DORADO 500

Indications

• Complicated intra-abdominal infections
• Complicated urinary tract infections
• Nosocomial pneumonia
• Severe skin and soft tissue infections

Dosage

Children: Refer to the BNF for Children for specific dosing information in paediatric patients.

Adults: The usual adult dosage for doripenem is 500 mg administered intravenously every 8 hours. The duration of therapy depends on the type and severity of the infection, typically ranging from 5 to 14 days.

Mechanism of action

Doripenem exerts its bactericidal effect by inhibiting penicillin-binding proteins (PBPs), which are critical for the cross-linking of peptidoglycan in the bacterial cell wall. This inhibition leads to cell lysis and death. Doripenem has a high affinity for several PBPs, including PBPs 1a, 1b, 2, and 3, with specific binding profiles varying by organism. Its structural modifications grant it resistance to hydrolysis by most beta-lactamases, enhancing its efficacy against resistant strains.

Pharmacodynamics

The effectiveness of doripenem is primarily correlated with the duration that the unbound plasma concentration exceeds the minimum inhibitory concentration (MIC) of the target pathogen, known as T>MIC. This pharmacodynamic property is similar to other beta-lactam antibiotics and underlines the importance of maintaining adequate dosing to achieve therapeutic levels.

Pharmacokinetics

Doripenem is administered intravenously and exhibits rapid distribution in body tissues. It is primarily eliminated via the kidneys, with renal clearance being the main pathway. The pharmacokinetic profile indicates a half-life that supports multiple daily dosing, depending on the severity of the infection and the patient's renal function. Dosage adjustments may be necessary in patients with compromised kidney function to prevent accumulation and potential toxicity.

Adverse effects

• diarrhea
• nausea
• vomiting
• rash
• headache
• dizziness

Interactions

• may reduce the efficacy of valproic acid
• probenecid may increase doripenem levels

Precautions

• use with caution in patients with a history of seizures
• monitor renal function in patients with renal impairment

Pregnancy

Limited data is available on the use of doripenem in pregnancy. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether doripenem is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Formulations

• intravenous injection
• intravenous infusion

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.

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.