.73 m also apply when imipenem and cilastatin sodium is used IV in patients with creatinine clearances of 5 mL/minute or less per 1.73 m who are undergoing hemodialysis. If imipenem and cilastatin sodium is used IV in hemodialysis patients, a supplemental dose of the drug should be given after each dialysis period and at 12-hour intervals thereafter. If the drug is used IV in dialysis patients, especially those with CNS disease, the patients should be carefully monitored for adverse CNS effects (e.g., confusion, myoclonic activity, seizures). (See Cautions: Precautions and Contraindications.)

Cautions

Adverse effects reported with imipenem and cilastatin sodium are similar to those reported with other b-lactam antibiotics, and the drug is generally well tolerated. Adverse CNS effects, including seizures and myoclonus, have been reported occasionally with IV imipenem and cilastatin sodium. Although further experience with the drug is needed before the true incidence of these adverse CNS effects can be determined, experience to date indicates that these effects may occur more frequently with IV imipenem and cilastatin sodium than with the IM formulation of the drug or with other currently available b-lactam antibiotics.

GI Effects

Adverse GI effects are among the most frequent adverse reactions to imipenem and cilastatin sodium. Nausea, diarrhea, and vomiting have been reported in up to 4% of patients receiving the drug. Nausea and vomiting appear to be related to the rate of IV infusion, especially when 1-g doses of the drug are being administered, and have rarely been accompanied by hypotension or hyperventilation. Nausea and vomiting are generally ameliorated by decreasing the IV infusion rate, but may occasionally be severe enough to require discontinuance of the drug. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis), caused by toxin-producing clostridia resistant to imipenem, has occurred in less than 0.2% of patients during or following discontinuance of imipenem and cilastatin sodium therapy. C. difficile and/or its toxin has been isolated from the feces of patients who developed diarrhea and/or colitis during therapy with the drug. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. If colitis is moderate to severe or is not relieved by discontinuance of imipenem and cilastatin sodium, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered. Other adverse GI effects that have been reported in less than 0.2% of patients receiving IV imipenem and cilastatin sodium include hemorrhagic colitis, gastroenteritis, abdominal pain, glossitis, papillar hypertrophy of the tongue, staining of the teeth and/or tongue, heartburn, pharyngeal pain, taste perversion, and increased salivation. Imipenem and cilastatin sodium therapy generally has only a minimal effect on normal bowel flora. Either no decrease or only a slight decrease in total bacterial counts of normal aerobic and anaerobic fecal flora occurs during or following therapy with the drug, presumably because only low concentrations of microbiologically active drug are attained in the intestine following IV administration.

Hematologic Effects

Eosinophilia has been reported in up to 4% of patients receiving imipenem and cilastatin sodium. Transient leukopenia, neutropenia, agranulocytosis, pancytopenia, bone marrow depression, hemolytic anemia, thrombocytopenia, and thrombocytosis have been reported in less than 2% of patients receiving the drug. Leukocytosis, monocytosis, lymphocytosis, and basophilia have also been reported rarely. Although decreased hemoglobin concentration, decreased hematocrit, decreased erythrocyte count, and prolonged prothrombin time have been reported rarely in patients receiving imipenem and cilastatin sodium, a causal relationship to the drug has not been established. Positive direct antiglobulin (Coombs’) test results, without clinical or laboratory evidence of hemolysis, have been reported in about 2%134, 196, 198 of patients receiving imipenem and cilastatin sodium.

CNS Effects

Adverse CNS effects have been reported occasionally in patients receiving IV imipenem and cilastatin sodium; however, similar CNS effects have not been reported to date with IM imipenem and cilastatin sodium therapy.

Seizures have been reported in up to 1.5%1, 134 and dizziness, somnolence, encephalopathy, confusion, myoclonus, tremor, paresthesia, vertigo, headache, and psychic disturbances, and hallucinations have been reported in less than 0.3% of patients receiving the drug IV. In most reported cases, seizures or myoclonus occurred in patients with preexisting CNS disorders (e.g., a history of seizures, brain lesions, recent head trauma) and/or who had received relatively high IV dosages of the drug in relation to renal function and body size (e.g., geriatric patients). However, seizures have also occurred during IV imipenem and cilastatin sodium therapy in some patients with no recognized or documented underlying CNS disorder. Generalized seizures developed during concurrent therapy with ganciclovir and subsided in some patients despite continued ganciclovir therapy when imipenem and cilastatin sodium was discontinued. (See Drug Interactions: Ganciclovir.) Further study is needed to identify other factors that may contribute to the development of adverse CNS effects during IV imipenem and cilastatin sodium therapy, but there is some evidence that the drug may potentiate seizure activity or lower the seizure threshold in patients with other predisposing factors. Therefore, if IM or IV imipenem and cilastatin sodium is used in patients with a known seizure disorder, anticonvulsant therapy should be continued during imipenem and cilastatin sodium therapy. If focal tremors, myoclonus, or seizures occur in patients receiving IV or IM imipenem and cilastatin sodium, anticonvulsant therapy should be initiated and dosage of imipenem and cilastatin sodium should be decreased or the drug discontinued.

Dermatologic and Hypersensitivity Reactions

Hypersensitivity reactions including rash, fever, pruritus, and urticaria have been reported in less than 3% of patients receiving imipenem and cilastatin sodium. Allergic dermatitis, erythema multiforme, facial edema or angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and flushing have also been reported rarely. Hypersensitivity reactions to imipenem and cilastatin sodium have occurred when the drug was administered to patients hypersensitive to penicillins. (See Cautions: Precautions and Contraindications.)If a hypersensitivity reaction occurs during imipenem and cilastatin sodium therapy, the drug should be discontinued. Severe hypersensitivity or anaphylactic reactions should be treated with appropriate therapy (e.g., epinephrine, oxygen, IV corticosteroids, airway management including intubation) as indicated.

Renal Effects

Transient increases in BUN and/or serum creatinine concentrations have been reported in less than 2% of patients receiving imipenem and cilastatin sodium. Oliguria/anuria, polyuria, proteinuria, discoloration of urine, acute renal failure, and the presence of erythrocytes, leukocytes, bilirubin, urobilinogen, bacteria, or casts in urine have also been reported rarely in patients receiving the drug. The role of imipenem and cilastatin sodium in producing these changes in renal function is difficult to determine, since factors predisposing to prerenal azotemia or to impaired renal function usually have been present. When given alone, imipenem is nephrotoxic in animals; however, concomitant administration of cilastatin sodium apparently may decrease the nephrotoxic potential of the drug. Acute tubular necrosis occurred in rabbits and monkeys who received imipenem alone in doses greater than 100 mg/kg; nephrotoxicity did not occur when 360-mg/kg doses of cilastatin sodium were administered concomitantly with 360-mg/kg doses of imipenem. Although the mechanism by which cilastatin apparently decreases the nephrotoxic potential of imipenem has not been determined to date, it has been suggested that since cilastatin competes with imipenem for tubular secretion it may protect the kidneys by preventing accumulation of imipenem and/or its metabolites in renal tubular cells. Usual dosages of imipenem and cilastatin sodium do not appear to be nephrotoxic in humans. Urinary β2-microglobulin concentrations were generally unaffected or increased only slightly in healthy adults who received 1-g doses of the drug IV every 6 hours for 10 days.

Local Effects

Phlebitis and/or thrombophlebitis have generally been reported in 2-5% of patients receiving imipenem and cilastatin sodium IV. In some studies, however, phlebitis occurred in up to 60% of patients receiving the drug. Phlebitis is generally mild, but may be severe enough to require discontinuance of the drug. Other adverse local reactions, including pain, erythema, induration, or infection at the IV infusion site, have been reported in 1% or less of patients receiving the drug. Pain at the site of injection has been reported in 1.2% of patients receiving imipenem and cilastatin sodium IM; concomitant injection with lidocaine hydrochloride 1% can minimize but not eliminate the risk of such pain.

Hepatic Effects

Transient increases in serum concentrations of AST (SGOT), ALT (SGPT), and alkaline phosphatase have been reported in 2-6% of patients receiving imipenem and cilastatin sodium; jaundice has been reported in less than 0.2% of patients receiving the drug. Increases in serum bilirubin and LDH1, 256 concentrations and hepatitis have also been reported rarely.

Other Adverse Effects

Hypotension has been reported in less than 1% and chest discomfort, dyspnea, hyperventilation, thoracic spinal pain, palpitation, tachycardia, polyarthralgia, and asthenia and/or weakness have been reported in less than 0.2% of patients receiving imipenem and cilastatin sodium. Other adverse effects that have been reported in less than 0.2% of patients receiving the drug include cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae, decreased serum sodium concentrations, increased serum potassium and chloride concentrations, tinnitus, and hearing loss.

Precautions and Contraindications

Prior to initiation of therapy with imipenem and cilastatin sodium, careful inquiry should be made concerning previous hypersensitivity reactions to b-lactam antibiotics, including penicillins and cephalosporins, or to other allergens. There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other b-lactam antibiotics, and hypersensitivity reactions to imipenem and cilastatin sodium have occurred in patients hypersensitive to penicillins. Therefore, imipenem and cilastatin sodium should be used with caution in patients with a history of hypersensitivity reactions to penicillins. Imipenem and cilastatin sodium is contraindicated in patients who are hypersensitive to any ingredient in the formulation. Imipenem and cilastatin sodium that has been reconstituted with lidocaine hydrochloride for IM injection is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block. IM imipenem and cilastatin sodium is not intended for use in severe and/or life-threatening infections (e.g., sepsis, endocarditis). (See Uses.) Care should be taken to avoid inadvertent injection of IM imipenem and cilastatin sodium into a blood vessel. Adverse CNS effects such as confusional states, myoclonus, and seizures have been reported with IV imipenem and cilastatin sodium, particularly when administered in dosages exceeding those recommended by the manufacturer. (See Cautions: CNS Effects.) Similar CNS effects have not been reported to date with IM imipenem and cilastatin sodium therapy. Although adverse CNS effects have been reported most frequently in patients with CNS disorders (e.g., a history of seizures, brain lesions, recent head trauma) and/or patients with renal impairment, these effects have also been reported in some patients with no recognized or documented underlying CNS disorders or renal impairment. Patients with renal impairment (i.e., those with creatinine clearances = 20 mL/minute per 1.73 m) whether or not undergoing hemodialysis, who received imipenem and cilastatin dosages exceeding those recommended by the manufacturer, had a higher risk of developing seizures than those without renal impairment. Dosage recommendations for imipenem and cilastatin sodium should be adhered to, especially in patients with factors known to predispose to seizures. Anticonvulsant therapy should be continued during IV and IM imipenem and cilastatin sodium therapy if the drug is used in patients with a known seizure disorder. If focal tremors, myoclonus, or seizures occur during imipenem and cilastatin sodium therapy, patients should be evaluated neurologically, anticonvulsant therapy should be initiated in patients who are not already receiving such therapy, and the imipenem and cilastatin sodium dosage should be reassessed to determine whether dosage should be decreased or the drug discontinued. Because safety and efficacy of imipenem and cilastatin sodium in patients with meningitis has not been established, the manufacturer states that the drug should not be used in patients with this condition. Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with imipenem and cilastatin sodium. Because serum concentrations of imipenem are higher and more prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of IV imipenem and cilastatin sodium should be decreased in patients with renal impairment. (See Dosage and Administration: Dosage in Renal Impairment and Reduced Body Weight.) Patients with severe or marked renal impairment, including those undergoing hemodialysis, have a higher risk of imipenem and cilastatin sodium-induced seizures when receiving the maximum recommended dosage of the drug than do patients with normal renal function. Therefore, the maximum recommended dosage of the drug should be used in such patients only when clearly needed. Patients with creatinine clearances of 5 mL/minute or less per 1.73 m should not receive imipenem and cilastatin sodium IV unless hemodialysis is instituted within 48 hours. In patients undergoing hemodialysis, IV imipenem and cilastatin sodium is recommended only when the potential benefit from the drug outweighs the possible risk of drug-induced seizures. If the drug is used IV in dialysis patients, particularly those with CNS disorders, the patients should be carefully monitored. The safety and efficacy of IM imipenem and cilastatin sodium therapy in patients with creatinine clearances of less than 20 mL/minute per 1.73 m have not been established. As with other anti-infective agents, prolonged use of imipenem and cilastatin sodium may result in overgrowth of nonsusceptible organisms, especially Candida, enterococci, and Pseudomonas. Resistant strains of Ps. aeruginosa have developed during therapy with the drug. Careful observation of the patient during imipenem and cilastatin sodium therapy is essential. If superinfection occurs, appropriate therapy should be instituted. Because Clostridium difficile-associated diarrhea and colitis has been reported with imipenem and cilastatin sodium, it should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drug.

Pediatric Precautions

The manufacturer states that safety and efficacy of IM imipenem and cilastatin sodium in children younger than 12 years of age have not been established. Safety and efficacy of IV imipenem and cilastatin sodium in neonates and children 16 years of age or younger is supported by evidence from adequate and controlled studies in adults and by pharmacokinetic and clinical efficacy studies in pediatric patients. Adverse effects reported with the drug in neonates and children are similar to those reported in adults and include GI effects (e.g., diarrhea, vomiting, gastroenteritis), rash, urogenital effects (e.g., urine discoloration, oliguria, anuria), and reactions at the site of IV infusion (e.g., phlebitis, IV site irritation). Such adverse effects generally have been reported in 1-4% of pediatric patients receiving imipenem and cilastatin sodium. However, seizures have been reported in neonates and children 3 months of age or younger receiving the drug. In addition, there was a high incidence of seizures in one study in children 3 months to 12 years of age who received imipenem and cilastatin sodium (25 mg/kg IV every 6 hours) for empiric treatment of bacterial meningitis. Therefore, because of the risk of seizures, the manufacturer states that IV imipenem and cilastatin sodium should not be used in pediatric patients with CNS infections. The manufacturer also states that because there is insufficient data to date evaluating IV imipenem and cilastatin sodium in pediatric patients with impaired renal function who weigh less than 30 kg, the drug shouldnot be used in these patients. Diluents containing benzyl alcohol should not be used to prepare imipenem and cilastatin sodium for IV administration to neonates or children 3 months of age or younger. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates. Toxicity has not been demonstrated in pediatric patients older than 3 months of age, although small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity.

Geriatric Precautions

Clinical studies of IM imipenem and cilastatin sodium have not included sufficient numbers of individuals 65 years of age and older to determine whether they respond differently than younger adults. In clinical studies of IV imipenem and cilastatin involving approximately 2800 adults 18 years of age or older, approximately 800 were 65 years of age or older and 300 were 75 years of age or older. There were no apparent differences in safety or effectiveness between these individuals and younger adults and other clinical experience has not revealed evidence of differences in response between these age groups. However, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Imipenem is substantially excreted by the kidney, and the risk of severe adverse reactions may be increased in patients with impaired renal function. Limited data indicate that the mean serum half-life of imipenem in healthy geriatric adults 65-75 years of age (with renal function normal for their age) is similar to that expected in individuals with slight renal impairment. The manufacturer states that age-based dosage adjustment does not appear to be necessary. However, because geriatric patients are more likely to have decreased renal function, the manufacturer states that dosage should be selected with caution in these patients and monitoring of renal function may be useful. Dosage should be modified in response to the degree of renal impairment. (See Dosage and Administration: Dosage in Renal Impairment and Reduced Body Weight.)

Mutagenicity and Carcinogenicity

In vitro studies using imipenem or cilastatin sodium alone in a microbial system (i.e., Ames test), imipenem or imipenem and cilastatin sodium in a mammalian cell system (i.e., V79 mammalian cell mutation assay), or imipenem and cilastatin sodium in an unscheduled DNA synthesis assay have not shown evidence of mutagenicity. There also was no evidence of mutagenicity when imipenem and cilastatin sodium was used in an in vivo mouse cytogenicity test. No long-term carcinogenicity studies of imipenem and cilastatin sodium have been performed to date.

Pregnancy, Fertitlity and Lactation

Reproduction studies in rabbits and rats using imipenem dosages up to 2 and 30 times the usual human dosage, respectively, and studies in rabbits using dosages equivalent to the usual human dosage have not revealed evidence of harm to the fetus. Similarly, reproduction studies in rabbits or rats using cilastatin sodium dosages 10 or 33 times the usual human dosage, respectively, have not revealed evidence of harm to the fetus. When imipenem and cilastatin sodium was given at dosages up to 11 times the usual human dosage to pregnant mice and rats during the period of major fetal organogenesis, there was no evidence of teratogenicity, nor was there evidence of adverse effects on fetal viability, fetal growth, or postnatal development of pups when pregnant rats were given dosages up to 8 times the usual human dosage. However, when the drug was administered to pregnant rabbits at dosages equivalent to or exceeding the usual human dosage, weight loss, diarrhea, and some abortions and maternal deaths were observed. When comparable doses of the drug were administered to nonpregnant rabbits, weight loss, diarrhea, and deaths also were observed. The manufacturer states that these adverse effects are similar to those observed in this species with other b-lactam antibiotics, and may be related to alteration of GI flora. Teratogenicity studies in cynomolgus monkeys receiving IV (by direct injection) or subcutaneous imipenem and cilastatin sodium dosages of 40 or 160 mg/kg daily, respectively, revealed maternal toxicity (e.g., emesis, lack of appetite, weight loss, diarrhea, abortion, maternal death). However, no similar toxicity was observed in nonpregnant cynomolgus monkeys receiving dosages up to 180 mg/kg daily subcutaneously. No maternal death or evidence of teratogenicity and only minimal maternal toxicity (consisting of occasional emesis) were observed in pregnant cynomolgus monkeys receiving the combination at an imipenem dosage of about 100 mg/kg daily (approximately 2 or 3 times the maximum recommended human IV or IM dosage, respectively) by IV infusion at a rate similar to that used in humans; however, there was an increase in embryonic loss when compared with control groups. The drug was well tolerated in other studies in pregnant rats and mice using dosages up to 11 times the average human dosage. Both imipenem and cilastatin sodium cross the placenta and are distributed into cord blood and amniotic fluid in humans. There are no adequate and controlled studies to date using imipenem and cilastatin sodium in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Reproduction studies in male and female rats using imipenem and cilastatin sodium dosages up to 8 times the usual human dosage have not revealed evidence of impaired fertility or effects on reproductive performance. Since imipenem is distributed into milk, the drug should be used with caution in nursing women. There was no evidence of adverse effect on lactation in rats administered the drug late in gestation.

Drug Interactions

Probenecid

Concomitant administration of probenecid and imipenem and cilastatin sodium produces higher and prolonged serum concentrations of cilastatin but results in only minimal increases in serum concentrations and half-life of imipenem. Therefore, there is no therapeutic benefit from concomitant use of the drugs and the manufacturer of imipenem and cilastatin sodium states that concomitant use of probenecid and the combination is not recommended.

Aminoglycosides

The antibacterial activity of imipenem and aminoglycosides is additive or synergistic in vitro against some gram-positive bacteria including Enterococcus faecalis (formerly Streptococcus faecalis), Staphylococcus aureus, and Listeria monocytogenes. Depending on the method used to determine in vitro synergism, the combination of imipenem and an aminoglycoside is synergistic against 35-98% of E. faecalistested. The combination of imipenem and an aminoglycoside is generally neither synergistic nor antagonistic in vitro against most strains of Pseudomonas aeruginosa and Enterobacteriaceae.

B-Lactam Antibiotic

s In vitro, imipenem antagonizes the antibacterial activity of other b-lactam antibiotics (including aztreonam and most cephalosporins and extended-spectrum penicillins) against many strains of Ps. aeruginosa and some strains of Citrobacter, Enterobacter, Klebsiella pneumoniae, Morganella morganii, and Serratia marcescens. The antagonism apparently occurs because imipenem, like cefoxitin, is a potent inducer of b-lactamase production and can derepress inducible, chromosomally mediated enzymes in organisms that possess these enzymes. Although inducible b-lactamases have no effect on the antibacterial activity of imipenem, the enzymes inactivate most cephalosporins and penicillins either by hydrolyzing the drugs or by binding to them to prevent access to penicillin-binding proteins. The clinical importance of this in vitro antagonism has not been determined to date, but imipenem and cilastatin sodium probably should not be used in conjunction with other b-lactam antibiotics.

Ganciclovir

Generalized seizures have occurred in several patients who received concomitant therapy with IV imipenem and cilastatin sodium and IV ganciclovir. While the mechanism of this potential interaction currently is not known, the seizures resolved in all but one patient when either both IV imipenem and cilastatin sodium and ganciclovir or just IV imipenem and cilastatin sodium was discontinued. In the patient whose seizures failed to resolve following discontinuance of IV imipenem and cilastatin sodium, continued seizures were attributed to encephalitis rather than the drugs. Because of the risk of seizures, IV imipenem and cilastatin sodium should be used concomitantly with ganciclovir only when the potential benefits are thought to outweigh the possible risks.

Other Anti-infectives

The clinical importance has not been determined to date, but the antibacterial activity of imipenem and co-trimoxazole has generally been synergistic in vitro against Nocardia asteroides. Results of an in vitro study using Klebsiella pneumoniae indicate that chloramphenicol can antagonize the bactericidal activity of imipenem. It has been suggested that if chloramphenicol is used in conjunction with imipenem and cilastatin sodium, chloramphenicol should be administered a few hours after the combination; however, the necessity of this precaution has not been established. In an in vitro study using strains of Ps. aeruginosa resistant to aminoglycosides and carbenicillin, the antibacterial activities of imipenem and norfloxacin were synergistic or partially synergistic against about one-third and indifferent against about two-thirds of strains tested; antagonism did not occur.

Laboratory Test Interferences

Tests for Urinary Glucose

Like most other currently available b-lactam antibiotics, imipenem and cilastatin sodium interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict’s solution, Clinitest®), but does not appear to interfere with glucose oxidase tests (e.g., Diastix®, Tes-Tape®).

Acute Toxcicity

The manufacturer states that there is no information to date on overdosage of imipenem and cilastatin sodium in humans. The IV LD50 of imipenem and cilastatin sodium when administered concomitantly in a 1:1 ratio in mice and rats is approximately 1 g (of imipenem) per kg daily. The IV LD50 of imipenem alone is approximately 1.5 g/kg in mice and greater than 2 g/kg in rats, and the IV LD50 of cilastatin sodium alone is approximately 8.7 and 5 g/kg, respectively. Ataxia, clonic seizures, and death were reported in mice 4-56 minutes following IV administration of 751- to 1359-mg/kg doses of imipenem and cilastatin sodium (administered concomitantly in a 1:1 ratio). In rats, toxicity was observed 5-10 minutes following IV administration of 771- to 1583-mg/kg doses of imipenem and cilastatin sodium. Drug toxicity in female rats was manifested by decreased activity, bradypnea, and death which was preceded by ptosis with clonic seizures; in male rats, ptosis, tremors, and clonic seizures were reported; however, tremors and seizures were not observed in male rats receiving IV administration of 771-mg/kg dose of imipenem and cilastatin sodium. In addition, death occurred 6-88 minutes following IV administration of 771- to 1734-mg/kg doses of imipenem and cilastatin sodium to male rats. In acute overdosage, the drug should be discontinued and the patient treated symptomatically (including supportive measures). Although imipenem and cilastatin sodium is hemodialyzable, the manufacturer states that the usefulness of this procedure in enhancing the elimination of imipenem and cilastatin sodium is questionable.

Mechanism of Action

Imipenem usually is bactericidal in action. Like other b-lactam antibiotics, the antibacterial activity of imipenem results from inhibition of mucopeptide synthesis in the bacterial cell wall. Imipenem has an affinity for and binds to most penicillin-binding proteins (PBPs) of susceptible organisms, including PBPs 1a, 1b, 2, 4, 5, and 6 of Escherichia coli; PBPs 1a, 1b, 2, 4, and 5 of Pseudomonas aeruginosa; and PBPs 1, 2, 3, and 4 of S. aureus. In susceptible gram-negative bacteria, imipenem has the greatest affinity for PBP 2 and the lowest affinity for PBP 3.2, 4, 55, 94, 95, 100, 111, 148, 197, 198 This results in the formation of spheroplasts or ellipsoidal cells without filament formation. Because imipenem also has a high affinity for PBPs 1a and 1b of these organisms, the spheroplasts lyse rapidly. Imipenem is able to penetrate the outer membrane of most gram-negative bacteria and gain access to the PBPs more readily than many other currently available b-lactam antibiotics. In vitro studies indicate that imipenem may have a postantibiotic inhibitory effect against some susceptible organisms. Although the mechanism of this postantibiotic effect has not been determined to date, in vitro studies using Staphylococcus aureus, E. coli, and Ps. aeruginosa indicate that following exposure to bactericidal concentrations of imipenem these organisms do not immediately resume growth after the drug is removed. It is not known whether a postantibiotic effect occurs in vivo, but it has been suggested that this effect would be beneficial since imipenem may be able to prevent regrowth of susceptible organisms although drug concentrations at the site of infection may fall below the MIC during a dosing interval. Cilastatin sodium reversibly and competitively inhibits dehydropeptidase I (DHP I). Imipenem is hydrolyzed in vivo to a microbiologically inactive metabolite by DHP I present on the brush border of proximal renal tubular cells; concurrent administration of cilastatin prevents this renal metabolism of the antibiotic. The normal physiologic role of DHP I has not been fully elucidated, but the enzyme does not appear to be essential to normal mammalian metabolism. Cilastatin is a specific inhibitor of DHP I and does not inhibit other dipeptidases or bacterial b-lactamases. Cilastatin sodium has no antibacterial activity and does not affect the mechanism of action of imipenem. Spectrum Imipenem has a spectrum of activity that is broader than that of most other currently available b-lactam antibiotics. Imipenem is active in vitro against most gram-positive and gram-negative aerobic bacteria as well as most gram-positive and gram-negative anaerobic bacteria. The drug also has some activity in vitro against Mycobacterium, but is inactive against Mycoplasma, Chlamydia, fungi, and viruses.Cilastatin sodium has no antibacterial activity and does not affect the antibacterial activity of imipenem when used concomitantly.

In Vitro Susceptibility Testing

For most organisms, inoculum size does not appear to affect susceptibility to imipenem. MICs of imipenem for Pseudomonas aeruginosa and most Enterobacteriaceae generally are only 2-4 times greater when the size of the inoculum is increased from 105 to 108 colony-forming units (CFU) per mL, although MICs for some strains of Enterobacter, Klebsiella, and Proteus may be 4-16 times greater when the inoculum is increased to 108 CFU/mL. Results of imipenem susceptibility tests generally are unaffected by the presence of serum. The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to imipenem, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to imipenem, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible. Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to imipenem, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials. NCCLS states that strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to imipenem, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to imipenem, a disk containing 10 mcg of imipenem should be used. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter with growth inhibition zones of 16 mm or greater are susceptible to imipenem, those with zones of 14-15 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 16 mm or greater are susceptible to imipenem.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterobacteriaceae, and Ps. aeruginosa and other non-Enterobacteriaceae gram-negative bacilli (e.g., other Pseudomonas spp., Acinetobacter, Stenotrophomonas maltophilia) with MICs of 4 mcg/mL or less are susceptible to imipenem, those with MICs of 8 mcg/mL have intermediate susceptibility, and those with MICs of 16 mcg/mL or greater are resistant to the drug. When dilution susceptibility testing of Haemophilus is performed according to NCCLS standardized procedures using HTM, isolates with MICs of 4 mcg/mL or less are considered susceptible to imipenem. Because of limited data on resistant strains, NCCLS recommends than any Haemophilus isolate that appears to be nonsusceptible to imipenem should be submitted to a reference laboratory for further testing. When broth dilution susceptibility testing of S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), S. pneumoniae with MICs of 0.12 mcg/mL or less are considered susceptible to imipenem, those with MICs of 0.25-0.5 mcg/mL have intermediate susceptibility, and those with MICs of 1 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

Gram-positive Aerobic Cocci

Imipenem is generally active in vitro against the following gram-positive aerobic cocci: penicillinase- and nonpenicillinase-producing strains of Staphylococcus aureus and S. epidermidis, S. saprophyticus, Streptococcus pneumoniae, S. pyogenes (group A b-hemolytic streptococci), group B streptococci (e.g., S. agalactiae), viridans streptococci, and groups C, G, and H streptococci. Unlike cephalosporins and many penicillins, imipenem has some activity against enterococci, although the drug is only bacteriostatic against these organisms. Imipenem is active in vitro against many strains of E. faecalis (formerly S. faecalis) and S. durans, but most strains of S. faecium are considered resistant to the drug. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of imipenem for penicillinase- and nonpenicillinase-producing S. aureus is 0.01-0.5 mcg/mL. The MIC90 of imipenem for S. epidermidisis generally 0.1-4 mcg/mL, although in a few studies the MIC90 was 32 mcg/mL. The in vitro activity of imipenem against staphylococci resistant to penicillinase-resistant penicillins is variable, and a wide range of MIC values has been reported depending on the method used to test susceptibility. In some in vitro studies, when cultures were incubated for up to 18 hours at 30-37°C, the MIC90 of imipenem for methicillin-resistant S. aureus (MRSA) ranged from 0.5-8 mcg/mL. In other in vitro studies when cultures were incubated for 48 hours at 30 or 35°C, the MIC90 of imipenem for MRSA was 25 mcg/mL or higher and most strains were considered resistant to the drug. Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to imipenem. The MIC90 of imipenem for S. pneumoniae is 0.01-1 mcg/mL, and the MIC90 of the drug for S. pyogenes, viridans streptococci, or groups B, C, G, or H streptococci is 0.01-0.125 mcg/mL. The MIC90 of imipenem reported for E. faecalis is 0.3-4 mcg/mL. Imipenem is less active in vitro against S. faecium than E. faecalis or S. durans.The MIC90 of imipenem reported for S. faecium ranges from 0.5-50 mcg/mL, and most strains are considered resistant to the drug. Imipenem is not bactericidal against enterococci. Although results vary depending on the method used to test bactericidal activity, the MBC90 (minimum bactericidal concentration of the drug at which 90% of strains tested are killed) of imipenem for most strains of E. faecalis is 64 mcg/mL or greater.

Gram-positive Aerobic Bacilli

Imipenem is active in vitro against most strains of Listeria monocytogenes, but the drug is not generally bactericidal against this organism. The MIC90 of imipenem reported for L. monocytogenes is 0.015-4 mcg/mL, and the MBC90 ranges from 0.25-250 mcg/mL. Imipenem is active in vitro against Bacillus, including B. cereus. Imipenem also is active in vitro against some strains of Nocardia asteroides, and the MIC90 of the drug reported for this organism is 0.19-8 mcg/mL. The mean MIC90 of imipenem for Erysipelothrix rhusiopathiae reportedly is 0.015 mcg/mL. Corynebacterium generally are resistant to imipenem and have a mean MIC90 of the drug of more than 32 mcg/mL.

Gram-negative Aerobic Bacteria

Neisseria

Imipenem is active in vitro against Neisseria meningitidis and most strains of penicillinase- and nonpenicillinase-producing Neisseria gonorrhoeae. The MIC90 of imipenem is 0.03-0.11 mcg/mL for N. meningitidis and 0.12-0.64 mcg/mL for nonpenicillinase- or penicillinase-producing N. gonorrhoeae.

Haemophilus

Imipenem is active in vitro against most b-lactamase- and non-b-lactamase-producing strains of Haemophilus influenzae and H. parainfluenzae. The MIC90 of the drug reported for H. influenzae and H. parainfluenzae is 0.25-8 mcg/mL. Imipenem is active in vitro against strains of H. influenzae resistant to ampicillin and/or chloramphenicol as well as some strains resistant to ampicillin, chloramphenicol, and co-trimoxazole. H. ducreyi also are inhibited in vitro by imipenem.

Enterobacteriaceae

Imipenem is active in vitro against most clinically important Enterobacteriaceae, including Citrobacter diversus, C. freundii, Enterobacter agglomerans, E. cloacae, E. aerogenes, Escherichia coli, Hafnia alvei, Klebsiella oxytoca, K. pneumoniae, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, Providencia rettgeri (formerly Proteus rettgeri), P. stuartii, Serratia liquefaciens, S. marcescens, Salmonella, Shigella, Yersinia enterocolitica, and Y. pseudotuberculosis. The MIC90 of imipenem for C. diversus, C. freundii, E. aerogenes, E. agglomerans, E. cloacae, E. coli, K. oxytoca, K. pneumoniae, and Y. enterocolitica is 0.1-4 mcg/mL. The MIC90 for M. morganii, P. mirabilis, P. vulgaris, P. rettgeri, P. stuartii, and S. marcescens is 0.5-8 mcg/mL. The MIC90 of imipenem reported for Salmonella is 0.1-2 mcg/mL. In one study, the MIC90 of the drug for S. enteritidis and S. typhi was 0.25-0.5 mcg/mL. The MIC90 of imipenem reported for Shigella is 0.1-0.5 mcg/mL.

Pseudomonas

Imipenem is active in vitro against many strains of Pseudomonas aeruginosa. In vitro on a weight basis, the activity of imipenem against Ps. aeruginosa appears to be approximately equal to or slightly greater than that of ceftazidime. In addition, imipenem is active in vitro against some strains of Ps. aeruginosa resistant to third generation cephalosporins, aminoglycosides, and extended-spectrum penicillins. The MIC90 of imipenem reported for Ps. aeruginosa is 1.1-16 mcg/mL. Imipenem is also active against some Pseudomonas other than Ps. aeruginosa. The MIC90 of imipenem reported for Ps. acidovorans, Ps. fluorescens, Ps. putida, and Ps. stutzeri is 0.5-2.5 mcg/mL.

Other Gram-Negative Aerobic Bacteria

Imipenem is active in vitro against Acinetobacter. The MIC90 of the drug reported for A. calcoaceticus var. anitratus is 0.25-0.5 mcg/mL, and the MIC90 reported for A. calcoaceticusvar. lwoffi is 0.15-0.39 mcg/mL. Moraxella catarrhalis (formerly Branhamella catarrhalis) generally is inhibited in vitro by imipenem concentrations of 0.03-0.12 mcg/mL. Imipenem is active in vitro against Bordetella bronchiseptica, Eikenella corrodens, and Pasteurella multocida. The MIC90 of the drug reported for B. bronchiseptica and E. corrodens is 0.25-4 mcg/mL. Brucella melitensis is inhibited in vitro by imipenem concentrations of 0.33-2 mcg/mL. Imipenem also is active in vitro against Alcaligenes denitrificans, A. xylosoxidans, Aeromonas hydrophila, and Plesiomonas shigelloides.The MIC90 of imipenem reported for A. xylosoxidans and A. denitrificans is 1.3-8 mcg/mL. Imipenem has some activity in vitro against Flavobacterium, but the MIC90 of imipenem reported for Chryseobacterium meningosepticum (formerly F. meningosepticum) is usually 20-32 mcg/mL and most strains of the organism are considered resistant to the drug. Imipenem is active in vitro against some strains of Brevundimonas diminuta (formerly Ps. diminuta). While some strains of Burkholderia cepacia (formerly Ps. cepacia) are inhibited in vitro by imipenem concentrations of 16 mcg/mL or less, most strains of the organism are resistant to the drug. Imipenem is active in vitro against Capnocytophaga. The MIC90 of imipenem reported for Capnocytophaga is 0.5 mcg/mL. Imipenem is active in vitro against Campylobacter coli, C. fetus subsp. fetus, and C. jejuni, including b-lactamase-producing strains. The MIC90 of imipenem reported for C. fetus subsp. fetus is 0.03-0.12 mcg/mL. The MIC90 of imipenem for Helicobacter pylori (C. pylori) reportedly is 0.13 mcg/mL. In vitro, Legionella pneumophila generally are inhibited by imipenem concentrations of 0.03-0.25 mcg/mL. Gardnerella vaginalis (formerly Haemophilus vaginalis) reportedly are inhibited in vitro by imipenem. Stenotrophomonas maltophilia (formerly Ps. maltophilia) generally is resistant to imipenem.

Anaerobic Bacteria

Imipenem is active in vitro against most gram-positive anaerobic bacteria including Actinomyces, Bifidobacterium, Clostridium,Eubacterium, Lactobacillus, Peptococcus, Peptostreptococcus, and Propionibacterium. The MIC90 of imipenem reported for most of these gram-positive anaerobic bacteria is 0.015-4 mcg/mL. C. perfringens are generally inhibited in vitro by imipenem concentrations of 0.015-1.3 mcg/mL. Unlike most other currently available b-lactam antibiotics, imipenem is active in vitro against some strains of C. difficile. The MIC90 of the drug reported for C. difficile is 2-16 mcg/mL. Imipenem is active in vitro against gram-negative anaerobic bacteria including most strains of Bacteroides, Fusobacterium, Leptotrichia buccalis, Prevotella, and Veillonella. The MIC90 of imipenem reported for Bacteroides fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, and B. vulgatus is 0.03-4 mcg/mL. Imipenem is active in vitro against some strains of Bacteroides, including B. fragilis, resistant to clindamycin and cefoxitin. Prevotella bivia, P. disiens, P. melaninogenica, and P. oralis (formerly B. bivius, B. disiens B. melaninogenicus, and B. oralis) are inhibited in vitro by imipenem concentrations of 4 mcg/mL or less. The MIC90 of imipenem reported for Fusobacterium, L. buccalis, and Veillonella is 0.015-2 mcg/mL.

Other Organisms

The clinical importance has not been determined to date, but imipenem is active in vitro against some Mycobacterium including M. fallax and M. fortuitum. In one study, 1012 isolates of M. fortuitum were inhibited in vitro by imipenem concentrations of 6.25 mcg/mL. Although a few strains of Chlamydia trachomatis were inhibited in vitro by imipenem in one study, the mean MIC90 of the drug for C. trachomatis usually is 32 mcg/mL or higher and the organism is considered resistant to imipenem. Resistance Imipenem has a high degree of stability against hydrolysis by bacterial b-lactamases, including both plasmid-mediated and chromosomally mediated enzymes. The drug generally is more stable against inactivation by b-lactamases than are cefoxitin, cefotaxime, or cefuroxime. Imipenem generally is stable against hydrolysis by staphylococcal b-lactamases and b-lactamases classified as Richmond-Sykes types I, II, III (TEM type), IV, or V (PSE and OXA types), but is inactivated by a b-lactamase produced by Bacteroides fragilis. Although imipenem is hydrolyzed to some extent by a b-lactamase produced by Stenotrophomonas maltophilia (formerly Pseudomonas maltophilia), resistance to imipenem in this organism may also be related to other factors since this enzyme has a low affinity for the drug. Resistance to imipenem in gram-positive bacteria, including Staphylococcus epidermidis and methicillin-resistant staphylococci, is generally the result of altered penicillin-binding proteins (PBPs). In vitro exposure of some strains of methicillin-resistant S. aureus (MRSA) to imipenem has induced imipenem resistance in strains that were originally susceptible to the drug. Tolerance to the bactericidal effects of imipenem has been reported in enterococci and some strains of Listeria monocytogenes and methicillin-resistant staphylococci. Although most susceptible organisms have an MBC of imipenem that is 1-4 times greater than the MIC of the drug, bacteria that are tolerant to imipenem have an MBC that is at least 16 times higher than the MIC. Resistant strains of Ps. aeruginosa have developed during therapy with imipenem and have resulted in treatment failures in some cases. The mechanism of imipenem resistance in these organisms is unclear, but resistance may develop rapidly following initiation of therapy with the drug. Resistance to imipenem in Ps. aeruginosa appears to result from chromosomal b-lactamase activity and decreased permeability due to loss of an outer-membrane porin protein (OprD2) or may result from a plasmid-mediated metallo-b-lactamase. Tolerance to the bactericidal effects of imipenem has been reported in some strains of Ps. aeruginosa. In vitro studies indicate that imipenem, like cefoxitin, is a potent inducer of b-lactamases and can reversibly derepress inducible, chromosomally mediated b-lactamases in Ps. aeruginosa and Enterobacteriaceae that possess these enzymes. Although these enzymes inactivate aztreonam and most cephalosporins and penicillins either by hydrolyzing the drugs or by binding to them to prevent access to PBPs, these b-lactamases have no effect on the antibacterial activity of imipenem. (See Drug Interactions: b-Lactam Antibiotics.) Imipenem does not appear to select mutants stably derepressed for b-lactamase production. Cross-resistance generally does not occur between imipenem and other anti-infective agents, including cephalosporins, penicillins, and aminoglycosides. However, strains of Ps. aeruginosa resistant to imipenem that also were resistant to meropenem have been reported rarely. There has been at least one report of a strain of metronidazole-resistant B. fragilis that was cross-resistant in vitro to imipenem, amoxicillin and clavulanate potassium, and tetracycline; the strain was susceptible to chloramphenicol or clindamycin in vitro.

Pharmacokinetics

Cilastatin prevents metabolism of imipenem by dehydropeptidase I (DHP I) present on the brush border of proximal renal tubular cells and, when administered concomitantly, results in urinary concentrations of active imipenem that are higher than could be obtained following administration of the antibiotic alone. Concomitant cilastatin also results in a slight increase in serum concentrations of imipenem, but does not appreciably affect its serum half-life. Imipenem has no effect on the pharmacokinetics of cilastatin sodium. Unless specified otherwise, serum and tissue concentrations of imipenem and pharmacokinetic parameters presented for imipenem and cilastatin were obtained from studies where imipenem monohydrate and cilastatin sodium were administered concomitantly in a 1:1 ratio. Imipenem is administered as the monohydrate, but dosages and concentrations of the drug are expressed in terms of anhydrous imipenem. Dosage of imipenem and cilastatin sodium is expressed in terms of the imipenem content of the drug.

Absorption

Neither imipenem nor cilastatin is appreciably absorbed from the GI tract and, therefore, imipenem and cilastatin sodium must be given parenterally. Following IV infusion over 20-30 minutes of a single 250-mg, 500-mg, or 1-g dose of imipenem and cilastatin sodium in healthy adults with normal renal function, peak serum concentrations of imipenem immediately following completion of the infusion range from 14-24, 21-58, and 41-83 mcg/mL, respectively. Serum concentrations 4-6 hours after these doses decline to 1.5 mcg/mL or less. In adults with infections who receive 500-mg or 1-g doses of imipenem and cilastatin sodium by IV infusion over 30-60 minutes every 6 hours, peak serum imipenem concentrations are 19.3-38.3 or 16.7-67.3 mcg/mL, respectively, and trough concentrations average 1 or 3.1 mcg/mL, respectively. Following IV infusion over 15-20 minutes of a single 25-mg/kg dose of imipenem and cilastatin sodium in children 2-12 years of age with infections, serum imipenem concentrations 0.5 and 6 hours after the dose average 33. and 0.79 mcg/mL, respectively. In children 3 months to 13 years of age with infections who received imipenem and cilastatin sodium in a dosage of 60-100 mg/kg daily, peak serum imipenem concentrations at steady state ranged from 12.-80. mcg/mL and trough serum concentrations ranged from 0-0. mcg/mL. In neonates 1-8 days of age with infections who received a single 25-mg/kg dose of the drug, serum imipenem concentrations averaged 97.3,45.5, 30.6, 14.4, 3.1, and 0.9 mcg/mL immediately following completion of the infusion and 1, 2, 4, 8, and 12 hours later, respectively. In a dose-ranging study in premature, low-birthweight neonates (0.-1. kg) 1 week of age or younger who received imipenem and cilastatin sodium in a dosage of 20 mg/kg every 12 hours given IV over 15-30 minutes, mean peak and trough plasma concentrations averaged 43 and 1.7 mcg/mL, respectively. While the clinical importance is unclear, multiple IV doses of imipenem and cilastatin sodium in neonates may result in moderate accumulation of cilastatin. Imipenem is incompletely absorbed following IM administration of the commercially available suspension, and plasma concentrations of the drug peak later but are more prolonged than those achieved following IV administration. Following IM administration of the commercially available suspension of imipenem and cilastatin sodium, the bioavailabilities of imipenem and cilastatin range from 60-75 and 95-100%, respectively. Following IM administration of a 500- or 750-mg dose of imipenem and cilastatin sodium suspension (diluted with 1% lidocaine hydrochloride injection without epinephrine), peak plasma concentrations of imipenem occur within 2 hours and average 10 or 12 mcg/mL, respectively; peak plasma concentrations of cilastatin occur within 1 hour and average 24 or 33 mcg/mL, respectively. Plasma concentrations of imipenem exceed 2 mcg/mL for at least 6 or 8 hours following IM administration of a 500- or 750-mg dose, respectively. Absorption of imipenem from the IM injection site continues for 6-8 hours; absorption of cilastatin is virtually complete by 4 hours. Following IV administration of single 500- or 750-mg doses of imipenem and cilastatin sodium solution, plasma imipenem concentrations during the first 2 hours exceeded those attained following IM administration of the same doses given as suspensions (reconstituted with lidocaine hydrochloride 1% without epinephrine); however, plasma imipenem concentrations achieved 4-6 hours after an IM dose exceeded those after an IV dose and they persisted longer. Following IV administration of a single 500- or 750-mg dose of imipenem and cilastatin sodium, peak plasma imipenem concentrations were 45 or 57 mcg/mL, respectively, and occurred at 25 minutes while those following the same IM doses were 10 or 11. mcg/mL, respectively, and occurred at 2 hours. Plasma concentrations of imipenem were undetectable 12 hours after IV administration; however, 12 hours after IM administration of a 500- or 750-mg dose, plasma imipenem concentrations were 0.5 or 0.8 mcg/mL, respectively.

Distribution

Following IV administration, imipenem is distributed into saliva, sputum, aqueous humor, bone, bile, reproductive organs, myometrium, endometrium, heart valve, intestine, and pleural, peritoneal, interstitial, blister, and wound fluids. In adults, the apparent volume of distribution of imipenem in the central compartment (Vc) averages 0.16 L/kg and the volume of distribution at steady state (Vss) averages 0.23-0. L/kg. In children 2-12 years of age, Vc averages 0.326 L/kg. In neonates 1-8 days of age, Vss ranges from 0.251-0. L/kg. Only low concentrations of imipenem diffuse into CSF following IV administration; CSF concentrations are generally 1-10% of concurrent serum concentrations. Following a single 1-g IV dose of imipenem and cilastatin sodium in patients with uninflamed meninges, CSF concentrations approximately 1 hour after the dose average 0.8 mcg/mL. In children 4 months to 11 years of age with meningitis who received 25-mg/kg IV doses of the drug every 6 hours, CSF imipenem concentrations ranged from 0.27-3. mcg/mL in samples obtained 1.5-3. hours after a dose; serum concentrations 1.7-3. hours after the dose ranged from 2.9-25 mcg/mL. CSF imipenem concentrations in these children did not appear to be affected by the degree of meningeal inflammation. Imipenem is 13-21% and cilastatin is approximately 40% bound to serum proteins. Both imipenem and cilastatin sodium cross the placenta and are distributed into cord blood and amniotic fluid. In one study in pregnant women who received a single 500-mg IV dose of imipenem and cilastatin sodium, amniotic fluid concentrations varied greatly. In women in early pregnancy, mean amniotic fluid concentrations in samples taken 3 hours after the dose were 47% of simultaneous maternal plasma concentrations; in women in late pregnancy, mean concentrations were 16% of simultaneous maternal plasma concentrations in samples obtained 30 minutes after the dose. Imipenem is distributed into milk.

Elimination

Serum imipenem concentrations appear to decline in a biphasic manner following IV administration of imipenem and cilastatin sodium in adults with normal renal function. In adults with normal renal function, the distribution half-life of IV imipenem averages 0.23-0. hours and the elimination half-life averages 0.85-1. hours. In healthy geriatric adults 65-75 years of age (with renal function normal for their age) who received a single dose of 500 mg of imipenem and 500 mg of cilastatin given IV over 20 minutes, the mean plasma half-lives of imipenem and cilastatin were 1.5 and 1.1 hours, respectively, and were similar to half-lives expected in individuals with slight renal impairment. Multiple doses have no effect on the pharmacokinetics of imipenem or cilastatin and accumulation does not occur. The elimination half-life of IV imipenem averages 1-1. hours in children 2-12 years of age and 1.5-2. hours in neonates 1-10 days of age. IV cilastatin has an elimination half-life of 0.83-1. hours in adults with normal renal function and 3.1-8. hours in neonates. The elimination half-life of imipenem following IM administration of imipenem and cilastatin sodium suspension is 2-3 hours. Little accumulation of imipenem and no accumulation of cilastatin appears to occur following repeated (i.e., every 12 hours) IM doses. If imipenem is administered alone, the drug is partially hydrolyzed in the kidneys by DHP I to a microbiologically inactive metabolite and only 5-43% of the dose is excreted unchanged in urine. However, when cilastatin sodium is administered concurrently with imipenem in a 1:1 ratio as a suspension or solution, approximately 50 or 70% of the imipenem dose, respectively, and approximately 75% of the cilastatin dose are excreted unchanged in urine within 10 hours. In adults, maximal urinary concentrations of active imipenem are obtained with a 4:1 ratio of imipenem to cilastatin; however, a 1:1 ratio of imipenem to cilastatin ensures that DHP I is inhibited for up to 8-10 hours. Urinary imipenem concentrations may be greater than 10 mcg/mL for up to 8 hours following a single 500-mg IV dose of imipenem and cilastatin sodium. Urinary imipenem concentrations exceed 10 mcg/mL for at least 12 hours after IM administration of 500- or 750-mg doses of the commercially available suspension of the drug. Imipenem is also metabolized to some extent by a nonrenal mechanism unrelated to DHP I. Approximately 20-30% of an imipenem dose is inactivated by nonspecific hydrolysis of the b-lactam ring. Although the microbiologically inactive metabolite is identical to that formed by renal DHP I, this nonspecific hydrolysis is unaffected by concurrent administration of cilastatin. Cilastatin is partially metabolized in the kidneys to N-acetylcilastatin, which is also an effective inhibitor of DHP I. Approximately 70-80% of an IV dose of cilastatin is excreted in urine unchanged and 12% is excreted as N-acetylcilastatin. The metabolic fate of the remainder of the dose has not been elucidated to date. Imipenem, cilastatin, and their metabolites are excreted principally in urine by both glomerular filtration and tubular secretion. Approximately 20-30% of the renal clearance of imipenem occurs by tubular secretion; however, cilastatin competitively inhibits active tubular secretion of imipenem. Less than 1% of an imipenem dose and less than 2% of a cilastatin dose are excreted in feces following IV administration. In adults with normal renal function, plasma clearance of imipenem and of cilastatin ranges from 165-207 and 207-218 mL/minute per 1.73 m, respectively. Plasma clearance of imipenem averages 270 mL/minute per 1.73 m in children 2-12 years of age and 3.4 mL/minute per kg in neonates 1-10 days of age. The serum half-lives of both imipenem and cilastatin are prolonged in patients with impaired renal function; however, the half-life of cilastatin is prolonged to a greater extent than that of imipenem. The serum half-life of IV imipenem and of cilastatin averages 2.1 and 2.5 hours, respectively, in adults with creatinine clearances of 17-33 mL/minute per 1.73 m, and 2.7-3.7 and 7-17 hours, respectively, in adults with creatinine clearances less than 10 mL/minute per 1.73 m. Both imipenem and cilastatin are removed by hemodialysis; however, the amount of the drugs removed during hemodialysis varies considerably depending on several factors (e.g., type of coil used, dialysis flow rate). In patients who received a single 250- or 500-mg dose of imipenem and cilastatin sodium, a 3- to 4-hour period of hemodialysis removed 20-90% of the imipenem dose and 38-82% of the cilastatin dose into the dialysate. Imipenem and cilastatin are removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Imipenem and cilastatin sodium is a fixed combination of imipenem monohydrate and the sodium salt of cilastatin. Imipenem is a semisynthetic carbapenem antibiotic and is the crystalline N-formimidoyl derivative of thienamycin, a carbapenem antibiotic produced by Streptomyces cattleya. Carbapenems are b-lactam antibiotics that contain a fused b-lactam ring and 5-membered ring system similar to that contained in penicillins; however, the 5-membered ring in carbapenems is unsaturated and contains a carbon rather than a sulfur atom. Imipenem has a hydroxyethyl group at position 6 of the b-lactam ring rather than the acylamino group present at this position in penicillins and cephalosporins; the hydroxyethyl group in imipenem has a trans configuration unlike the acylamino groups in penicillins and cephalosporins which have a cis configuration. These structural differences result in increased antibacterial activity and stability against hydrolysis by most b-lactamases. Imipenem contains a basic alkylthio side chain on the 5-membered ring; this side chain results in antipseudomonal activity. Cilastatin sodium, the sodium salt of a derivatized heptenoic acid, is a specific and reversible inhibitor of dehydropeptidase I (DHP I). DHP I is a dipeptidase present on the brush border of proximal renal tubular cells which inactivates imipenem by hydrolyzing the b-lactam ring. 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.(See Pharmacokinetics.) Imipenem and cilastatin sodium is commercially available as a sterile powder for injection for IV use and as a sterile powder for injectable suspension for IM use; these powders contain a 1:1 ratio of imipenem to cilastatin. Commercially available imipenem and cilastatin sodium for injection or for injectable suspension contains 3.2 or 2.8 mEq of sodium per gram of imipenem, respectively. Potency of imipenem monohydrate is expressed in terms of imipenem, calculated on the anhydrous basis, and potency of cilastatin sodium is expressed in terms of cilastatin. Imipenem monohydrate occurs as a white or off-white, nonhygroscopic, crystalline compound and has solubilities of 11 mg/mL in water at room temperature and approximately 0.2 mg/mL in alcohol at 25°C. Cilastatin sodium occurs as an off-white to yellowish-white, hygroscopic, amorphous compound and has solubilities of greater than 2 g/mL in water and approximately 6 mg/mL in alcohol at 25°C. When reconstituted as directed, solutions of imipenem and cilastatin sodium prepared from the powder for injection for IV use are clear and colorless to yellow, have a pH of 6.5-7., and have osmolarities that approximate those of the diluents. Reconstituted suspensions of the drug prepared from the sterile powder for IM use are white to light tan in color; variations of color within this range do not affect potency.

Stability

Commercially available imipenem and cilastatin sodium sterile powders for injection or for injectable suspension should be stored at less than 25°C. Solutions and suspensions of imipenem and cilastatin sodium may darken (i.e., IV solutions may turn deep yellow or IM suspensions may turn light tan) with time; this color change does not indicate loss of potency. However, IV solutions of the drug should be discarded if they become brown. Imipenem and cilastatin sodium is stable for 4 hours at room temperature or 24 hours when refrigerated at 5°C following reconstitution with 100 mL of one of the following IV solutions: 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. Following reconstitution of ADD-Vantage® vials containing imipenem and cilastatin sodium with the diluent provided by the manufacturer (i.e., 100 mL of 0.9% sodium chloride injection or 5% dextrose injection), solutions of the drug are stable for 4 hours at room temperature. Following reconstitution of the powder for injectable suspension with lidocaine hydrochloride 1% injection (without epinephrine), the imipenem and cilastatin sodium suspension should be used within 1 hour. The stability of imipenem is temperature and pH dependent. Solutions of imipenem and cilastatin sodium should not be frozen since freezing at temperatures warmer than -70°C results in decomposition of the drug similar to that observed with ampicillin. The drug is inactivated at alkaline or acidic pH, but is generally stable at neutral pH. Imipenem is unstable in vitro at room temperature, 35-37°C, or -20°C in serum or urine and in certain media used for in vitro susceptibility testing. Serum, urine, and dialysate specimens to be assayed for imipenem should be stabilized immediately following collection by the addition of appropriate buffers and then frozen at -70 to -80°C. The manufacturer should be consulted for specific information on how to stabilize imipenem in serum, urine, or dialysate specimens. Because of the potential for incompatibility, the manufacturer states that imipenem and cilastatin sodium solution or suspension and other anti-infective agents should not be admixed.

Preparations

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

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