Cilastatin

Cilastatin is a drug that is administered together with the antibiotic imipenem and is said to delay the rapid metabolism of the imipenem. Cilastatin is one of the protease inhibitors. It inhibits the kidney enzyme dehydropeptidase-I, which is responsible for the metabolism of imipeneme.

What is cilastatin?

Cilastatin (chemical molecular formula: C16H26N2O5S) is a white to light yellow amorphous powder (cilastatin sodium). In pharmacy it is used as a protease inhibitor, i.e. it inhibits the peptidases (formerly called proteases) and thus prevents the breakdown of proteins.

Cilastatin inhibits the enzyme dehydropeptidase-I. The inhibition is competitive and reversible, i.e. Cilastatin competes with dehydropeptidase-I for the occupation of the same receptors. After the cilastatin has been discontinued, the inhibition is lifted because the enzyme can re-occupy the receptors.

Pharmacological effect

Cilastatin is used as a powder that is made up into a solution for infusion. From this it can be deduced that the application always takes place intravenously. Regarding pharmacokinetics, it can be said that the drug's plasma half-life is on average one hour.

Cilastatin is given in the form of its salt, cilastatin sodium. The mechanism of action of cilastatin consists in inhibiting dehydropeptidase-I, a kidney enzyme that is responsible for the metabolism of imipeneme.

When administered at the same time, there is a competitive inhibition, i.e. the cilastatin occupies the same receptors as the kidney enzyme and 'fights' with this to occupy the receptors. The activity of dehydropeptidase-I is inhibited or prevented from being active. This is the desired effect of the medicinal substance, since this process delays the metabolism of the imipeneme.

The delayed metabolism results in higher concentrations and a longer duration of action of the imipenem. The imipenem is hydrolyzed in the kidney, that is, it is broken down by the addition of a water molecule. This metabolism of imipeneme, which is delayed by the cilastatin, results in inactive nephrotoxic metabolites. Animal experiments have shown that cilastatin can reduce nephrotoxicity.

Medical application & use

Cilastatin is used in a fixed combination with imipenem, an antibiotic from the group of ß-lactam antibiotics. Its job is to prevent the imipenem from being rapidly metabolized. This is necessary in order to obtain a sufficiently high concentration of the antibiotic for the desired therapeutic effect.

In addition, animal experiments showed a reduction in the nephrotoxic effect of imipenem when it was used in combination with cilastatin. Cilastatin itself does not have an antibacterial effect. It does not affect the antibacterial effect of the imipenem, it only prevents the rapid metabolism of the imipenem, which increases its concentration in the plasma. From a chemical point of view, cilastatin is a derivative of the natural amino acid (R) -cysteine.

Imipenem, the antibiotic that is administered together with cilastatin, has a bactericidal effect by inhibiting the cell wall synthesis of the bacteria. There is a stability towards bacterial beta-lactamases. Imipenem is a broad-spectrum antibiotic that detects aerobic and anaerobic, gram-positive and gram-negative bacteria.

It is used as a reserve antibiotic for the treatment of life-threatening bacterial infections. Mixed infections are also among the indications for imipenem. The above indications result in a strict indication for the use of the combination imipenem / cilastatin. For this reason, imipenem is always given in combination with cilastatin.

Risks & side effects

The side effects and risks that can be caused by the cilastatin include hypersensitivity with localized tissue hardening and pain; allergic reactions such as local skin irritation, skin redness, rashes, itching, urticaria (hives); Changes in the blood count such as thrombocytosis or eosinophilia and temporary liver dysfunction.

The contraindications of cilastatin or the combination of cilastatin with imipenem include hypersensitivity to cilastatin, hypersensitivity to imipenem or other beta-lactamase antibiotics and kidney dysfunction in children. In addition, the drug must not be used during pregnancy or breastfeeding. Use in small children is also contraindicated.