Imipenem/ cilastatin

Imipenem/ cilastatin belonging to the carbapenem antibiotics. respectively, used to treat a variety of bacterial infections including intra-abdominal infections, urinary tract infections, skin and soft tissue infections, pneumonia, sepsis, diabetic foot infections, and others. It is also used to treat infections in patients with neutropenia and cystic fibrosis. Imipenem/ cilastatin is a broad-spectrum antibiotic that works by inhibiting the synthesis of the bacterial cell walls, leading to the death of the bacteria.

Imipenem/ cilastatin is administered intravenously and rapidly achieves peak plasma concentrations within 30 minutes of administration. The drug is rapidly hydrolyzed by renal dehydropeptidase-I, an enzyme in the kidneys, and thus co-administration with cilastatin is required to inhibit this enzyme and prolong imipenem's half-life. The drug is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. The plasma half-life is approximately 1 hour in patients with normal renal function. There is no significant metabolism of Imipenem/ cilastatin in the liver, and no known active metabolites. There is no evidence of significant accumulation in plasma or tissues with repeated dosing.

Imipenem/ cilastatin shows common side effects like diarrhea, nausea, vomiting, headache, rash, itching, fever, and pain or inflammation at the injection site. Less common but more serious side effects may include allergic reactions, seizures, liver problems, and low blood cell counts.

Imipenem/ cilastatin is available in the form of powder for injection, solution for injection, and premixed solution for infusion.

Imipenem/ cilastatin is available in United States, Canada, United Kingdom, Australia, Germany, France, Italy, Spain, Japan, South Korea, and many others.

Imipenem/ cilastatin is a combination of two drugs that work together to treat bacterial infections. Imipenem is a broad-spectrum antibiotic that belongs to the carbapenem class and inhibits bacterial cell wall synthesis by binding to and inactivating the penicillin-binding proteins (PBPs), which are essential for bacterial cell wall formation. Cilastatin, on the other hand, is a renal dehydropeptidase inhibitor that prevents the breakdown of imipenem in the kidneys, thereby increasing its half-life and allowing for a longer duration of action. Together, Imipenem/ cilastatin provides broad-spectrum coverage against various bacterial pathogens and is used to treat a range of infections, including sepsis, pneumonia, urinary tract infections, and intra-abdominal infections.

The maximum plasma concentration (Cmax) of imipenem occurs approximately 1 hour after intravenous administration, while the Cmax of cilastatin occurs around 0.5 to 1 hour after administration. The onset of action is rapid, with antibacterial effects observed within 30 minutes after administration. The duration of action varies depending on the severity of the infection, dosage, and patient factors, but Imipenem/ cilastatin is generally administered every 6 to 8 hours.

Imipenem/ cilastatin is available in the form of powder for injection, solution for injection, and premixed solution for infusion.

Imipenem/ cilastatin is a combination antibiotic medication that is used to treat a variety of bacterial infections, including complicated urinary tract infections, intra-abdominal infections, and skin and soft tissue infections. It works by inhibiting the growth and reproduction of bacteria, which helps to stop the spread of infection in the body. The medication is available in several dosage strengths, and the appropriate dose will depend on the type and severity of the infection being treated, as well as the patient's age, weight, and kidney function. While Imipenem/ cilastatin can be a highly effective treatment for bacterial infections, it is important to follow the dosing instructions carefully and to complete the full course of treatment, even if symptoms improve before the medication is finished.

Effective against a wide range of bacteria: Imipenem/ cilastatin has a broad spectrum of activity against both gram-positive and gram-negative bacteria, making it useful in treating a wide range of bacterial infections.

Rapid onset of action: Imipenem/ cilastatin starts working quickly and can provide rapid relief from symptoms associated with bacterial infections.

High efficacy rates: Imipenem/ cilastatin has high efficacy rates, meaning it is effective at killing bacteria and treating infections.

Good safety profile: Imipenem/ cilastatin is generally well-tolerated and has a good safety profile when used as directed.

Can be used in combination therapy: Imipenem/ cilastatin can be used in combination with other antibiotics to enhance its effectiveness against certain bacterial infections.

Imipenem/ cilastatin is approved for use in the following clinical indications:

• Bloodstream infection: Imipenem/ cilastatin is used to treat bacterial infections in the bloodstream, also known as bacteremia. It works by inhibiting the synthesis of the bacterial cell walls, leading to the death of the bacteria.
• Cystic fibrosis, acute pulmonary exacerbation: This medication is used in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis, which is a genetic disorder that affects the respiratory and digestive systems. Imipenem/ cilastatin works by killing the bacteria that cause the infection and reducing inflammation in the lungs.
• Diabetic foot infection, moderate to severe: Imipenem/ cilastatin is used in the treatment of moderate to severe infections of the diabetic foot, which can occur as a complication of diabetes. The medication works by inhibiting the growth and spread of bacteria that cause the infection.
• Intra-abdominal infection, health care-associated or high-risk community-acquired infection: Imipenem/ cilastatin is used to treat serious infections of the intra-abdominal cavity, which can be caused by healthcare-associated or high-risk community-acquired infections. It works by killing the bacteria that cause the infection and reducing inflammation in the affected area.
• Melioidosis: Melioidosis is a rare and potentially fatal bacterial infection that can affect multiple organs. Imipenem/ cilastatin is one of the first-line treatments for this infection and works by killing the bacteria and reducing inflammation in the body.
• Mycobacterial infection: Imipenem/ cilastatin is sometimes used in combination with other medications to treat infections caused by Mycobacterium avium complex (MAC). It works by inhibiting bacterial cell wall synthesis, leading to the death of the bacteria.
• Neutropenic enterocolitis: This is a serious condition that can occur in patients with weakened immune systems, where there is inflammation and infection of the small intestine. Imipenem/ cilastatin is used in the treatment of this condition and works by killing the bacteria that cause the infection and reducing inflammation in the intestine.
• Neutropenic fever, high-risk patients with cancer: Imipenem/ cilastatin is used to treat neutropenic fever in high-risk cancer patients. It works by killing the bacteria that cause the infection and reducing inflammation in the body.
• Nocardiosis, severe: Nocardiosis is a rare bacterial infection that can affect the lungs, brain, and other parts of the body. Imipenem/ cilastatin is one of the first-line treatments for severe cases of this infection and works by killing the bacteria that cause the infection and reducing inflammation in the affected area.
• Peritonitis, treatment: Peritonitis is an inflammation and infection of the peritoneum, which is the lining of the abdominal cavity. Imipenem/ cilastatin is used in the treatment of this condition and works by killing the bacteria that cause the infection and reducing inflammation in the abdominal cavity.
• Pneumonia: Imipenem/ cilastatin is used in the treatment of bacterial pneumonia, which is an infection of the lungs. It works by killing the bacteria that cause the infection and reducing inflammation in the lungs.
• Sepsis and septic shock: Sepsis and septic shock are life-threatening conditions that can occur as a result of an infection. Imipenem/ cilastatin is used to treat these conditions and works by killing the bacteria that cause the infection and reducing inflammation in the body.
• Skin and soft tissue infection, moderate to severe: Imipenem/ cilastatin is used in the treatment of moderate to severe skin and soft infections.

• Bloodstream infection: 500 mg to 1 gram IV every 6 to 8 hours
• Cystic fibrosis, acute pulmonary exacerbation: 500 mg IV every 6 hours
• Diabetic foot infection, moderate to severe: 500 mg IV every 6 hours
• Intra-abdominal infection, healthcare-associated or high-risk community-acquired infection: 500 mg to 1 gram IV for every 6 to 8 hours
• Melioidosis: 1 gram IV every 6 hours
• Mycobacterial infection: 500 mg to 1 gram IV every 6 to 8 hours
• Neutropenic enterocolitis: 500 mg to 1 gram IV every 6 to 8 hours
• Neutropenic fever, high-risk patients with cancer: 500 mg to 1 gram IV every for 6 to 8 hours
• Nocardiosis, severe: 500 mg to 1 gram IV every 6 to 8 hours
• Peritonitis, treatment: 500 mg to 1 gram IV every 6 to 8 hours
• Pneumonia: 500 mg to 1 gram IV every 6 to 8 hours
• Sepsis and septic shock: 500 mg to 1 gram IV every 6 to 8 hours
• Skin and soft tissue infection, moderate to severe: 500 mg to 1 gram IV every for 6 to 8 hours
• Urinary tract infection, complicated: 500 mg to 1 gram IV for every 6 to 8 hours

The combination of Imipenem/ cilastatin is available as following strengths:

• 250mg/250mg powder for injection
• 500mg/500mg powder for injection
• 750mg/750mg powder for injection
• 1g/1g powder for injection
• 500mg/500mg and 500mg/500mg premixed solution for injection in flexible containers
• 1g/1g premixed solution for injection in flexible containers

The available dosage forms for Imipenem/ cilastatin include powder for injection, solution for injection, and premixed solution for infusion.

• Dosage Adjustment in Kidney Patient

Dosage adjustment may be necessary for patients with impaired renal function while using Imipenem/ cilastatin. The drug is primarily eliminated via the kidneys, and thus, reduced renal function may lead to increased drug levels in the body, which can cause adverse effects. The manufacturer recommends that the dose of Imipenem/ cilastatin be adjusted in patients with creatinine clearance (CrCl) less than or equal to 70 mL/min. For patients with a CrCl between 31-70 mL/min, the recommended dose is 500 mg every 6 hours. In patients with a CrCl less than or equal to 30 mL/min, the recommended dose is 500 mg every 8 hours. In patients requiring hemodialysis, the recommended dose is 500 mg every 6 hours, with additional dosing after each dialysis session. Close monitoring of renal function and drug levels is recommended in patients with renal impairment to ensure optimal dosing and to minimize the risk of adverse effects.

There are no specific dietary restrictions that need to be followed when prescribing Imipenem/ cilastatin to patients. However, it is important to provide clear dosing instructions, which may include taking the medication with or without food depending on the patient's individual needs. It is also essential to advise patients to avoid alcohol consumption while taking this medication, as it can increase the risk of certain adverse effects.

Imipenem/ cilastatin is contraindicated in patients with

• Patients who are hypersensitive to Imipenem/ cilastatin or any other ingredients of the medication.

The physician should closely monitor the patients as well as keep pharmacovigilance as follows:

• Understanding Hypersensitivity Reactions and Imipenem/ cilastatin

Hypersensitivity reactions, also known as anaphylactic reactions, are serious and sometimes fatal adverse reactions that can occur in patients receiving therapy with beta-lactams, including Imipenem/ cilastatin. Individuals with a history of sensitivity to multiple allergens, including penicillins, cephalosporins, and other beta-lactams, are at a higher risk of experiencing these reactions.

Before initiating therapy with Imipenem/ cilastatin, it is important to inquire about any previous hypersensitivity reactions to antibiotics and other allergens. If an allergic reaction to Imipenem/ cilastatin occurs, the drug should be discontinued immediately. Serious anaphylactic reactions require emergency treatment as clinically indicated.

• Potential Seizure Risk with Imipenem/ cilastatin

Seizures and other CNS adverse experiences, such as confusion and myoclonic activity, have been reported during treatment with Imipenem/ cilastatin, especially when recommended dosages were exceeded. These experiences are more common in patients with CNS disorders or compromised renal function, but they can also occur in patients without underlying CNS disorders or compromised renal function.

Patients with known seizure disorders should continue anticonvulsant therapy. If focal tremors, myoclonus, or seizures occur, it is advised that patients should be evaluated neurologically, also placed on anticonvulsant therapy if not already instituted, and the dosage of Imipenem/ cilastatin re-evaluated to determine whether it should be decreased or discontinued.

• Interaction with Valproic Acid

The concomitant administration of Imipenem/ cilastatin and valproic acid/divalproex sodium may decrease valproic acid concentrations, increasing the risk of breakthrough seizures. It is generally not recommended to use these drugs together. Consider using other antibacterials than carbapenems to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium. If Imipenem/ cilastatin administration is necessary, supplemental anticonvulsant therapy should be considered.

• Clostridium difficile-Associated Diarrhea (CDAD)

The use of nearly all antibacterial agents, including Imipenem/ cilastatin, can lead to Clostridium difficile-associated diarrhea (CDAD). If Clostridium difficile-associated diarrhea is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued, and appropriate management should be initiated. Prolonged use of Imipenem/ cilastatin may result in overgrowth of nonsusceptible organisms, leading to the development of drug-resistant bacteria. Therefore, careful consideration and evaluation are necessary when prescribing Imipenem/ cilastatin to ensure the best possible outcome for the patient.

Alcohol can interact with Imipenem/ cilastatin and increase the risk of certain side effects. Specifically, consuming alcohol while taking Imipenem/ cilastatin may increase the risk of seizures and other central nervous system (CNS) adverse effects, such as confusion and myoclonic activity. Therefore, it is recommended that individuals avoid consuming alcohol while taking this medication.

In addition, alcohol consumption can also impair the effectiveness of Imipenem/ cilastatin in treating bacterial infections. This is because alcohol can weaken the immune system and make it more difficult for the body to fight off infections.

The excretion of imipenem-cilastatin sodium in human milk is unknown. As with many drugs that can be excreted in human milk, caution should be exercised when administering Imipenem/ cilastatin to a nursing woman.

Pregnancy Category C

Imipenem/ cilastatin belongs to Pregnancy Category C, and its use during pregnancy should be carefully evaluated, weighing the potential benefits against the potential risks

Animal studies have shown no evidence of teratogenicity with imipenem, cilastatin sodium, or their combination. In these studies, doses up to 60 and 900 mg/kg/day of imipenem were administered intravenously to rabbits and rats, respectively, while cilastatin sodium was given to rabbits at doses up to 300 mg/kg/day and to rats subcutaneously at doses up to 1000 mg/kg/day. These doses were approximately 0.4 to 2.9 times the maximum recommended human daily dose based on the body surface area.

In pregnant cynomolgus monkeys, intravenous doses of imipenem-cilastatin sodium up to approximately 100 mg/kg/day were not associated with teratogenicity but showed an increase in embryonic loss relative to controls. However, maternal toxicity, including death and embryofetal loss, was observed at a dose of 40 mg/kg

In rats, no adverse effects on the fetus or lactation were observed when imipenem-cilastatin sodium was administered subcutaneously in late gestation at dosages up to 320 mg/kg/day, which is approximately equal to the highest recommended human dose based on body surface area. Although a slight decrease in live fetal body weight had been observed at the high dose, there were found to be no adverse effects on fetal viability, growth, or postnatal development of pups.

There are no specific food warnings related to the use of Imipenem/ cilastatin. However, it is important to follow the dosing instructions provided by your healthcare provider, which may include taking the medication with food or on an empty stomach depending on the individual's needs. Additionally, it is important to avoid consuming alcohol while taking Imipenem/ cilastatin as it can increase the risk of certain side effects.

The adverse reactions related to Imipenem/ cilastatin can be categorized as follows:

Common

• Phlebitis
• Nausea
• Diarrhea
• Vomiting

Less common

• Eosinophilia
• Potentially false-positive Coombs test
• Miscellaneous dermatologic effects
• Miscellaneous hematologic effects
• Transient increase in blood urea nitrogen (BUN) or serum creatinine
• Seizures

Rare

• Abnormal urinalysis
• Agitation
• Anaphylaxis
• Anemia
• Confusion (acute)
• Dizziness
• Dyskinesia
• Emergence of resistant strains of Pseudomonas aeruginosa
• Fever
• Hypersensitivity
• Hypotension
• Elevated liver function test (LFT) results
• Increased prothrombin time (PT)
• Neutropenia (including agranulocytosis)
• Palpitations
• Pruritus
• Pseudomembranous colitis

The clinically relevant drug interactions of Imipenem/ cilastatin are briefly summarized here:

Ganciclovir and Imipenem/ cilastatin

• Generalized seizures had been reported in patients who received ganciclovir and Imipenem/ cilastatin.
• Concomitant use of these drugs should be avoided unless potential benefits outweigh the risks.

Probenecid and Imipenem/ cilastatin

• Concomitant use of probenecid and Imipenem/ cilastatin results in increased plasma level and half-life of imipenem.
• It is not recommended to give probenecid concomitantly with Imipenem/ cilastatin.

Valproic Acid and Imipenem/ cilastatin

• Co-administration of carbapenems, including Imipenem/ cilastatin, to patients receiving valproic acid or divalproex sodium results in reduced valproic acid concentrations.
• This interaction may increase the risk of breakthrough seizures.
• The concomitant use of Imipenem/ cilastatin and valproic acid/divalproex sodium is generally not recommended.
• Other antibiotics should be considered to treat infections in patients whose seizures are well-controlled on valproic acid or divalproex sodium.

The common side effects of Imipenem/ cilastatin include the following:

• Diarrhea
• Nausea and vomiting
• Headache
• Skin rash
• Injection site reactions (such as pain, redness, and swelling)
• Abdominal pain
• Fever
• Increased liver enzymes
• Decreased white blood cell count

• Pregnancy

Pregnancy Category C

Imipenem/ cilastatin belongs to Pregnancy Category C, and its use during pregnancy should be carefully evaluated, weighing the potential benefits against the potential risks.

Animal studies have shown no evidence of teratogenicity with imipenem, cilastatin sodium, or their combination. In these studies, doses up to 60 and 900 mg/kg/day of imipenem were administered intravenously to rabbits and rats, respectively, while cilastatin sodium was given to rabbits at doses up to 300 mg/kg/day and to rats subcutaneously at doses up to 1000 mg/kg/day. These doses were approximately 0.4 to 2.9 times the maximum recommended human daily dose based on the body surface area.

In pregnant cynomolgus monkeys, intravenous doses of imipenem-cilastatin sodium up to approximately 100 mg/kg/day were not associated with teratogenicity but showed an increase in embryonic loss relative to controls. However,

maternal toxicity, including death and embryofetal loss, was observed at a dose of 40 mg/kg. In rats, no adverse effects on the fetus or lactation were observed when imipenem-cilastatin sodium was administered subcutaneously in late gestation at dosages up to 320 mg/kg/day, which is approximately equal to the highest recommended human dose based on the body surface area. Although a slight decrease in live fetal body weight had been observed at the high dose, there were found to be no adverse effects on fetal viability, growth, or the postnatal development of pups.

• Nursing Mothers

The excretion of imipenem- cilastatin sodium in human milk is unknown. As with many drugs that can be excreted in human milk, caution is to be exercised when administering Imipenem/ cilastatin to a nursing woman.

• Pediatric Use

Imipenem/ cilastatin has been shown to be safe and effective in pediatric patients through well-controlled trials in adults as well as clinical studies in pediatric patients .

However, it is important to note that the use of Imipenem/ cilastatin is not recommended in pediatric patients with central nervous system (CNS) infections due to the increased risk of seizures.

Additionally, for pediatric patients who weigh less than 30 kg and have renal impairment, Imipenem/ cilastatin is not recommended as there is currently no available data regarding its safety and effectiveness in this population.

• Geriatric Use

Clinical studies of Imipenem/ cilastatin, which included over 3600 subjects aged 18 years and older, including postmarketing studies, showed that approximately 2800 of these subjects received Imipenem/ cilastatin. Among these, data was available on approximately 800 subjects who were aged 65 years and over, including around 300 subjects who were 75 years and older. The results did not show any of the significant differences in safety or effectiveness between older and younger subjects. Although no differences in response have been identified between elderly and younger patients, it is possible that some older individuals may be more sensitive to the drug.

As Imipenem/ cilastatin is primarily excreted through the kidneys, patients with impaired renal function may have a higher risk of experiencing toxic reactions to the drug. Since elderly patients are said to more likely to have a decreased renal function, it is important to use caution when selecting the appropriate dose and to monitor renal function when necessary. However, no dosage adjustments are required based on age.

If an overdosage of Imipenem/ cilastatin occurs, discontinue the medication immediately and provide symptomatic treatment and supportive measures as needed. It is important to note that Imipenem/ cilastatin can be removed from the body by the method hemodialysis. Therefore, this treatment modality can be considered if appropriate.

• Pharmacodynamic

Imipenem-cilastatin sodium is a combination antibiotic drug used for treating bacterial infections. Imipenem is a carbapenem antibiotic that works by inhibiting the synthesis of bacterial cell walls, resulting in bacterial death. Cilastatin, on the other hand, is a renal dehydropeptidase inhibitor that is said to prevent the metabolism of imipenem in the kidneys, allowing adequate antibacterial levels of imipenem to be achieved in the urine when the two drugs are given concomitantly.

• Pharmacokinetics

Introduction

Imipenem/ cilastatin is a combination of two drugs, imipenem and cilastatin, that are used for treating bacterial infections. The pharmacokinetics of Imipenem/ cilastatin describes the way these drugs move through the body, including their absorption, distribution, metabolism, and elimination.

Intravenous Infusion of Imipenem/ cilastatin

Imipenem/ cilastatin is given through intravenous infusion, which takes about 20 minutes to complete. The 500 mg dose of the drug results in peak plasma levels of imipenem antimicrobial activity ranging from 21 to 58 mcg/mL, while the 1000 mg dose results in peak levels ranging from 41 to 83 mcg/mL. The peak plasma levels of cilastatin are 31 to 49 mcg/mL for the 500 mg dose and 56 to 88 mcg/mL for the 1000 mg dose. At these doses, the levels of imipenem antimicrobial activity in plasma decrease to below 1 mcg/mL in 4 to 6 hours.

Distribution

Imipenem and cilastatin have a binding affinity to human serum proteins of approximately 20% and 40%, respectively. Imipenem has been shown to penetrate into various human tissues, such as vitreous humor, aqueous humor, lung, peritoneal fluid, CSF, bone, interstitial fluid, skin, as well as fascia. Nevertheless, there is a lack of adequate and well-controlled studies on the treatment of imipenem in these additional body sites, and the clinical importance of these tissue concentration findings remains unknown.

Metabolism

When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase I, resulting in low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, prevents renal metabolism of imipenem, allowing adequate antibacterial levels of imipenem to be achieved in the urine when the two drugs are given concomitantly.

Elimination

The plasma half-life of both imipenem and cilastatin is approximately 1 hour. Within 10 hours of administration, around 70% of the imipenem dose is eliminated through urine, and no further urinary excretion is detected afterward. Imipenem concentrations in urine exceeding 10 mcg/mL can persist for up to 8 hours with a 500-mg dose of Imipenem/ cilastatin. Similarly, about 70% of the cilastatin sodium dose is eliminated through urine within 10 hours of administration. Even when given as frequently as every 6 hours to patients with normal kidney function, Imipenem/ cilastatin does not accumulate in plasma or urine.

• Therapeutic Benefits of Imipenem/ cilastatin Combination

Clinical studies have demonstrated various therapeutic benefits of Imipenem/ cilastatin combination. Some of the benefits observed in these studies include:

1. Treatment of multi-drug resistant infections: Imipenem/ cilastatin combination has shown efficacy in treating multi-drug resistant infections caused by bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii.
2. Treatment of hospital-acquired pneumonia: Clinical studies have shown that Imipenem/ cilastatin combination is effective in treating hospital-acquired pneumonia caused by susceptible strains of bacteria.
3. Treatment of complicated urinary tract infections: The combination has demonstrated efficacy in treating complicated urinary tract infections caused by susceptible strains of bacteria.
4. Treatment of bacterial meningitis: Imipenem/ cilastatin combination has been shown to be effective in treating bacterial meningitis caused by susceptible strains of bacteria.
5. Treatment of intra-abdominal infections: Clinical studies have demonstrated that the combination is effective in treating complicated intra-abdominal infections which is caused by susceptible strains of bacteria.

Overall, Imipenem/ cilastatin combination has been found to be a broad-spectrum antibiotic with efficacy against a variety of bacterial infections. However, like all antibiotics, it should be used judiciously and only when necessary to minimize the risk of antibiotic resistance.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050587s074lbl.pdf
• https://www.sandoz.ca/sites/www.sandoz.ca/files/Imipenem_Cilastatin_Product_Monograph.pdf
• https://www.medsafe.govt.nz/profs/datasheet/i/imipenemAndcilastatinRBXinj.pdf
• https://www.webmd.com/drugs/2/drug-2216/imipenem-cilastatin-intravenous/details/list-sideeffects
• https://www.rxlist.com/consumer_imipenemcilastatin_Imipenem/ cilastatin/drugs-condition.htm
• https://www.drugs.com/sfx/cilastatin-imipenem-side-effects.html
• https://reference.medscape.com/drug/Imipenem/ cilastatin-imipenem-cilastatin-342562#4