Cilastatin

Overview of Use

Cilastatin is a medication that is always administered in combination with the antibiotic imipenem. It is used to treat serious infections caused by bacteria in various parts of the body. While cilastatin does not kill bacteria itself, it prevents the kidneys from breaking down the antibiotic, which helps the treatment work more effectively.

Types of Infections Treated

This combination therapy is typically reserved for severe or complicated infections, including:

• Lower respiratory tract infections: Such as certain types of pneumonia.
• Urinary tract infections (UTIs): Including infections that have spread to the kidneys.
• Intra-abdominal infections: Infections occurring inside the stomach or abdominal cavity.
• Skin and soft tissue infections: Serious infections of the skin and the layers beneath it.
• Bone and joint infections: Bacterial infections affecting the skeletal system.
• Gynecological infections: Infections of the female reproductive organs.
• Septicemia: Serious bacterial infections that have entered the bloodstream.
• Endocarditis: An infection of the lining of the heart or heart valves.

In some cases, it may also be used to treat patients who have a fever and a very low white blood cell count, as these individuals are at a high risk for developing life-threatening bacterial infections.

Mechanism of Action

Cilastatin is not an antibiotic and does not kill bacteria on its own. Its primary role is to protect specific antibiotics, such as imipenem, from being destroyed by the body's natural processes. It belongs to a group of drugs called dehydropeptidase inhibitors.

Protecting the Antibiotic

When certain antibiotics enter the kidneys, an enzyme called dehydropeptidase I quickly breaks them down. Cilastatin works by blocking this enzyme. By stopping this breakdown, cilastatin provides several benefits:

• Increased Effectiveness: It allows the antibiotic to stay in the bloodstream and tissues at higher levels for a longer time.
• Urinary Concentration: It ensures that higher levels of the active antibiotic reach the urine, which is helpful for treating urinary tract infections.
• Kidney Protection: It may help reduce the risk of kidney irritation that can occur when the antibiotic is broken down into certain metabolites.

Because cilastatin has no antibacterial effect of its own, it is only administered in combination products to enhance the performance of the accompanying antibiotic medication.

Common Side Effects

Some people may experience mild side effects during treatment. These commonly include:

• Nausea or vomiting
• Diarrhea
• Dizziness or drowsiness
• Pain, redness, or swelling at the site of injection

Serious Side Effects

Seek medical attention immediately if you experience any of the following serious symptoms:

• Neurological symptoms: Seizures, confusion, tremors, or uncontrollable shaking of a part of the body.
• Allergic reactions: Skin rash, hives, itching, or swelling of the face, throat, tongue, or lips.
• Severe intestinal issues: Watery or bloody stools, stomach cramps, or fever, which may occur during treatment or several months after the last dose.
• Respiratory distress: Difficulty breathing or swallowing.

This medication may also cause changes in kidney function or blood cell counts, which are typically monitored by a healthcare provider through regular testing.

Allergic Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibiotics. Before starting treatment, it is important to determine if there is a history of hypersensitivity to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, the medication must be discontinued immediately.

Central Nervous System Effects

Central nervous system adverse experiences, such as seizures, tremors, and confusion, have been reported. These effects occur most commonly in patients with pre-existing central nervous system disorders (such as brain lesions or a history of seizures) or those with compromised kidney function. Dosage adjustments are necessary for patients with decreased kidney function to reduce the risk of these effects.

Diarrhea and Colitis

Clostridioides difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents. This condition can range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to the overgrowth of C. difficile.

Drug Interactions

The use of this medication with valproic acid or divalproex sodium is generally not recommended. Combining these drugs can lead to a significant decrease in valproic acid concentrations, which may increase the risk of breakthrough seizures.

Kidney Function

Because the medication is primarily excreted by the kidneys, patients with renal impairment require monitoring and dosage adjustments. Failure to adjust the dose according to kidney function may increase the risk of toxicity and central nervous system side effects.

Development of Drug-Resistant Bacteria

Prescribing the medication in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit and increases the risk of the development of drug-resistant bacteria.

Pregnancy

Information regarding the use of cilastatin during pregnancy is limited, as there are no adequate and well-controlled studies in humans. In animal studies where cilastatin was administered in combination with imipenem, some adverse effects on the fetus were observed at very high doses, though other studies showed no evidence of harm. Due to the lack of definitive human data, healthcare providers typically recommend using this medication during pregnancy only when the potential benefits justify the potential risks to the developing fetus.

Breastfeeding

It is not known whether cilastatin passes into human breast milk. However, imipenem, which is almost always administered with cilastatin, has been found in human milk. Because many drugs are excreted in breast milk, caution is advised. It is important for breastfeeding individuals to consult with their healthcare provider to weigh the benefits of treatment against any potential risks to the nursing infant.

Available Forms

Cilastatin is not available as a standalone product. It is provided in combination with the antibiotic imipenem, and sometimes with relebactam, in the following forms:

• Powder for Intravenous Infusion: This form is dissolved and administered into a vein.
• Powder for Intramuscular Injection: This form is prepared for injection into a muscle.

These products are intended for use in a clinical setting and are administered by healthcare professionals.

FDA Approval Status

Cilastatin is approved by the U.S. Food and Drug Administration (FDA) only as a component of combination drug products. It was first approved in 1985 for use with the antibiotic imipenem. It is also available in a three-drug combination that includes imipenem and the beta-lactamase inhibitor relebactam.

Approved Indications

The combination of imipenem and cilastatin is indicated for the treatment of serious infections caused by susceptible bacteria, including:

• Lower respiratory tract infections
• Urinary tract infections
• Intra-abdominal infections
• Gynecologic infections
• Bacterial septicemia
• Bone and joint infections
• Skin and skin structure infections
• Endocarditis

Cilastatin itself does not have antibacterial activity; it is included to prevent the breakdown of imipenem in the kidneys, which allows the antibiotic to reach higher levels in the body.

Regulatory Safety Information

There are currently no FDA boxed warnings or Risk Evaluation and Mitigation Strategies (REMS) associated with cilastatin. Regulatory oversight focuses on its use within combination products, which are typically administered by intravenous or intramuscular injection in clinical settings.

Cost Considerations

Cilastatin is not available as a standalone medication; it is always administered in combination with other drugs, such as imipenem or relebactam. Because these medications are typically given by injection or infusion in a hospital or clinic, the cost is often bundled with other medical services and supplies rather than being a separate retail pharmacy charge.

Factors Influencing Price

• Generic Availability: Generic versions of imipenem and cilastatin are available, which may be less expensive than brand-name versions.
• Insurance Coverage: Most health insurance plans, including Medicare and Medicaid, generally cover these injections when they are medically necessary. Out-of-pocket costs will depend on the specific plan's deductible and coinsurance rates.
• Setting of Care: Costs can vary significantly between inpatient hospital stays and outpatient infusion centers.
• Dosage and Duration: The total price is influenced by the specific dose required and the length of the treatment course.

Patients are encouraged to contact their insurance provider or the billing department of their healthcare facility for specific information regarding out-of-pocket costs.