Usage
Doripenem is a broad-spectrum carbapenem antibiotic indicated for the treatment of adults with the following infections:
- Nosocomial pneumonia (including ventilator-associated pneumonia). However, note increased mortality risk compared to other treatments (see Precautions).
- Complicated intra-abdominal infections.
- Complicated urinary tract infections (including pyelonephritis).
Pharmacological Classification: Carbapenem Antibiotic
Mechanism of Action: Doripenem inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This leads to bacterial cell death. It exhibits activity against a broad range of aerobic and anaerobic Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa.
Alternate Names
Doripenem is the generic name.
Brand Name: Doribax
How It Works
Pharmacodynamics: Doripenem exerts its bactericidal effect by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs). Specifically, it has high affinity for PBP-2 and PBP-3. This binding disrupts the final transpeptidation step of peptidoglycan synthesis, leading to cell wall instability and bacterial lysis.
Pharmacokinetics:
- Absorption: Administered intravenously; thus, 100% bioavailability.
- Distribution: Distributes widely into tissues and body fluids, including the lungs, ascitic fluid, and urine. Approximately 8.1% protein binding. Volume of distribution is similar to extracellular fluid volume.
- Metabolism: Undergoes minimal metabolism by CYP450 enzymes.
- Elimination: Primarily eliminated renally as unchanged drug, with a small amount excreted in the feces.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
500 mg every 8 hours via intravenous infusion over 1 hour. For nosocomial pneumonia, a 4-hour infusion may be more appropriate for infections with less susceptible pathogens or in severe infections.
Children:
Doripenem is not recommended for use in children under 18 years old due to a lack of data on safety and efficacy.
Special Cases:
- Elderly Patients: No dosage adjustment is necessary unless there is moderate to severe renal impairment.
- Patients with Renal Impairment: Dosage adjustments are necessary. See Dosage Adjustments below.
- Patients with Hepatic Dysfunction: No dosage adjustment is necessary.
- Patients with Comorbid Conditions: Monitor patients with CNS disorders (e.g., brain lesions, history of seizures) for seizures during treatment.
Clinical Use Cases
Dosages for specific clinical use cases follow the standard adult dosage guidelines (500 mg every 8 hours intravenously over 1 hour) unless renal impairment necessitates adjustments. For nosocomial pneumonia, particularly severe cases or those involving less susceptible pathogens might benefit from a 4-hour infusion.
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations
Dosage Adjustments
Renal impairment requires dosage adjustments as follows:
- Mild Renal Impairment (CrCl 51-79 mL/min): No dosage adjustment required.
- Moderate Renal Impairment (CrCl 30-50 mL/min): 250 mg every 8 hours.
- Severe Renal Impairment (CrCl <30 mL/min): 250 mg every 12 hours. Use with caution due to increased drug exposure.
Doripenem is hemodialyzable; however, there are no established guidelines for dosage adjustment in patients on dialysis. It is not recommended for use in patients receiving any form of dialysis.
Side Effects
Common Side Effects:
Headache, nausea, diarrhea, rash, phlebitis/infusion site reactions (pain, redness, swelling).
Rare but Serious Side Effects:
Seizures (especially in patients with CNS disorders, renal impairment, or receiving higher doses), Clostridium difficile-associated diarrhea (CDAD), allergic reactions (including anaphylaxis), severe skin reactions.
Long-Term Effects:
Potential for Clostridium difficile-associated diarrhea that can occur up to two months after treatment discontinuation.
Adverse Drug Reactions (ADR):
Anaphylaxis, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis.
Contraindications
- Hypersensitivity to doripenem, other carbapenems, or beta-lactams.
Drug Interactions
- Valproic Acid: Doripenem significantly decreases valproic acid levels, increasing the risk of seizures. Avoid concomitant use or consider alternative anticonvulsants/antibacterials.
- Probenecid: Probenecid reduces renal clearance of doripenem, increasing doripenem plasma concentrations. Avoid co-administration.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Category B. Animal studies have not shown evidence of teratogenicity, but there are no adequate and well-controlled studies in pregnant women. Use only if clearly needed and if the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: It is unknown if doripenem is excreted in human milk. Exercise caution when administering to breastfeeding women.
Drug Profile Summary
- Mechanism of Action: Inhibits bacterial cell wall synthesis by binding to PBPs.
- Side Effects: Headache, nausea, diarrhea, rash, phlebitis; rarely, seizures, CDAD, allergic reactions.
- Contraindications: Hypersensitivity to doripenem, other carbapenems, or beta-lactams.
- Drug Interactions: Valproic acid, probenecid.
- Pregnancy & Breastfeeding: Category B; unknown if excreted in human milk. Use cautiously.
- Dosage: Adults: 500 mg IV every 8 hours over 1 hour; adjustments required for renal impairment. Not recommended for children under 18.
- Monitoring Parameters: Renal function (especially in patients with renal impairment), signs of superinfection (e.g., CDAD), and neurological status (for seizures), hepatic function (monitor liver function tests).
Popular Combinations
Information not available in the given sources.
Precautions
- General Precautions: Obtain cultures before starting therapy. Monitor for signs of hypersensitivity reactions and superinfections.
- Specific Populations: See Dosage and Pregnancy and Breastfeeding sections for details related to pregnant/breastfeeding women, children, and the elderly.
- Increased Mortality in Ventilator-Associated Bacterial Pneumonia: Doripenem use for ventilator-associated bacterial pneumonia (VABP) has been associated with increased mortality in clinical trials compared to other treatments. Consider alternative therapies for VABP when possible.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Doripenem?
A: The recommended dosage for adults is 500 mg every 8 hours via IV infusion over 1 hour. Dosage adjustments are necessary for patients with renal impairment. Doripenem is not recommended for children under 18.
Q2: How is Doripenem administered?
A: Doripenem is administered intravenously (IV) as an infusion over 1 hour (or 4 hours for certain nosocomial pneumonia cases).
Q3: What are the most common side effects of Doripenem?
A: Common side effects include headache, nausea, diarrhea, rash, and phlebitis.
Q4: What are the serious side effects of Doripenem?
A: Serious side effects include seizures, Clostridium difficile-associated diarrhea (CDAD), and severe allergic reactions.
Q5: Can Doripenem be used in pregnant or breastfeeding women?
A: Doripenem is Pregnancy Category B. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown whether doripenem is excreted in breast milk. Exercise caution if administering to breastfeeding mothers.
Q6: Does Doripenem interact with any other medications?
A: Yes, significant interactions exist with valproic acid and probenecid. Concurrent use should generally be avoided.
Q7: Are there any contraindications to using Doripenem?
A: Doripenem is contraindicated in patients with known hypersensitivity to doripenem, other carbapenems, or beta-lactams.
Q8: Can Doripenem be used in children?
A: Doripenem is not recommended for use in children under 18 years of age due to a lack of safety and efficacy data.
Q9: How should Doripenem be used in patients with renal impairment?
A: Dosage adjustments are necessary for patients with moderate and severe renal impairment (see Dosage Adjustments section). It is not recommended for patients on dialysis.
Q10: What should I monitor in patients receiving Doripenem?
A: Monitor renal function, signs of superinfection (e.g., CDAD), and neurological status (for seizures), and liver function tests.
