Introduction
Doripen IV Infusion 250 mg/vial is a broad-spectrum carbapenem antibiotic used to treat serious bacterial infections, particularly complicated urinary tract infections and complicated intra-abdominal infections. It exerts its bactericidal effect by inhibiting bacterial cell wall synthesis, making it active against a wide range of Gram-positive, Gram-negative, and anaerobic bacteria. Clinical studies, however, found that doripenem was associated with increased mortality and lower clinical cure rates in patients with ventilator-associated pneumonia compared with imipenem/cilastatin, and it is therefore not recommended for this indication.
Uses
Doripen IV Infusion 250 mg/vial is an antibiotic of the penem class used to treat complicated intra-abdominal and urinary tract infections.
Doripen IV Infusion 250 mg/vial is indicated in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, caused by designated susceptible bacteria.
Associated Conditions
Pharmacodynamics
Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC (T>MIC) of the infecting organism has been shown to best correlate with efficacy in animal models of infection.
Mechanism of Action
Doripen IV Infusion 250 mg/vial 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. Doripen IV Infusion 250 mg/vial 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.
Absorption
Doripen IV Infusion 250 mg/vial 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.
Volume of Distribution
The average Vd is 16.8 L (8.09-55.5 L) at steady-state in healthy subjects. Doripen IV Infusion 250 mg/vial penetrates into many tissues and fluids, including potential sites of approved indication infections.
Protein Binding
8.1%
Route of Elimination
Doripen IV Infusion 250 mg/vial is primarily eliminated unchanged by the kidneys and undergoes glomerular filtration and active tubular secretion. A mean of 71% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours of 500 mg dose in healthy adults. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.
Half Life
1 hour, in healthy non-elderly adults.
Clearance
10.3 L/hour.
Toxicity
Dosage adjustment is necessary in patients with moderate and severe renal impairment.
Doripen IV Infusion 250 mg/vial'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. Doripen IV Infusion 250 mg/vial 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.
Doripen IV Infusion 250 mg/vial 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.
Food Interactions
No interactions found.
Dosage
- Complicated intra-abdominal infection: 500 mg every 8 hours for 5-14 days. Infusion time: 1 hour.
- Complicated UTI, including pyelonephritis: 500 mg every 8 hours for 10 days. Infusion time: 1 hour.
- CrCI >50 mL/min: No dosage adjustment necessary
- CrCI ≥30 to ≤ 50 mL/min: 250 mg administered intravenously (over 1 hour) every 8 hours.
- CrCI >10 to <30 mL/min: 250 mg administered intravenously (over 1 hour) every 12 hours.
