Doritrum

Uses

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doritrum and other antibacterial drugs, Doritrum should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Complicated Intra-Abdominal Infections: Doritrum injection is used for a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

Complicated Urinary Tract Infections, Including Pyelonephritis: Doritrum injection is used for a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Acinetobacter baumannii.

Doritrum is also used to associated treatment for these conditions: Bacterial Infections, Catheter-related Bloodstream Infection (CRBSI) NOS, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Pyelonephritis

How Doritrum works

Doritrum 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. Doritrum 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.

Dosage

Doritrum dosage

Intravenous-

• Complicated intra-abdominal infections: 500 mg 8 hrly infused over 1 hr for 5-14 days. May switch to an appropriate oral therapy, after at least 3 days of parenteral therapy.
• Complicated UTI, Pyelonephritis: 500 mg 8 hrly infused over 1 hr for 10 days. May switch to an appropriate oral therapy, after at least 3 days of parenteral therapy.
• Patient with concurrent bacteraemia: Duration can be extended up to 14 days.

Renal impairment-

• CrCI (30-50 ml/min): 250 mg every 8 hr by IV infusion over 1 hr
• CrCI (11 -29 ml/min): 250 mg every 12 hr by IV infusion over 1 hr

Side Effects

Headache, nausea, diarrhoea, rash, pruritus, phlebitis, elevated hepatic enzymes, oral candidiasis, anaemia, vulvomycotic infection, thrombocytopenia, neutropenia.

Toxicity

Dosage adjustment is necessary in patients with moderate and severe renal impairment.

Doritrum'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. Doritrum 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.

Doritrum 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.

Precaution

Patient with known or suspected CNS disorders (e.g. brain lesions, history of seizures). Not intended for treatment of any type of pneumonia. Renal impairment. Pregnancy and lactation. Monitoring Parameters Monitor renal function and for signs of anaphylaxis during 1st dose. Consider haematologic assessment during prolonged therapy.

Interaction

Increased plasma concentration with probenecid. May decrease plasma levels of valproic acid thus, increasing the risk of seizures.

Food Interaction

Doritrum Disease Interaction

Major: colitis, renal dysfunctionModerate: CNS disorders, hemodialysis

Volume of Distribution

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

Elimination Route

Doritrum 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.

Half Life

1 hour, in healthy non-elderly adults.

Clearance

10.3 L/hour.

Elimination Route

Doritrum 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.

Pregnancy & Breastfeeding use

Pregnancy Category B. Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Contraindication

Hypersensitivity to doripenem, other carbapenem antibacterial agents; history of anaphylactic reaction to β-lactams (e.g. penicillins, cephalosporins).

Storage Condition

Reconstituted suspension may be held for 1 hr prior to dilution in infusion bag. Following dilution of the suspension with NaCl 0.9%, stability is 8 hr at room temperature or 24 hr between 2-8°C. Stability of solution when diluted with dextrose 5% injection is 4 hr at room temperature or 24 hr between 2-8°C.

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