Singapore Drugs Database

Indication

Doripenem is indicated in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, caused by designated susceptible bacteria.

Mechanism of Action

Doripenem is a broad-spectrum carbapenem antibiotic with activity against many gram-positive and gram-negative aerobic bacteria, as well as a variety of anaerobes. Like other beta-lactam antibiotics, doripenem's bactericidal mechanism of action is mostly due to cell death after inhibition of bacterial enzymes called penicillin-bindng proteins (PBPs), which are responsible for peptidoglycan cross-linking during the synthesis of the bacterial cell wall. Carbapenems mainly have high affinity for PBPs 1a, 1b, 2 and 3. Inhibition of each PBP usually results in a different inactivating mechanism. Inhibition of PBPs 1a and 1b results in fast bacterial killing through the formation of spheroplasts, inhibition of PBP 2 results in rod-shaped bacteria to become spherical, and inhibition of PBP 3 results in filamentous-shaped organisms. The PBPs preferentially bound by different carbapenems depend on the organism. In E.coli and P.aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4. Doripenem has a 1-beta-methyl side chain, which allows it to be relatively resistant to dehydropeptidase, as well as a trans-alpha-1-hydroxyethyl group at position 6 which provides beta-lactamase resistance. Like other carbapenems, doripenem is different from most beta-lactams due to its stability against hydrolysis by most beta-lactamases, including penicillinases, cephalosporinases, ESBL, and Amp-C producing enterobacteriaceae.

Pharmacokinetics

Absorption

Doripenem is administered intravenously as an infusion. There was no accumulation of doripenem following mulitiple infusions of either 500mg or 1g administered every 8 hours for 7-10 days in subjects with normal renal function.

Distribution

The average Vd is 16.8 L (8.09-55.5 L) at steady-state in healthy subjects. Doripenem penetrates into many tissues and fluids, including potential sites of approved indication infections.

Metabolism

Metabolism of doripenem is via dehydropeptidase-I (also called dipeptidase-1) into a microbiologically inactive ring-opened metabolite, doripenem-M1. Doripenem does not appear to be a substrate of the hepatic CYP450 enzymes.

Elimination

Clearance

10.3 L/hour.

Toxicity

Dosage adjustment is necessary in patients with moderate and severe renal impairment. Doripenem's FDA label includes a warning against use in ventilator-associated bacterial pneumonia, as a clinical trial for that indication resulted in increased mortality with doripenem (23% vs. 16.7% recieving imipenem) as well as lower clinical response rates. Seizures have been reported with doripenem treatment; patients at greater risk of developing seizures we found to have pre-existing central nervous system (CNS) conditions, compromised renal function, or patients receiving higher doses than 500 mg every 8 hours. Doripenem also reduces plasma levels of valproic acid when administered concomitantly; therefore patients with pre-existing seizure disorders on valproic acid are at even higher risk of breakthrough seizures if receiving both drugs at the same time. Doripenem is considered pregnancy category B as it was not found to be teratogenic or produce effects on ossification, developmental delays, or fetal weight in rat and rabbit studies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. It is not known whether doripenem is excreted into breast milk, therefore caution should be exercised with doripenem administration to nursing women.

Active Ingredient/Synonyms

Doripenem | Doripenem |