Cilastatin

The dosage of Cilastatin is always tied to the dosage of imipenem, usually in a 1:1 ratio. For most systemic infections in adults with normal kidney function, the standard dose ranges from 250 mg to 1000 mg of Cilastatin administered every 6 to 8 hours.

• Mild Infections: 250 mg every 6 hours (1 gram total per day).
• Moderate Infections: 500 mg every 6 to 8 hours (1.5 to 2 grams total per day).
• Severe, Life-Threatening Infections: 1000 mg every 6 to 8 hours (up to 4 grams total per day).

The maximum daily dose typically does not exceed 4 grams or 50 mg/kg, whichever is lower. Healthcare providers will determine the specific dose based on the severity of the infection and the patient's body weight.

Cilastatin is approved for use in pediatric patients, including neonates.

• Infants and Children (>3 months): The recommended dose is 15 to 25 mg/kg administered every 6 hours. For bone and joint infections, higher doses may be required.
• Neonates (0-3 months): Dosing is highly dependent on weight and age in weeks. For those weighing less than 1500g, doses may be 25 mg/kg every 12 hours. For older or heavier neonates, the frequency may increase to every 8 hours.

Cilastatin is generally not recommended for pediatric patients with CNS infections due to the risk of seizures, nor is it recommended for children with significant renal impairment, as data in this population is limited.

Renal Impairment

Because Cilastatin is primarily cleared by the kidneys, dosage adjustments are mandatory for patients with a Creatinine Clearance (CrCl) of less than 70 mL/min/1.73m².

• CrCl 31-70 mL/min: 500 mg every 6-8 hours.
• CrCl 21-30 mL/min: 500 mg every 8-12 hours.
• CrCl 6-20 mL/min: 250 mg to 500 mg every 12 hours.
• Hemodialysis Patients: If CrCl is less than 5 mL/min, the drug should only be given if hemodialysis is started within 48 hours. A supplemental dose is usually required after each dialysis session because the procedure removes Cilastatin from the blood.

Hepatic Impairment

No specific dosage adjustments are required for patients with liver disease, as Cilastatin is not significantly metabolized by the liver. However, these patients should still be monitored for overall clinical status.

Elderly Patients

Older adults often have decreased renal function even if their serum creatinine appears normal. Healthcare providers typically use the Cockcroft-Gault equation to estimate renal function and adjust the dose of Cilastatin accordingly to prevent accumulation and toxicity.

Cilastatin is administered only by healthcare professionals in a clinical setting (hospital or infusion center).

• Intravenous Infusion: Doses of 250-500 mg should be infused over 20 to 30 minutes. Doses of 1000 mg should be infused over 40 to 60 minutes. If a patient develops nausea during the infusion, the rate may be slowed.
• Intramuscular Injection: This form is for mild-to-moderate infections only. It is injected into a large muscle mass (like the gluteus maximus). It is not for IV use.
• Storage: Reconstituted solutions are generally stable for 4 hours at room temperature or 24 hours under refrigeration. Do not freeze the reconstituted solution.

In a hospital setting, it is unlikely that a dose will be missed. However, if you are receiving home infusion therapy and miss a scheduled dose, contact your healthcare provider or infusion nurse immediately. Do not double the next dose to catch up. Timely administration is crucial for maintaining effective antibiotic levels in the blood.

Symptoms of a Cilastatin/Imipenem overdose may include an intensification of side effects, such as severe nausea, vomiting, confusion, tremors, or seizures. In the event of a suspected overdose, the medication must be stopped immediately. Treatment is supportive and symptomatic. Cilastatin is hemodialyzable, meaning it can be removed from the blood using a dialysis machine, which may be beneficial in cases of extreme toxicity.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or stop the treatment without medical guidance, as this can lead to antibiotic resistance.

Because Cilastatin is always administered with imipenem, it is difficult to isolate side effects caused solely by Cilastatin. However, the combination is generally well-tolerated. The most common side effects reported in clinical trials include:

• Nausea and Vomiting: This occurs in approximately 1% to 11% of patients. It is often related to the speed of the infusion; faster infusions are more likely to trigger a queasy feeling or active vomiting. This typically resolves shortly after the infusion rate is slowed.
• Diarrhea: Loose stools are common with many broad-spectrum antibiotics as they alter the natural bacteria in the gut. This usually lasts for the duration of the treatment and resolves afterward.
• Injection Site Reactions: Patients may experience redness, pain, swelling, or a hard lump (induration) where the needle was inserted. Phlebitis (inflammation of the vein) is also common with IV administration.

• Rash and Pruritus: Some patients may develop a mild skin rash or itchy skin (pruritus). This is often a mild allergic response but should be monitored closely.
• Fever: A low-grade fever may occur as the body responds to the medication or the underlying infection.
• Dizziness and Somnolence: Some patients report feeling lightheaded or unusually sleepy following a dose.
• Eosinophilia: A transient increase in a specific type of white blood cell (eosinophils) may be detected on blood tests.

• Seizures: This is a significant concern, occurring in about 0.4% of patients. It is most common in those with pre-existing brain lesions, a history of epilepsy, or those with kidney failure who receive doses that are too high.
• Liver Enzyme Elevations: Temporary increases in AST, ALT, and alkaline phosphatase may occur, indicating stress on the liver.
• Thrombocytopenia: A rare drop in platelet counts, which could theoretically increase the risk of bruising or bleeding.
• Confusion or Hallucinations: Psychotic disturbances or acute confusional states have been reported, particularly in elderly patients.

> Warning: Stop taking Cilastatin and call your doctor immediately if you experience any of these serious symptoms.

• Anaphylaxis: A severe allergic reaction characterized by swelling of the face, lips, or tongue, difficulty breathing, a rapid heart rate, and a sharp drop in blood pressure. This is a medical emergency.
• Clostridioides difficile-Associated Diarrhea (CDAD): This can range from mild diarrhea to fatal colitis. If you experience watery or bloody stools, severe stomach cramps, and fever—even weeks after finishing treatment—contact your doctor immediately.
• Severe Skin Reactions: Conditions like Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) are rare but life-threatening. Watch for skin peeling, blisters, or sores in the mouth and eyes.
• Seizures and CNS Toxicity: If you experience tremors, muscle twitching, or a seizure, the medication must be discontinued immediately.
• Nephrotoxicity: While Cilastatin is designed to protect the kidneys, in rare cases, patients may show signs of worsening kidney function, such as decreased urine output or swelling in the legs.

Cilastatin is typically used for short-term acute infections (7 to 14 days). Long-term use is rare. However, prolonged exposure to broad-spectrum antibiotics can lead to 'superinfections,' where resistant bacteria or fungi (like oral thrush or vaginal yeast infections) overgrow because the normal protective bacteria have been killed off. There is no evidence that Cilastatin causes permanent organ damage when used correctly, but chronic use requires frequent monitoring of blood counts and organ function.

As of 2026, there are no FDA black box warnings specifically for Cilastatin. However, it carries significant warnings regarding its potential to cause central nervous system (CNS) effects, including seizures, especially when used in patients with underlying neurological conditions or impaired renal function. The label emphasizes that the risk-benefit ratio must be carefully weighed in patients with known seizure disorders.

Report any unusual symptoms to your healthcare provider. Even mild symptoms can sometimes be early indicators of a more significant reaction.

Cilastatin is a potent medication that must be used with caution. The most critical safety consideration is that it must never be used as a standalone treatment; it is only effective and safe when combined with imipenem. Patients must inform their healthcare providers of their full medical history, especially any history of allergies to antibiotics, as cross-reactivity is a significant concern. Additionally, because the drug is cleared by the kidneys, maintaining adequate hydration and monitoring urine output is essential during therapy.

No FDA black box warnings for Cilastatin. However, clinicians are advised to strictly adhere to dosing guidelines to avoid CNS toxicity.

• Allergic Reactions / Anaphylaxis Risk: There is a high risk of cross-sensitivity between Cilastatin/Imipenem and other beta-lactam antibiotics, such as penicillins and cephalosporins. If you have ever had a severe reaction (hives, swelling, or trouble breathing) to penicillin, you may be at risk for a similar reaction to this medication.
• Central Nervous System (CNS) Risks: Cilastatin can lower the seizure threshold. This risk is amplified in patients with a history of seizures, head injuries, or those taking other medications that also increase seizure risk (like ganciclovir). If CNS symptoms occur, the dose should be evaluated or the drug discontinued.
• Renal Function Monitoring: Since the drug accumulates in the presence of kidney disease, patients with a CrCl < 70 mL/min require mandatory dose reductions. Failure to adjust the dose significantly increases the risk of seizures.
• C. diff Diarrhea: Like all potent antibiotics, this drug can kill the 'good' bacteria in your gut, allowing C. difficile to grow. This can cause severe, life-threatening inflammation of the colon.

While receiving Cilastatin, your healthcare team will perform regular tests to ensure your safety:

• Renal Function Tests: Frequent monitoring of serum creatinine and BUN (blood urea nitrogen) to assess kidney health and adjust dosages.
• Liver Function Tests: Periodic checks of AST, ALT, and bilirubin levels.
• Complete Blood Count (CBC): To monitor for rare effects on white blood cells, red blood cells, and platelets.
• Neurological Assessment: Monitoring for tremors, confusion, or other signs of CNS irritability.

Cilastatin may cause dizziness, confusion, or somnolence in some patients. You should not drive, operate heavy machinery, or engage in dangerous activities until you know how the medication affects you. If you experience any neurological side effects, avoid these tasks entirely during the course of treatment.

There is no direct chemical interaction between Cilastatin and alcohol. However, alcohol can dehydrate the body and put additional stress on the liver and kidneys, which are already processing a severe infection and potent medications. It is generally advised to avoid alcohol while being treated for a serious bacterial infection to allow the immune system to function optimally.

In a hospital setting, your doctor will decide when to stop the medication. It is vital to complete the full course of therapy as prescribed. Stopping too early—even if you feel better—can allow the remaining bacteria to multiply and develop resistance, making the infection much harder to treat in the future. There is no 'withdrawal syndrome' associated with Cilastatin, but the risk of infection relapse is high if the course is incomplete.

> Important: Discuss all your medical conditions, especially kidney disease or seizure disorders, with your healthcare provider before starting Cilastatin.

• Valproic Acid / Sodium Valproate: This is a critical interaction. Carbapenems (the antibiotics Cilastatin is paired with) can cause a rapid and significant drop in valproic acid levels in the blood, often falling below the therapeutic range. This can lead to a loss of seizure control and the development of breakthrough seizures. This interaction is generally not manageable by simply increasing the dose of valproic acid; therefore, alternative antibiotics should be considered for patients on valproate therapy.

• Ganciclovir: When Cilastatin/Imipenem is used with ganciclovir (an antiviral), generalized seizures have been reported. These drugs should not be used together unless the potential benefits outweigh the risks.
• Probenecid: Probenecid is a medication used for gout that slows the renal excretion of many drugs. Taking probenecid with Cilastatin can lead to significantly higher and prolonged levels of Cilastatin in the blood. While this is not usually toxic, it is generally recommended that they not be used concurrently.

• Other Beta-Lactams: Using Cilastatin with other penicillins or cephalosporins may increase the risk of allergic reactions and does not typically provide additional antibacterial benefit.
• Cyclosporine: There is a potential for increased neurotoxicity when these drugs are used together, though data is limited. Monitoring for CNS side effects is advised.

Since Cilastatin is administered intravenously or intramuscularly, food does not affect its absorption. There are no known interactions with specific foods like grapefruit, dairy, or high-fat meals. However, maintaining a healthy, balanced diet and staying well-hydrated is important for recovery from infection.

There are no well-documented interactions between Cilastatin and common herbal supplements like St. John's Wort or Ginkgo Biloba. However, because many supplements can affect kidney function or the seizure threshold, you should inform your doctor about all natural products you are taking. For example, supplements that have stimulant properties should be used with caution as they might theoretically contribute to CNS irritability.

Cilastatin may interfere with certain laboratory tests:

• Coombs Test: A positive direct Coombs test may develop during treatment, which can interfere with blood cross-matching or indicate drug-induced hemolytic anemia.
• Urinary Glucose: It may cause a false-positive result for glucose in the urine when using copper reduction methods (like Benedict's solution or Clinitest). Use enzymatic glucose oxidase tests instead.

For each major interaction, the mechanism usually involves competition for renal tubular secretion or a pharmacodynamic effect on the central nervous system. The clinical consequence is typically either an increased risk of seizures or a reduction in the efficacy of the co-administered drug (like valproic acid). Management strategies involve selecting alternative therapies or performing intensive blood level monitoring.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and vitamins.

Cilastatin must NEVER be used in the following circumstances:

• Severe Hypersensitivity: If a patient has a known, documented life-threatening allergy (anaphylaxis) to Cilastatin, imipenem, or any other carbapenem antibiotic. The risk of a fatal reaction is too high to justify use.
• Lidocaine Allergy (IM Form Only): The intramuscular formulation of Cilastatin/Imipenem is often reconstituted with lidocaine. If a patient is allergic to lidocaine or other local anesthetics of the amide type, the IM form is absolutely contraindicated.
• Severe Heart Block (IM Form Only): Due to the lidocaine content in the IM diluent, it should not be used in patients with severe heart block or severe shock.

In these cases, the healthcare provider must perform a careful risk-benefit analysis:

• Known Seizure Disorders: Because Cilastatin/Imipenem lowers the seizure threshold, it should be used with extreme caution in patients with epilepsy. It is usually only used if no other safer antibiotic options are available.
• Mild to Moderate Penicillin Allergy: While not an absolute contraindication, there is a risk of cross-reactivity. Patients with a history of mild rash from penicillin may be able to take Cilastatin, but they must be monitored very closely for the first several doses.
• Severe Renal Impairment (CrCl < 5 mL/min): Unless the patient is undergoing hemodialysis, the drug is generally avoided because the risk of accumulation and CNS toxicity is exceptionally high.

Patients should be aware of 'class-wide' sensitivities. If you are allergic to one carbapenem (like meropenem, ertapenem, or doripenem), you are highly likely to be allergic to Cilastatin/Imipenem. Furthermore, about 1% to 10% of patients with a penicillin allergy may also react to carbapenems. Always provide your doctor with a detailed description of any past allergic reactions to antibiotics, including what the reaction looked like (e.g., hives vs. just a stomach ache).

> Important: Your healthcare provider will evaluate your complete medical history, including all past allergic reactions, before prescribing Cilastatin.

Cilastatin is classified by the FDA as Pregnancy Category C. This means that animal reproduction studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies in humans. In animal studies, high doses of the imipenem/cilastatin combination resulted in embryonic loss. Therefore, Cilastatin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is generally reserved for life-threatening infections where safer alternatives have failed or are not appropriate. There is no evidence currently linking Cilastatin to fertility treatments or specific teratogenic patterns in humans, but caution is paramount.

It is known that imipenem and potentially Cilastatin are excreted in human breast milk in small amounts. While the risk to the nursing infant is generally considered low because the drug is poorly absorbed from the infant's gut, there are risks of altering the infant's bowel flora (causing diarrhea) or sensitizing the infant to future allergic reactions. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Many doctors recommend 'pumping and discarding' milk during the treatment period and for 24 hours after the last dose.

Cilastatin is approved for pediatric use, including in newborns. However, it is not recommended for children with CNS infections (like meningitis) because of the increased risk of seizures. It is also not typically used in children with kidney impairment, as the safety and appropriate dosing in this specific group have not been well-established. For children with normal kidney function, it is an effective treatment for serious systemic infections when dosed by weight.

Clinical studies have shown that Cilastatin is effective in elderly patients. However, because this population is much more likely to have decreased renal function, the risk of toxic reactions (especially seizures) is higher. Doctors must be diligent in calculating the estimated Creatinine Clearance and adjusting the dose. Elderly patients should also be monitored more closely for confusion or other mental status changes during therapy.

This is the most critical special population for Cilastatin. As the GFR (Glomerular Filtration Rate) drops, the half-life of Cilastatin increases from 1 hour to several hours. Dose adjustments are required for any patient with a CrCl below 70 mL/min. In patients on dialysis, the timing of the dose is vital; it should be given after the dialysis session because the procedure effectively 'washes' the drug out of the bloodstream.

Since the liver plays a minimal role in the clearance of Cilastatin, patients with liver disease (Child-Pugh Class A, B, or C) do not usually require dose modifications. However, severe systemic infection can often cause secondary liver stress, so monitoring of liver enzymes remains a standard part of clinical care for these patients.

> Important: Special populations require individualized medical assessment and frequent monitoring by a specialized healthcare team.

Cilastatin is a competitive inhibitor of dehydropeptidase-I (DHP-I). This enzyme is a membrane-bound glycoprotein found on the brush border of the renal proximal tubule. DHP-I's natural role is the hydrolysis of dipeptides, but it also breaks the beta-lactam ring of imipenem. By binding to the zinc-containing active site of DHP-I, Cilastatin prevents this hydrolysis. This results in two effects: it increases the concentration of active imipenem in the urine and prevents the formation of potentially nephrotoxic metabolites. It has no effect on bacterial enzymes or other human enzymes outside the kidney.

The pharmacodynamics of Cilastatin are defined by its ability to maintain imipenem levels. There is a direct dose-response relationship between the amount of Cilastatin given and the percentage of imipenem recovered in the urine. Without Cilastatin, only about 5-20% of imipenem is recovered; with Cilastatin, this increases to 70%. The onset of action is immediate upon IV administration, and the duration of effect lasts as long as therapeutic concentrations are maintained in the renal tubules, typically 6-8 hours.

| Parameter | Value |

|---|---|

| Bioavailability | 100% (IV); 75% (IM) |

| Protein Binding | ~40% |

| Half-life | 1.0 hour (Normal Renal Function) |

| Tmax | Immediate (IV); 1-2 hours (IM) |

| Metabolism | Minimal (~10% to N-acetyl-cilastatin) |

| Excretion | Renal (70-80% unchanged) |

• Molecular Formula: C16H25N2NaO5S
• Molecular Weight: 380.44 g/mol
• Solubility: Highly soluble in water.
• Structure: Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. It is a white to off-white hygroscopic powder. Its chemical name is [R-[R,S-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid, monosodium salt.

Cilastatin is a renal dehydropeptidase inhibitor. It is the only member of this class currently in widespread clinical use. It is always categorized as part of the carbapenem combination therapies, specifically paired with imipenem. It is functionally similar to beta-lactamase inhibitors (like clavulanic acid) in that it protects an antibiotic from degradation, but it targets a human enzyme rather than a bacterial one.