Imipenem/cilastatin

Imipenem/cilastatin

Combination of
Imipenem	Carbapenem antibiotic
Cilastatin	Dehydropeptidase inhibitor
Clinical data
MedlinePlus	a605011
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)
Routes	Intravenous, intramuscular
Identifiers
CAS number	92309-29-0 Y
ATC code	J01DH51
PubChem	CID 11954222
ChemSpider	21106325 Y
ChEMBL	CHEMBL296854 Y
Y (what is this?)  (verify)

Imipenem/cilastatin (marketed as Primaxin in the USA, and as CILASAFE in India) is a broad spectrum beta-lactam antibiotic containing equal quantities of imipenem and cilastatin.^[1] It is related to the penicillin/cephalosporin family of antibiotics but is classified as belonging to the carbapenem class.

Mechanism

Imipenem/cilastatin has the ability to kill a wide variety of bacteria. Imipenem is the active antibiotic agent and works by interfering with their ability to form cell walls, and therefore the bacteria break up and die.

Imipenem is rapidly degraded by the renal enzyme dehydropeptidase if administered alone (making it less effective); the metabolites can cause kidney damage.^[2] Imipenem is a broad spectrum betalactam antibiotic which is used for severe bacterial infections caused by susceptible organisms. Because imipenem is rapidly inactivated by renal dehydropeptidase I, it is given in combination with cilastatin, a DHP-I inhibitor which increases half-life and tissue penetration of imipenem. Imipenem/cilastatin, like other carbapenems, binds to bacterial penicillin binding proteins and interferes with bacterial cell wall integrity and synthesis. It is a broad spectrum antibiotic with activity against many aerobic and anaerobic gram-positive and gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species. Imipenem/cilastatin was approved for use in the United States in 1985. Imipenem/cilastatin is indicated for the treatment of severe or complicated skin, tissue, joint, respiratory tract, intra-abdominal, urinary tract and urogenital infections, But not meningitis (as it doesn't pass through the blood brain barrier), endocarditis and sepsis due to susceptible organisms. Its use is generally restricted to severe infections largely in hospitalized patients. The recommended dosage is 250 mg to 1 gram given intravenously every 6 to 8 hours or in intramuscular doses of no more than 1.5 gm daily, usually for 5 to 14 days. It is commercially available as Primaxin as 250 mg or 500 mg infusion bottles for IV use or 500 mg or 750 mg vials of lyophilized powder for im injection. The most common side effects of imipenem are diarrhea, nausea, vomiting, skin rash, pruritus (itch) and injection site reactions.

Pharmacology

Mechanism of Action Imipenem inhibits bacterial cell-wall synthesis by binding to penicillin-binding proteins; cilastatin prevents renal metabolism of imipenem

Absorption Bioavailability (IM): Imipenem, 60–75%; cilastatin, 95–100%

Distribution: Distributed rapidly and widely to most tissues and fluids, including sputum, pleural fluid, peritoneal fluid, interstitial fluid, bile, aqueous humor, reproductive organs, and bone; highest concentrations in pleural fluid, interstitial fluid, peritoneal fluid, and reproductive organs; low concentrations in CSF; crosses placenta; enters breast milk

Protein binding: Imipenem, 13–21%; cilastatin, 40%

Metabolism: Imipenem is metabolized in the kidney by dehydropeptidase 1; activity is blocked by cilastatin

Elimination Half-life (both drugs): 60 min; prolonged with renal impairment Excretion (both drugs): Urine (~70% as unchanged drug)

Availability and description

Primaxin IV is a combination of imipenem, cilastatin sodium and sodium bicarbonate which is added as a buffer.^[1] Primaxin IM lacks the sodium bicarbonate buffer.^[3]

Indications

Primaxin is indicated in: lower respiratory tract infections (IV, IM), urinary tract infections (IV), intra-abdominal infections (IV, IM), gynecologic infections (IV, IM), bacterial septicemia (IV), bone and joint infections (IV), skin and skin structure infections (IV, IM), endocarditis (IV) and polymicrobic infections (IV).^[1][3]

Precautions

Patients who are allergic to penicillin, cephalosporins and related drugs should tell their doctor.^[4] It is important tell your doctor or pharmacist your medical history, especially of: brain disorders (e.g., seizures, head injury, tumor), kidney disease, liver disease, stomach/intestinal diseases (e.g., colitis).^[1]

Hepatotoxicity

In large clinical trials, imipenem was associated with transient and asymptomatic elevations in serum aminotransferase levels in approximately 6% of patients given the drug for 5 to 14 days. More serious hepatic injury from imipenem/cilastatin is rare, but jaundice and liver test abnormalities have been reported in 0.1% of patients in prospective trials of the agent. Several instances of cholestatic jaundice arising during or shortly after therapy have been reported with imipenem-cilastatin and other carbapenems. The latency to onset has been within 1 to 3 weeks and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to the carbapenems has been reported. Imipenem and other carbapenems have not been linked to cases of acute liver failure.

Mechanism of Liver Injury

The cause of the mild, transient serum enzyme elevations during imipenem-cilastatin therapy is not know. The cholestatic hepatitis attributed to imipenem-cilastin and the carbapenems is probably immunoallergic and resembles the rare clinically apparent liver injury that has been linked to penicillins and cephalosporins.

Outcome and Management

The liver injury due to the carbapenems is usually mild and self-limited. Rarely, the carbapenems can cause a clinically apparent acute cholestatic hepatitis that is usually self-limiting and not requiring therapy or intervention. In patients with vanishing bile duct syndrome, corticosteroids are often used but have not been shown to be beneficial and are best avoided. Some patients may benefit from symptomatic therapy of the pruritus associated with cholestasis using antihistamines, ursodiol or cholestyramine. There is little information on possible cross-sensitivity to liver injury among the different betalactam antibiotics, but patients with clinically apparent liver injury due to imipenem should probably avoid the other carbapenems.

Dosage and administration

The dosage for Primaxin IV in adults is 125 mg, 250 mg, or 500 mg (of each drug) over 20–30 minutes. Each 750 mg or 1000 mg dose should be infused over 40–60 minutes.^[1] Primaxin IM given for intra-abdominal infections may be dosed at 750 mg every 12 hours. Other infections may be treated with 500 mg or 750 mg administered every 12 hours depending on its severity.^[3]

IV Incompatibilities

Solution: D5/LR, LR, sodium bicarbonate, sodium lactate (D5W and NS causes some activity loss but are recommended for short-term use)

Y-site: Allopurinol, amiodarone, amphotericin B cholesteryl sulfate, azithromycin, etoposide phosphate, fluconazole, gemcitabine, lorazepam, meperidine, midazolam, sargramostim, sodium bicarbonate

IV Preparation: Reconstitute infusion bottles with 100 mL of compatible diluent Reconstitute vials with a portion (usually 10 mL) of IV fluid withdrawn from the IV container, dissolve, and return to container; repeat

Reconstituted solutions are stable for 4 hours at room temperature and 24 hours refrigerated (4 °C) in NS Normal color ranges from clear to yellow; these variations do not affect potency, but solution should be discarded if brown Imipenem is inactivated at acidic or alkaline pH

IM Administration:

Prepare 500 mg vial with 2 mL of 1% lidocaine; prepare 750 mg vial with 3 mL of 1% lidocaine (do not use lidocaine with epinephrine) Administer by deep injection into large muscle (gluteal or lateral thigh muscle) Aspiration is necessary to avoid inadvertent injection into blood vessel

IV Administration:

Do not administer by IV push

Final concentration should not exceed 5 mg/mL

Infuse ≤500 mg over 20–30 minutes (15–30 minutes in children); infuse >500 mg over 40-60 min

Vial contents must be transferred to 100 mL of infusion solution

If nausea or vomiting occurs during administration, reduce infusion rate

Drug must not be mixed or physically added to other antibiotics; however, it may be administered concomitantly

Side effects

Common side effects for both forms are:^[4]

• Upset stomach
• Vomiting
• Stomach pain

Major side effects requiring medical attention:^[4]

• Diarrhea
• Rash
• Fever
• Facial swelling
• Difficulty breathing
• Unusual bleeding
• Seizures

This medicine is passed through breast milk so its usage during pregnancy or breast feeding should only be done when clearly needed.^[3] Primaxin is cleared from the body via the kidneys so it is important to tell your doctor about any other drugs you take that are also cleared through the kidneys (such as other antibiotics), espcially for older patients as kidney function declines with age.^[1][3]

Interactions

• valproic acid (Depakene, Stavzor)^[5]
• ganciclovir (Cytovene)^[5]
• probenecid (Benemid)^[5]
• penicillin antibiotics such as amoxicillin (Amoxil, Augmentin), ampicillin (Omnipen, Principen), dicloxacillin (Dycill, Dynapen), oxacillin (Bactocill), or penicillin (Beepen-VK, Ledercillin VK, Pen-V, Pen-Vee K, Pfizerpen, V-Cillin K, Veetids, and others);^[5] or
• cephalosporin antibiotics such as cefaclor (Ceclor), cefuroxime (Ceftin), cefadroxil (Duricef), cephalexin (Keflex), and others.^[5]

Marketing

Imipenem/cilastatin is marketed by Merck & Co. under the trade names Primaxin, Tienam and Zienam whereas in India it is marketed as ICL (by Zuventus Healthcare Ltd). The combination is also marketed by Ranbaxy Laboratories & BIOCON in India under the brand name Cilanem and IMICELUM respectively, as well as by New Medicon Pharma under the brand name Tinaxin and Lupin as Lupinem. It is also marketed by Highnoon Laboratories Ltd. in Pakistan under the trade name Prepenem. Prepenem was launched by Highnoon in May 2007 and was the first generic brand after the research brand Tienam.

References