Imipenem and cilastatin sodium is a fixed combination of imipenem monohydrate (a carbapenem β-lactam antibiotic) and cilastatin sodium (a renal dehydropeptidase inhibitor that prevents renal metabolism of imipenem). 1
Lower Respiratory Tract Infections
The fixed combination of imipenem and cilastatin sodium (imipenem/cilastatin) is used in adults and pediatric patients for the treatment of lower respiratory tract infections caused by susceptible strains of the following microorganisms: Staphylococcus aureus (penicillinase-producing isolates), Acinetobacter species, Enterobacter species, Escherichia coli , Haemophilus influenzae , Haemophilus parainfluenzae , Klebsiella species, and Serratia marcescens .1 Imipenem/cilastatin has also been used for the treatment of community-acquired pneumonia (CAP) in hospitalized patients with risk factors for or infections caused by Pseudomonas aeruginosa † and as part of empiric therapy for coverage of or infections caused by susceptible strains of Pseudomonas aeruginosa in patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).315, 512, 544
The efficacy of imipenem/cilastatin has been studied in 3 randomized, double-blind, active-controlled trials in patients with pneumonia.544, 545, 560 In 1 study, IV imipenem/cilastatin was compared with IV ciprofloxacin in 402 hospitalized adult patients with severe pneumonia, including nosocomial pneumonia (78%) and CAP (22%).544 The most common causative organisms included Pseudomonas aeruginosa , Haemophilus influenzae , methicillin-susceptible Staphylococcus aureus (MSSA), Klebsiella pneumoniae , and Escherichia coli .544 There were 17.3% of patients in the ciprofloxacin group with bacteremia versus 14.5% of patients in the imipenem/cilastatin group.544 For the main efficacy endpoint of bacteriological response at 3-7 days after completion of therapy, patients treated with IV ciprofloxacin had a higher bacteriological eradication rate compared with patients treated with imipenem/cilastatin.544 Patients treated with IV ciprofloxacin also had a higher clinical response rate than patients treated with imipenem/cilastatin.544
In another study, imipenem/cilastatin was compared with tigecycline for the treatment of HAP, including VAP (25%), in 383 hospitalized adult patients.545 Patients were randomized to receive either tigecycline with or without ceftazidime and an aminoglycoside or imipenem/cilastatin with or without vancomycin and an aminoglycoside for 7-14 days.545 For the main efficacy endpoint of clinical response at 10-21 days after the last day of therapy in the clinical modified intent-to-treat population, patients treated with the tigecycline regimen had a similar rate of cure compared with patients treated with the imipenem/cilastatin regimen.545 However, in the clinically evaluable population, patients treated with the tigecycline regimen had a lower rate of cure than patients treated with the imipenem/cilastatin regimen.545
Another randomized, double-blind, multicenter study compared imipenem/cilastatin with the fixed combination of piperacillin and tazobactam (piperacillin/tazobactam) in 221 hospitalized adults with nosocomial pneumonia.560 The most common organisms isolated were Enterobacteriaceae and Staphylococcus aureus .560 For the main efficacy endpoint of clinical efficacy at 3 ± 1 days after end of treatment, a similar therapeutic response was seen in patients treated with piperacillin/tazobactam compared with patients treated with imipenem/cilastatin.560
The 2019 American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guideline on the diagnosis and treatment of adults with CAP provides recommendations for outpatients and inpatients.512 For empiric treatment of adult inpatients with non-severe CAP without risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa , the ATS/IDSA guideline recommends either combination therapy with a β--lactam (i.e., ampicillin and sulbactam, cefotaxime, ceftriaxone, or ceftaroline) and a macrolide (i.e., azithromycin or clarithromycin) or monotherapy with a respiratory fluoroquinolone (i.e., levofloxacin or moxifloxacin).512 For adult inpatients with severe CAP without risk factors for MRSA or Pseudomonas aeruginosa , a β--lactam plus a macrolide or a β--lactam plus a respiratory fluoroquinolone are recommended.512 Empiric coverage for MRSA or Pseudomonas aeruginosa in adults with CAP is only recommended if there are locally validated risk factors for either pathogen.512 For MRSA, empiric treatment options include vancomycin or linezolid.512 For Pseudomonas aeruginosa , empiric treatment options include piperacillin/tazobactam, cefepime, ceftazidime, aztreonam, meropenem, or imipenem.512
The 2016 ATS and IDSA guideline on the management of adults with HAP and VAP provides recommendations for empiric therapy and pathogen-specific therapy.315 For empiric therapy of non-ventilator-associated HAP, an antibiotic therapy regimen with coverage for Staphylococcus aureus , Pseudomonas aeruginosa , and other gram-negative bacilli is recommended.315 For patients with HAP who have risk factors for MRSA, vancomycin or linezolid is recommended as part of empiric therapy.315 For patients with HAP without risk factors for MRSA and who are not at high risk of mortality, an antibiotic with activity against MSSA is suggested.315 Piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem are suggested for MSSA coverage as part of empiric therapy regimens.315 For patients with suspected VAP, an antibiotic regimen with coverage for Staphylococcus aureus , Pseudomonas aeruginosa , and other gram-negative bacilli is recommended for empiric therapy.315 Similar to HAP, piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem are also suggested for VAP for MSSA coverage.315 For patients with HAP/VAP who have risk factors increasing the likelihood for Pseudomonas or other gram-negative infections or who have a high risk for mortality, prescribing 2 antibiotics from different classes with activity against Pseudomonas is suggested as part of empiric therapy.315 A single agent with activity against Pseudomonas aeruginosa is otherwise suggested as part of empiric therapy for HAP/VAP.315 For the treatment of HAP/VAP caused by Acinetobacter species, a carbapenem (e.g., imipenem) or ampicillin/sulbactam is suggested for treatment if the isolate is susceptible to these agents.315 For the treatment of HAP/VAP definitively caused by Pseudomonas aeruginosa , the choice of antibiotic recommended should be based on the results of antimicrobial susceptibility testing.315
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of urinary tract infections (UTIs; including complicated and uncomplicated infections) caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , and Pseudomonas aeruginosa .1 Imipenem/cilastatin has also been used for the treatment of uncomplicated cystitis caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E)† and pyelonephritis or complicated UTIs caused by ESBL-E†.549
The efficacy of imipenem/cilastatin has been studied in 3 randomized, active-controlled trials in patients with UTIs.546, 547, 561 In 1 randomized, double-blind, multicenter study, piperacillin/tazobactam was compared with imipenem/cilastatin in 327 hospitalized adults with acute uncomplicated pyelonephritis or complicated UTIs.561 For the main efficacy outcome of clinical response rate at the test-of-cure visit (5-9 days after antibiotic therapy), patients treated with piperacillin/tazobactam had a similar success rate compared with patients treated with imipenem/cilastatin.561
Another study compared IV imipenem/cilastatin with IV ceftazidime plus avibactam (ceftazidime/avibactam) in adult patients with severe complicated UTIs due to gram-negative pathogens, including acute pyelonephritis.546 The most common causative organism was Escherichia coli .546 For the main efficacy endpoint of favorable microbiological response at 5-9 days after the last dose of study therapy, patients treated with ceftazidime/avibactam had a similar response rate compared with patients treated with imipenem/cilastatin.546
In another study, imipenem/cilastatin was compared with IV cefiderocol for the treatment of complicated UTIs with or without pyelonephritis and acute uncomplicated pyelonephritis in hospitalized adults at risk of multidrug-resistant (MDR) gram-negative infections.547 The median duration of antibiotic treatment was about 9 days for both groups.547 For the main efficacy endpoint, a composite of clinical response and microbiological response at 7 days after the end of antibiotic treatment, cefiderocol was found to be non-inferior to imipenem/cilastatin.547
In 2025, the IDSA published clinical guidelines for the treatment and management of complicated UTIs.567 Within these guidelines, the definitions of complicated UTIs and uncomplicated UTIs were revised.567 Uncomplicated UTIs are infections confined to the bladder in women or men; complicated UTIs are infections beyond the bladder in women or men and include pyelonephritis, febrile or bacteremic UTI, catheter-associated UTI (CAUTI), and prostatitis.567 For empiric antibiotic therapy for patients with suspected complicated UTIs, a four-step approach has been proposed that assesses the severity of illness (i.e., presence or absence of sepsis), risk factors for resistance, patient-specific risk factors (e.g., allergies, contraindications, drug-drug interactions), and, for septic patients, local antibiogram.567 Preferred empiric options for patients with sepsis, with or without shock, due to complicated UTI include third- or fourth-generation cephalosporins (ceftriaxone, ceftazidime, cefotaxime, or cefepime), carbapenems (imipenem/cilastatin, doripenem, meropenem, or ertapenem), piperacillin/tazobactam, or fluoroquinolones (ciprofloxacin or levofloxacin).567 For patients with complicated UTIs without sepsis for which an IV route of therapy is indicated, preferred treatment options include third- or fourth-generation cephalosporins, piperacillin/tazobactam, or fluoroquinolones.567 Alternative options include carbapenems, novel β-lactams/β-lactamase inhibitors (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, or imipenem/cilastatin/relebactam), cefiderocol, plazomicin, or older aminoglycosides (gentamicin, amikacin, or tobramycin).567 For patients with microbiologically confirmed complicated UTI, a definitely effective antibiotic with a targeted spectrum based on the results of the urine culture should be selected and used for the completion of treatment, rather than continuing empiric broad-spectrum antibiotics.567
The IDSA published a 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections in the United States (US).549 Included within this guidance are recommendations for infections caused by ESBL-E.549 For uncomplicated cystitis caused by ESBL-E, co-trimoxazole and nitrofurantoin are preferred treatment options; carbapenems, ciprofloxacin, and levofloxacin are alternative treatment options.549 For pyelonephritis or complicated UTIs caused by ESBL-E, co-trimoxazole, ciprofloxacin, or levofloxacin are preferred treatment options.549 In case of resistance or toxicities, ertapenem, meropenem, and imipenem/cilastatin are then preferred.549
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of intra-abdominal infections (IAIs) caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus species, Pseudomonas aeruginosa , Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, Bacteroides species including B. fragilis , and Fusobacterium species.1
The efficacy of imipenem/cilastatin has been studied in 5 randomized, active-controlled trials in patients with IAIs.550, 551, 552, 553, 554 In 1 randomized controlled trial, IV imipenem/cilastatin was compared with IV tobramycin plus IV clindamycin in 162 adults with IAIs.550 Patients in the tobramycin plus clindamycin group had an average of 3 bacterial isolates per patient versus an average of 3.8 isolates per patient for those in the imipenem/cilastatin group.550 The most common causative organisms were Escherichia coli , Alpha streptococci, Enterococci , and Bacteroides fragilis .550 Patients treated with tobramycin plus clindamycin had a higher prediction of treatment failure than those treated with imipenem/cilastatin.550 When evaluating for only gram-negative IAIs, patients treated with imipenem/cilastatin had a higher success rate than those treated with tobramycin plus clindamycin.552
In an open-label randomized study, imipenem/cilastatin was compared with IV meropenem in 249 adults with complicated IAIs.551 Patients treated with imipenem/cilastatin had a similar rate of cure compared with patients treated with meropenem.551
A double-blind, randomized controlled trial compared IV imipenem/cilastatin with sequential IV to oral treatment of ciprofloxacin plus metronidazole in 671 adults with complicated IAIs.552 For this study, the most common source of infection was the colon, followed by the appendix and small bowel.552 There were 9 patients who also received vancomycin, equally distributed between the 2 treatment groups.552 The overall clinical success rates for each of the treatment arms were found to be similar.552
In another randomized, double-blind trial, 825 hospitalized adults were randomized and received either IV tigecycline or imipenem/cilastatin for complicated IAIs.553 The most common diagnoses in this study were complicated appendicitis, perforated intestine, and gastric/duodenal ulcer.553 Tigecycline was found to be non-inferior to imipenem/cilastatin for the main efficacy outcome of clinical cure rate at the test-to-cure visit at 14-35 days after therapy.553
Another double-blind randomized study compared IV cefepime plus IV metronidazole with imipenem/cilastatin in 122 adults with IAIs.554 The most common types of infection were diffuse peritonitis and diverticulitis, and the most common causative organisms were Bacteroides fragilis and Escherichia coli .554 Patients treated with cefepime plus metronidazole had a substantially higher rate of clinical cure, the main efficacy outcome, versus patients treated with imipenem/cilastatin.554
Guidelines from the Surgical Infection Society (SIS) provide recommendations for the treatment of IAIs.548 The use of antimicrobial regimens that have activity against typical gram-negative Enterobacteriaceae , gram-positive cocci, and obligate anaerobes typically involved in IAIs is recommended.548 The guidelines recommended the use of imipenem/cilastatin or meropenem as a treatment option for empiric therapy in adults and pediatric patients >1 month of age.548 However, use should be reserved for higher-risk patients due to their broad spectrum of antimicrobial activity.548
Archived guidelines from the IDSA/SIS also recommend imipenem/cilastatin as a treatment option for empiric therapy of extra-biliary, community-acquired infection of high risk or severity (i.e., severe physiologic disturbance, advanced age, immunocompromised state); community-acquired acute cholecystitis of severe physiologic disturbance, advanced age, or immunocompromised state; acute cholangitis following bilioenteric anastomosis of any severity; healthcare-associated biliary infection of any severity; or if expanded spectrum coverage is needed against gram-negative aerobic and facultative bacilli.555
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of gynecologic infections caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Streptococcus agalactiae (Group B streptococci), Enterobacter species, Escherichia coli , Gardnerella vaginalis , Klebsiella species, Proteus species, Bifidobacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, and Bacteroides species including B. fragilis .1
The efficacy of imipenem/cilastatin has been studied in 3 randomized, active-controlled trials in patients with gynecologic infections.556, 557, 558 In an open-label, randomized controlled trial, IV imipenem/cilastatin was compared with IV clindamycin plus an aminoglycoside in 49 patients with postpartum endometritis.556 Over 60% of the patients in both groups developed endometritis following cesarean section.556 Bacteremia was present in 1 patient in the imipenem/cilastatin group and in 3 patients in the clindamycin plus an aminoglycoside group.556 For the main efficacy outcome of overall clinical response, patients treated with imipenem/cilastatin had a similar rate of response compared with patients treated with clindamycin plus an aminoglycoside.556
In another open-label, randomized study, imipenem/cilastatin was compared with IV clindamycin plus gentamicin in 94 women with serious pelvic infections.557 Most patients in this study had salpingitis (n=77), followed by pelvic abscess (n=12), and pelvic cellulitis following gynecologic surgery (n=5).557 Patients treated with imipenem/cilastatin had a similar rate of treatment success compared with patients treated with clindamycin plus gentamicin.557
Another open-label, randomized controlled trial compared IV imipenem/cilastatin with meropenem in 105 hospitalized adult female patients with obstetric and gynecologic infections, including pelvic inflammatory disease (PID), endometritis, salpingitis, pelvic peritonitis, and post-caesarean section and vaginal cuff infections.558 At the end of treatment, patients treated with meropenem had a substantially higher clinical response rate compared with patients treated with imipenem/cilastatin.558
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of bacterial septicemia caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Enterobacter species, Escherichia coli , Klebsiella species, Pseudomonas aeruginosa , Serratia species, and Bacteroides species including B. fragilis .1
In an open-label, randomized, multicenter study, levofloxacin (IV or IV to oral switch therapy) was compared with imipenem/cilastatin for the treatment of bacteremia/sepsis in hospitalized adults.562 Respiratory tract infections, including pneumonia, were the most common source of sepsis, followed by UTIs (including pyelonephritis), and IAIs.562 For the main efficacy outcome of clinical cure rate, levofloxacin was found to be as effective as imipenem/cilastatin in the treatment of bacteremia/sepsis.562
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of bone and joint infections caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Enterobacter species, and Pseudomonas aeruginosa .1
The efficacy of imipenem/cilastatin has been studied in a randomized, open-label, active-controlled trial in 32 adults with chronic osteomyelitis.563 Patients were randomized to receive oral ofloxacin or IV imipenem/cilastatin.563 If anaerobic organisms were isolated or suspected, oral clindamycin was added to ofloxacin.563 Patients were treated with antibiotics for 30-45 days.563 The most common organism isolated was Staphylococcus aureus followed by Pseudomonas aeruginosa .563 A similar percentage of patients in both treatment groups were cured.563
Guidelines have been published by the IDSA for the diagnosis and treatment of native vertebral osteomyelitis in adults.564 Empiric antimicrobial therapy should be started in patients with native vertebral osteomyelitis presenting with hemodynamic instability, sepsis, septic shock, or progressive or severe neurologic symptoms.564 When empiric antimicrobial therapy is appropriate, regimens with coverage against staphylococci (including MRSA), streptococci, and gram-negative bacilli should be used.564 Other considerations for empiric antimicrobial therapy are dependent on the host, clinical situation, epidemiologic risk, and local historical in vitro susceptibility data.564 Carbapenems can be part of select regimens in combination with vancomycin.564 For coverage of Pseudomonas aeruginosa suspected native vertebral infections, cefepime, doripenem, or meropenem are listed as first choices.564 For coverage of Enterobacteriaceae , cefepime or ertapenem are first choices.564 The choice of antimicrobial should be based on in vitro susceptibility, patient allergies and intolerances, and potential drug interactions or contraindications to a specific antimicrobial.564
Skin and Skin Structure Infections
Imipenem/cilastatin is used in adults and pediatric patients for the treatment of skin and skin structure infections caused by susceptible strains of the following microorganisms: Enterococcus faecalis , Staphylococcus aureus (penicillinase-producing isolates), Staphylococcus epidermidis , Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , Pseudomonas aeruginosa , Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis , and Fusobacterium species.1 Imipenem/cilastatin has also been used in the treatment of necrotizing fasciitis† , infected animal bite-related wounds†, and glanders†.543
The efficacy of imipenem/cilastatin has been studied in 2 randomized, active-controlled trials in patients with skin and soft tissue infections.565, 566
In an open-label, randomized, multicenter study, IV meropenem was compared with imipenem/cilastatin for the treatment of skin or soft tissue infections in 249 hospitalized adults.565 The expected duration of treatment for this study was 3-10 days with a maximum of 28 days.565 For the main efficacy outcomes of clinical and bacteriologic responses, assessed at 2-4 weeks after treatment, patients treated with meropenem had similar rates of satisfactory responses as patients treated with imipenem/cilastatin.565
In a double-blind, randomized, multicenter study, IV meropenem was compared with imipenem/cilastatin for the treatment of complicated skin or soft tissue infections in hospitalized adults and pediatric patients ≥13 years of age.566 Patients with complicated cellulitis, complex and perirectal abscesses, surgical site and traumatic wound infections, infected diabetic and ischemic ulcers, and other bacterial skin infections requiring hospitalization, surgical intervention, and parenteral antibiotic therapy were eligible for enrollment.566 For the main efficacy endpoint of clinical response, meropenem was found to be non-inferior to imipenem/cilastatin for the treatment of complicated skin and soft tissue infections.566
Guidelines have been published by the IDSA for the diagnosis and management of skin and soft tissue infections.543 Recommendations for antibiotics are dependent on the presence of purulence and severity of infection.543 For severe erysipelas and cellulitis infections, vancomycin plus either piperacillin/tazobactam, imipenem, or meropenem is recommended as a reasonable empiric regimen.543 For the treatment of incisional surgical site infections from surgery of the intestinal or genitourinary tract, single-drug regimens recommended include ticarcillin plus clavulanate (ticarcillin/clavulanate), piperacillin/tazobactam, imipenem/cilastatin, meropenem, or ertapenem.543
For the treatment of necrotizing fasciitis, including Fournier gangrene, empiric antibiotic treatment should be broad; example regimens include vancomycin or linezolid plus piperacillin/tazobactam or a carbapenem (e.g., imipenem/cilastatin), or vancomycin or linezolid plus ceftriaxone and metronidazole.543
For the treatment of infected animal bite-related wounds, antimicrobial agents active against both aerobic and anaerobic bacteria (e.g., amoxicillin/clavulanate) should be used.543 Second-generation cephalosporins (IV or by mouth) plus clindamycin or metronidazole are alternative regimens.543 Treatment with a carbapenem, moxifloxacin, or doxycycline is also an appropriate option.543
For the treatment of glanders, ceftazidime, gentamicin, imipenem, doxycycline, or ciprofloxacin is recommended based on in vitro susceptibility.543
Imipenem/cilastatin is used for the treatment of endocarditis caused by susceptible penicillinase-producing strains of S. aureus .1 However, guidelines from the American Heart Association (AHA) do not include imipenem/cilastatin as a recommended or alternative drug for the treatment of staphylococcal endocarditis in adults or pediatric patients.450, 452
Imipenem/cilastatin has been used for the treatment of MDR tuberculosis† (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin) in adults and pediatric patients.254, 255, 256 Guidelines published by ATS, the US Centers for Disease Control and Prevention (CDC), European Respiratory Society (ERS), and IDSA suggest including a carbapenem, always to be used with amoxicillin/clavulanic acid, in a regimen for treatment of patients with MDR tuberculosis.254 Guidelines published by the World Health Organization (WHO) state that imipenem/cilastatin or meropenem, in conjunction with clavulanic acid, may be included in the treatment of MDR rifampin-resistant tuberculosis for patients on longer regimens.255, 256 Patients with MDR tuberculosis are at high risk for treatment failure and acquisition of further drug resistance, and ATS, CDC, IDSA, and other experts recommend that such patients be referred to or that consultation be obtained from a specialized treatment center as identified by local or state health departments or the CDC.254
Imipenem has also been used for the treatment of nontuberculous mycobacteria (NTM) pulmonary disease caused by Mycobacterium abscessus † in adults.253 Guidelines published by the ATS, ERS, European Society for Microbiology and Infectious Diseases, and IDSA list imipenem as one of several preferred options for inclusion in multiple-drug regimens used for treatment.253
Fever and Neutropenia in Patients with Cancer
Imipenem/cilastatin has been used for the management of fever and neutropenia in adult patients with cancer†.568 Guidelines published by the American Society of Clinical Oncology (ASCO) and IDSA provide recommendations for the management of fever and neutropenia in patients with cancer who require treatment.568 Patients who present with neutropenic fever syndromes may require IV therapy and/or hospitalization.568 Empiric therapy may include monotherapy with an antipseudomonal agent such as cefepime, a carbapenem (e.g., imipenem/cilastatin), or piperacillin/tazobactam.568 Additional anti-infectives may be added depending on complications and antimicrobial resistance.568 For fluoroquinolone-resistant, β-lactam/cephalosporin-resistant gram-negative infections, patients should be treated as inpatients with a carbapenem-based regimen, likely requiring multiple doses per day.568
Antimicrobial-resistant Gram-negative Infections
Imipenem/cilastatin has been used for the management of antimicrobial-resistant gram-negative infections caused by ESBL-E and non-carbapenemase-producing carbapenem-resistant Enterobacterales (CRE) outside of the urinary tract†.549 Guidance published by the IDSA provides recommendations for antimicrobial-resistant gram-negative infections.549 For treatment of infections outside of the urinary tract caused by ESBL-E, meropenem, imipenem/cilastatin, or ertapenem is preferred.549 Meropenem and imipenem/cilastatin are the preferred carbapenems for patients who are critically ill and/or are experiencing hypoalbuminemia.549 For the treatment of infections outside of the urinary tract caused by CRE that are not carbapenemase-producing and exhibit susceptibility to meropenem and imipenem, the use of extended-infusion meropenem or imipenem/cilastatin is suggested.549
Imipenem/cilastatin has been used alone or in combination with other anti-infective agents for the treatment of anthrax†.569 Guidelines from the CDC provide recommendations on the prevention and treatment of anthrax, a zoonotic disease caused by infection with Bacillus anthracis .569 Imipenem/cilastatin is recommended as an alternative antimicrobial drug (i.e., non-first-line) for the empiric treatment of adults and pediatric patients ≥1 month of age with cutaneous anthrax, without signs and symptoms of meningitis, and as first-line as part of an empiric treatment regimen for adults with systemic anthrax, with or without meningitis.569 The CDC states that the use of imipenem/cilastatin is not advised for treatment of infections involving the CNS due to the risk of seizures; however, if imipenem/cilastatin is needed for anthrax meningitis, anticonvulsants can be used with imipenem/cilastatin to reduce the seizure risk.569
Imipenem has been used for the management of diabetes-related foot infections† and Nocardia infections after solid organ transplantation†.570, 571 Guidelines by the International Working Group on the Diabetic Foot and IDSA list imipenem as a potential empiric regimen for moderate or severe diabetic foot infection, especially in cases where gram-negative rod infections are common (i.e., presence of a macerated ulcer, warm climate, ischemic limb, or necrosis).570 The Infectious Diseases Community of Practice of the American Society of Transplantation guidelines for Nocardia infections in solid organ transplantation suggest imipenem as part of a regimen for empiric therapy for cerebral Nocardia infection, critical pulmonary Nocardia infection, and disseminated Nocardia infection, as well as an alternative agent as part of a regimen for stable pulmonary Nocardia infection.571
Imipenem/cilastatin is administered by IV infusion.1 The fixed-combination preparation is commercially available as a powder that must be reconstituted and further diluted prior to IV infusion.1
Imipenem/cilastatin should not be admixed with other antibacterials.1
Single-dose vials containing 250 mg of imipenem and 250 mg of cilastatin or single-dose vials containing 500 mg of imipenem and 500 mg of cilastatin should be reconstituted by adding approximately 10 mL of compatible IV solution (5% dextrose injection; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride injection; 0.9% sodium chloride injection) to provide a suspension.1 The suspension should be shaken well and should appear colorless to yellow; variations in color within this color range do not affect potency.1
The suspension should then be diluted by transferring into 100 mL of a compatible IV solution.1 To ensure complete transfer of vial contents, an additional 10 mL from the IV solution container should be added to the vial and then transferred back into the IV solution container.1 The diluted solution should be agitated until clear.1 Imipenem/cilastatin solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1
Commercially available imipenem/cilastatin dry powder vials should be stored at <25°C.1
The manufacturer states that following reconstitution of imipenem/cilastatin powder with 10 mL of an appropriate IV solution (5% dextrose injection; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride injection; 0.9% sodium chloride injection), the resulting suspension of the drug maintains satisfactory potency for 4 hours at room temperature or 24 hours when refrigerated at 5°C.1 Reconstituted suspensions and final diluted solutions of the drug should not be frozen.1
The rate of IV infusion of imipenem/cilastatin depends on the dose of imipenem.1 If nausea occurs during administration, the infusion rate may be decreased.1
The manufacturer recommends that imipenem doses of ≤500 mg should be infused over 20-30 minutes and imipenem doses >500 mg should be infused over 40-60 minutes.1
Dosage of imipenem/cilastatin is usually expressed in terms of the imipenem content of the fixed combination; dosage of imipenem monohydrate is expressed in terms of anhydrous imipenem.1
Dosage of imipenem (administered as the fixed combination of imipenem/cilastatin) recommended in adults is based on imipenem susceptibility of the suspected or confirmed causative organism(s) and the patient's renal function.1
Lower Respiratory Tract Infection
For the treatment of lower respiratory tract infection suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of urinary tract infection (complicated or uncomplicated) suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of intra-abdominal infection suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of gynecologic infection suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of bacterial septicemia caused by bacteria with suspected or proven susceptibility to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of bone and joint infection suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
Skin and Skin Structure Infection
For the treatment of skin and skin structure infection suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the treatment of endocarditis suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1 In adults demonstrating intermediate bacterial susceptibility to imipenem with a creatinine clearance of ≥90 mL/minute, the manufacturer recommends a dosage of 1 g of imipenem IV every 6 hours.1
The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1
For the empiric treatment of cutaneous anthrax in adults without meningitis†, imipenem and cilastatin has been given in a dosage of 1 g IV every 6 hours.569 For empiric treatment of systemic anthrax in adults with or without meningitis†, imipenem and cilastatin has been given in a dosage of 1 g IV every 6 hours in combination with ampicillin 2 g IV every 4 hours.569
Antimicrobial-resistant Gram-negative Infections
For the empiric treatment of antimicrobial-resistant uncomplicated cystitis†, imipenem and cilastatin has been given in a dosage of 500 mg IV every 6 hours, infused over 30 minutes.549 For other antimicrobial-resistant gram-negative infections†, imipenem and cilastatin has been given in a dosage of 500 mg IV every 6 hours, infused over 3 hours (if feasible).549
As part of an empiric regimen for hospital-associated pneumonia or ventilator-associated pneumonia in adults weighing ≥70 kg†, imipenem and cilastatin has been given in a dosage of 500 mg IV every 6 hours.315
For the empiric treatment of necrotizing fasciitis in adults†, imipenem and cilastatin has been given in a dosage of 1 g IV every 6<8 hours.543
Nontuberculosis Mycobacterial Pulmonary Disease
For the empiric treatment of nontuberculosis mycobacterial pulmonary disease in adults†, imipenem and cilastatin has been given in a dosage of 500 mg to 1 g IV 2<3 times daily.253
Dosage of imipenem (administered as the fixed combination of imipenem/cilastatin) recommended in pediatric patients is based on the age of the patient.1 Imipenem and cilastatin should not be used in pediatric patients with CNS infections due to the increased risk of seizures.1
Lower Respiratory Tract Infection
For the treatment of lower respiratory tract infection in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of urinary tract infection (complicated or uncomplicated) in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of intra-abdominal infection in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of gynecologic infection in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of bacterial septicemia in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of bone and joint infection in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
Skin and Skin Structure Infection
For the treatment of skin and skin structure infection in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
For the treatment of endocarditis in neonates who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those <1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1 In infants 1-3 months of age who weigh ≥1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1 In children ≥3 months of age, the manufacturer recommends a dosage of 15-25 mg/kg IV every 6 hours.1
The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1
The manufacturer provides no specific dosage recommendations in hepatic impairment.1
Dosage of imipenem (administered as imipenem/cilastatin) must be reduced in adults with creatinine clearance less than 90 mL/minute.1 (See Table 1.)
The manufacturer states that imipenem/cilastatin is not recommended in pediatric patients with renal impairment who weigh <30 kg since data are not available.1
Imipenem Susceptibility | Creatinine clearance 60 to <90 mL/minute | Creatinine clearance 30 to <60 mL/minute | Creatinine clearance 15 to <30 mL/minutea |
|---|---|---|---|
Infections suspected or proven to be caused by susceptible bacteria | 400 mg every 6 hours OR 500 mg every 6 hours | 300 mg every 6 hours OR 500 mg every 8 hours | 200 mg every 6 hours OR 500 mg every 12 hours |
Infections suspected or proven to be caused by bacteria with intermediate susceptibility | 750 mg every 8 hours | 500 mg every 6 hours | 500 mg every 12 hours |
aPatients with creatinine clearance 15 to <30 mL/minute may be at increased risk of seizures.
Imipenem/cilastatin should not be used in patients with creatinine clearance <15 mL/minute unless hemodialysis is initiated within 48 hours.1
Imipenem/cilastatin should be used in hemodialysis patients only if benefits outweigh the potential risk for seizures.1 If the drug is used in patients with creatinine clearances <15 mL/minute undergoing hemodialysis, imipenem dosage recommended for patients with creatinine clearances of 15 to <30 mL/minute should be used (see Table 1).1 Because both imipenem and cilastatin are cleared from the circulation during hemodialysis, the drug should be administered after hemodialysis and at intervals timed from the end of that hemodialysis session.1 Dialysis patients, especially those with underlying CNS disease, should be carefully monitored during imipenem/cilastatin treatment.1
The manufacturer states that information is insufficient to recommend the use of imipenem/cilastatin in patients receiving peritoneal dialysis.1
The manufacturer states that age-based dosage adjustment of imipenem/cilastatin is not necessary.1 However, because geriatric patients are more likely to have decreased renal function, dosage should be selected with caution in these patients and monitoring of renal function may be useful.1 Dosage should be modified in response to the degree of renal impairment.1
Severe and occasionally fatal hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving therapy with β-lactam antibiotics.1 These reactions are more likely to occur in patients with a history of sensitivity to multiple allergens.1 There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe hypersensitivity when treated with another β-lactam antibiotic.1
Prior to therapy with imipenem/cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to other β-lactam antibiotics, including penicillins and cephalosporins, or to other allergens.1 If a hypersensitivity reaction occurs during imipenem and cilastatin therapy, the drug should be immediately discontinued.1 Serious anaphylactic reactions require immediate emergency treatment with appropriate therapy as clinically indicated.1
Seizures and other adverse CNS effects such as confusional states and myoclonus have been reported with IV imipenem/cilastatin, particularly when administered in dosages exceeding those recommended by the manufacturer.1 Although adverse CNS effects have been reported most frequently in patients with CNS disorders (e.g., a history of seizures, brain lesions) and/or patients with renal impairment, these effects have also been reported in some patients with no recognized or documented underlying CNS disorder or renal impairment.1
Anticonvulsant therapy should be continued during imipenem/cilastatin therapy if the drug is used in patients with known seizure disorders.1 If focal tremors, myoclonus, or seizures occur during imipenem and cilastatin therapy, patients should be evaluated neurologically, anticonvulsant therapy should be initiated in patients who are not already receiving such therapy, and the imipenem/cilastatin dosage should be reassessed to determine whether dosage should be decreased or the drug discontinued.1 Safety and efficacy of imipenem and cilastatin have not been established in patients with meningitis, and the manufacturer states that the drug should not be used in such patients.1 Use of imipenem and cilastatin also is not recommended in pediatric patients with CNS infections because of the risk of seizures.1
Increased Seizure Potential Due to Interaction with Valproic Acid
Case reports have demonstrated that in patients receiving valproic acid or divalproex sodium, concomitant use of carbapenems (including imipenem/cilastatin) has resulted in decreased plasma concentrations of valproic acid.1 Because of this interaction, valproic acid concentrations may drop below the therapeutic range and the risk of breakthrough seizures may be increased.1 Increasing the dosage of valproic acid or divalproex sodium in patients receiving a carbapenem may not be sufficient to overcome this interaction.1
Concomitant use of imipenem/cilastatin and valproic acid or divalproex sodium is generally not recommended.1 In patients whose seizures are well controlled on valproic acid or divalproex sodium, use of antibacterials other than carbapenems should be considered to treat infections.1 If concomitant use of imipenem/cilastatin is necessary in such patients, supplemental anticonvulsant therapy should be considered.1 Recommended dosage and dosage schedules should be adhered to, especially in patients with known factors that predispose to convulsive activity.1
Clostridioides difficile-associated Diarrhea (CDAD)
Treatment with anti-infectives alters the normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile ).1 C. difficile -associated diarrhea (CDAD; also known as antibiotic-associated pseudomembranous colitis) has been reported with nearly all anti-infectives, including imipenem/cilastatin, and may range in severity from mild diarrhea to fatal colitis.1 C. difficile produces toxins A and B, which contribute to the development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since these infections may be refractory to anti-infective therapy and may require colectomy.1
Because CDAD has been reported with imipenem/cilastatin, it should be considered in the differential diagnosis of all patients who develop diarrhea during or following therapy with the drug.1 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1 If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile may need to be discontinued.1 Patients should be managed with appropriate anti-infective therapy directed against C. difficile , supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.1 Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if frequent watery or bloody stools occur during or as late as 2 months or longer after the last dose.1
Development of Drug-resistant Bacteria
As with other anti-infective agents, prolonged use of imipenem/cilastatin may result in overgrowth of nonsusceptible organisms.1 Careful observation of the patient's condition during imipenem/cilastatin therapy is essential.1 If superinfection occurs, appropriate measures should be taken.1
To reduce development of drug-resistant bacteria and maintain effectiveness of imipenem/cilastatin and other antibacterials, the fixed-combination preparation should be used only for the treatment of infections proven or strongly suspected to be caused by susceptible bacteria or a prophylactic indication.1 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1
Data available from small numbers of postmarketing cases of imipenem/cilastatin use during pregnancy are insufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.1
Developmental toxicity studies in animals (mice, rats, rabbits, monkeys) using imipenem and cilastatin (alone or in combination) administered at doses 0.4-2.9 times the recommended human dose (based on body surface area) showed no evidence of drug-induced fetal malformations.1 Embryofetal development studies using imipenem and cilastatin in cynomolgus monkeys at doses similar to the recommended human dose (based on body surface area) showed an increase in embryonic loss.1
Data are insufficient regarding the presence of imipenem and cilastatin in human milk, and data are not available on possible effects on the breast-fed child or effects on milk production.1 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for imipenem/cilastatin and any potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.1
Safety and efficacy of imipenem/cilastatin in pediatric patients is supported by evidence from adequate and well-controlled studies in adults and clinical studies in pediatric patients.1
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).1 Such adverse effects generally have been reported in 1-4% of pediatric patients receiving imipenem and cilastatin.1 However, seizures have been reported in neonates and children ≤3 months of age receiving the drug.1 Therefore, because of the risk of seizures, the manufacturer recommends that IV imipenem/cilastatin should not be used in pediatric patients with CNS infections.1 The manufacturer also recommends that because there are insufficient data to date evaluating IV imipenem/cilastatin in pediatric patients with impaired renal function who weigh <30 kg, the drug should not be used in these patients.1
Diluents containing benzyl alcohol should not be used to prepare imipenem/cilastatin for IV administration to neonates.1 Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.1 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.1
In clinical studies of imipenem/cilastatin involving approximately 2800 adults 18 years of age or older, approximately 800 were ≥65 years of age and 300 were ≥75 years of age.1 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.1 However, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1
Imipenem is substantially excreted by the kidney, and the risk of severe adverse reactions may be increased in patients with impaired renal function.1 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.1 The manufacturer states that age-based dosage adjustment is not necessary.1 However, because geriatric patients are more likely to have decreased renal function, dosage should be selected with caution in these patients and monitoring of renal function may be useful.1 Dosage should be adjusted in geriatric patients with renal impairment.1
The pharmacokinetics of imipenem/cilastatin in patients with hepatic impairment are not known.1
Patients with renal impairment are at an increased risk for CNS effects (e.g., seizures), especially if the usual dosage of imipenem/cilastatin is exceeded.1 Patients with creatinine clearance <15 mL/minute should not receive imipenem/cilastatin unless hemodialysis is instituted within 48 hours.1 Do not use in patients undergoing hemodialysis unless benefits outweigh possible risk of drug-induced seizures.1 Monitor closely for adverse CNS effects (e.g., confusion, myoclonic activity, seizures), especially in those with CNS disease.1
Dosage must be adjusted in adults with creatinine clearance <90 mL/minute.1
The most common adverse effects reported in ≥0.2% of adults include phlebitis, nausea, diarrhea, vomiting, rash, pain and erythema at the injection site, fever, hypotension, seizures, dizziness, pruritus, vein induration, urticaria, and somnolence.1
The most common adverse effects reported in >1% of pediatric patients ≥3 months of age include diarrhea, rash, phlebitis, gastroenteritis, vomiting, IV site irritation, and urine discoloration.1
The most common adverse effects reported in >1% of neonates and infants <3 months of age include convulsions, diarrhea, oliguria/anuria, oral candidiasis, rash, and tachycardia.1
Generalized seizures have occurred in patients who received concomitant therapy with imipenem/cilastatin and ganciclovir.1 Because of the risk of seizures, imipenem/cilastatin should be used concomitantly with ganciclovir only when the potential benefits are thought to outweigh the possible risks.1
Concomitant administration of probenecid and imipenem/cilastatin increases the plasma concentrations and half-life of imipenem.1 Therefore, the manufacturer of imipenem/cilastatin states that concomitant use of probenecid is not recommended.1
In patients receiving valproic acid or divalproex sodium, concomitant use of carbapenems (including imipenem and cilastatin) results in decreased plasma concentrations of valproic acid.1 Because of this interaction, valproic acid concentrations may drop below the therapeutic range and the risk of breakthrough seizures may be increased.1 Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing serum concentrations of valproic acid.1 Increasing the dosage of valproic acid or divalproex sodium in patients receiving a carbapenem may not be sufficient to overcome this interaction.1
Concomitant use of imipenem/cilastatin and valproic acid or divalproex sodium is generally not recommended.1 In patients whose seizures are well controlled on valproic acid or divalproex sodium, use of antibacterials other than carbapenems should be considered to treat infections.1 If concomitant use of imipenem/cilastatin is necessary in such patients, supplemental anticonvulsant therapy should be considered.1 Recommended dosage and dosage schedules should be adhered to, especially in patients with known factors that predispose to convulsive activity.1
Imipenem usually is bactericidal in action.1 The antibacterial activity of imipenem results from inhibition of synthesis in the bacterial cell wall.1 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 and PBPs 1a, 1b, 2, 4, and 5 of Pseudomonas aeruginosa .1 The bactericidal effect of imipenem is related to its binding to PBP2 and PBP1B.1
Cilastatin, an inhibitor of dehydropeptidase I in the kidneys, prevents the renal metabolism of imipenem, so when given concomitantly, adequate antibacterial levels of imipenem are attained in the urine.1
Cilastatin prevents metabolism of imipenem by dehydropeptidase I (DHP I) in the kidneys and, when administered concomitantly, results in urinary concentrations of active imipenem that are higher than could be obtained following administration of the antibiotic alone.1
Imipenem is administered as the monohydrate, but dosages and concentrations of the drug are expressed in terms of anhydrous imipenem.1 Dosage of imipenem and cilastatin is expressed in terms of the imipenem content of the drug.1
Following IV infusion over 20 minutes of a single 500-mg or 1-g dose of imipenem/cilastatin, peak plasma levels of imipenem antimicrobial activity range from 21-58 and 41-83 mcg/mL, respectively.1 Plasma levels of antimicrobial activity declined to 1 mcg/mL or less within 4-6 hours.1 In a dose-ranging study in premature, low-birthweight neonates (0.7-1.9 kg) 1 week of age or younger who received imipenem/cilastatin in a dosage of 20 mg/kg every 12 hours given by IV infusion over 15-30 minutes, peak and trough plasma concentrations averaged 43 and 1.7 mcg/mL, respectively.1 While the clinical importance is unclear, multiple IV doses of imipenem/cilastatin in neonates may result in moderate accumulation of cilastatin.1 No accumulation of imipenem or cilastatin occurs following multiple doses in patients with normal renal function.1 Following IV administration, imipenem distributes into tissues, including vitreous humor, aqueous humor, lung, peritoneal fluid, CSF, bone, interstitial fluid, skin, and fascia.1 Imipenem is approximately 20% and cilastatin is approximately 40% bound to serum proteins.1 The elimination half-life of imipenem and cilastatin is approximately 1 hour.1 In healthy geriatric individuals 65-75 years of age (with normal renal function 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 approximately 1.5 and 1.1 hours, respectively, and were similar to half-lives expected in individuals with slight renal impairment.1 Multiple doses in healthy geriatric individuals have no effect on the pharmacokinetics of either imipenem or cilastatin and accumulation of imipenem/cilastatin has not been observed.1 Approximately 70% of the imipenem/cilastatin dose is excreted in urine within 10 hours.1 Urine concentrations of imipenem in excess of 10 mcg/mL can be maintained for up to 8 hours with a 500-mg dose of imipenem and cilastatin.1
Imipenem is active in vitro against many gram-positive and gram-negative aerobic bacteria as well as many gram-positive and gram-negative anaerobic bacteria.1 Imipenem is highly stable in the presence of β--lactamases, both penicillinases and cephalosporinases, produced by gram-positive and gram-negative organisms.1 It is a potent inhibitor of β--lactamases produced by certain gram-negative bacteria that are resistant to most β--lactam antibiotics (e.g., Pseudomonas aeruginosa , Serratia species, and Enterobacter species).1
Imipenem is active clinically and in vitro against the following gram-positive aerobic bacteria: Staphylococcus aureus and S. epidermidis , Streptococcus pneumoniae , S. pyogenes (group A β-hemolytic streptococci), and group B streptococci (e.g., S. agalactiae ).1 Imipenem is active against E. faecalis , but not S. faecium .1
Although the efficacy of imipenem in treating infections due to these bacteria has not been established in well-controlled clinical trials, at least 90% of strains tested for the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for imipenem against isolates of a similar genus or organism group: Bacillus species, Listeria monocytogenes , Nocardia species, S. saprophyticus , viridans streptococci, and group C and G streptococci.1
Imipenem is active clinically and in vitro against the following gram-negative aerobic bacteria: Acinetobacter , Citrobacter , and Enterobacter species, E. coli , Gardnerella vaginalis , Haemophilus influenzae and H. parainfluenzae , Klebsiella species, Morganella morganii , Proteus vulgaris , Providencia rettgeri , P. aeruginosa , and Serratia species, including S. marcescens .1 In vitro, imipenem has also demonstrated synergistic activity with aminoglycosides against some isolates of P. aeruginosa .1
Although the efficacy of imipenem in treating infections due to these bacteria has not been established in well-controlled clinical trials, at least 90% of strains tested for the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for imipenem against isolates of a similar genus or organism group: Aeromonas hydrophila , Alcaligenes species, Capnocytophaga species, H. ducreyi , Neisseria gonorrhoeae , Pasteurella species, and Providencia stuartii .1
Imipenem demonstrates clinical activity and activity in vitro against the following gram-positive anerobic bacteria: Bifidobacterium , Clostridium , Eubacterium , Peptococcus , Peptostreptococcus , and Propionibacterium species.1
Imipenem demonstrates clinical activity and activity in vitro against the following gram-negative anerobic bacteria: Bacteroides species, including B. fragilis , and Fusobacterium species.1
Although the efficacy of imipenem in treating infections due to these bacteria has not been established in well-controlled clinical trials, at least 90% of strains tested for the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for imipenem against isolates of a similar genus or organism group: Prevotella bivia , P. disiens , P. melaninogenica , and Veillonella species.1
Imipenem is inactive in vitro against E. faecium , Stenotrophomonas maltophilia , and some isolates of Burkholderia cepacia .1 Methicillin-resistant staphylococci should be reported as resistant to imipenem.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 250 mg (of anhydrous imipenem) and 250 mg (of cilastatin)* | Imipenem and Cilastatin for Injection | |
500 mg (of anhydrous imipenem) and 500 mg (of cilastatin)* | Imipenem and Cilastatin for Injection, | |||
Primaxin® I.V. | Merck |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Merck Sharp & Dohme LLC. Primaxin® (imipenem and cilastatin) for injection, for intravenous use) prescribing information. Rahway, NJ. 2022 May.
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254. Nahid P, Mase, SR, Sotgiu, G et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med . 2019; 200(10):1-77. [PubMed 31729908]
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315. Kalil AC, Metersky ML, Klompas M et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis . 2016; 63:e61-e111. [PubMed 27418577]
450. Baddour LM, Wilson WR, Bayer AS et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation . 2015; 132:1435-86. [PubMed 26373316]
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512. Metlay JP, Waterer GW, Long AC et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med . 2019; 200:e45-e67. [PubMed 31573350]
543. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis . 2014; 59:147-59. Updates may be available at IDSA website at www.idsociety.org. [PubMed 24947530]
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