Doripenem is a broad-spectrum, carbapenem antibiotic with bactericidal and beta-lactamase resistant activities. Doripenem binds to penicillin-binding proteins (PBPs) located on the bacterial cell wall, particularly PBPs 2 and 3, thereby inhibiting the final transpeptidation step in the synthesis of peptidoglycan, an essential component of the bacterial cell wall. Inhibition results in a weakening and eventually lysis of the bacterial cell wall. This agent is two- to 16-fold more potent than imipenem and comparable to ertapenem and meropenem.
Doripenem is a broad-spectrum carbapenem antibiotic used primarily for the treatment of aerobic gram-negative bacterial infections. Doripenem, like other carbapenems, is associated with transient and asymptomatic elevations in serum enzymes. The carbapenems have also been linked to rare instances of clinically apparent, acute cholestatic liver injury.
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-binding proteins (PBPs), which are responsible for peptidoglycan cross-linking during the synthesis of the bacterial cell wall. Carbapenems mainly have a 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 becoming 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.
Indications of Doripenem
- Doripenem is indicated in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, caused by designated susceptible bacteria.
- Doribax is indicated for the treatment of the following infections in adults: nosocomial pneumonia (including ventilator-associated pneumonia); complicated intra-abdominal infections; complicated urinary tract infections. Consideration should be given to official guidance on the appropriate use of antibacterial agents.
- Intraabdominal Infection
- Kidney Infections
- Urinary Tract Infection
Contraindications of Doripenem
Hypersensitivity to doripenem, other drugs in the same class, or any component of the formulation; patients who have experienced anaphylactic reactions to beta-lactams
- diarrhea from infection with Clostridium difficile bacteria
- decreased blood platelets
- lesion of the brain
- seizures
- chronic kidney disease stage 4 (severe)
- chronic kidney disease stage 5 (failure)
- kidney disease with likely reduction in kidney function
- Allergies to Betalactams and Carbapenems
Dosage of Doripenem
- Strengths: 500 mg; 250 mg
Intraabdominal Infection
- 500 mg via IV infusion every 8 hours
- Duration of therapy: 5 to 14 days
Pyelonephritis
- 500 mg via IV infusion every 8 hours
- Duration of therapy: 10 days
Urinary Tract Infection
- 500 mg via IV infusion every 8 hours
- Duration of therapy: 10 days
Doripenem injection comes as a liquid to be injected intravenously (into a vein). It is usually given every 8 hours. The length of your treatment depends on the type of infection being treated.
Side Effects of Doripenem
Most Common
- blisters on the skin, mouth, nose, and eyes
- sloughing (shedding) of skin
- fever
- difficulty breathing or swallowing
- seizures
- watery or bloody stools (up to 2 months after your treatment)
- Bluish color
- diarrhea
- pain, tenderness, or swelling of the foot or leg
- pale skin
- troubled breathing with exertion
- unusual bleeding or bruising
- unusual tiredness or weakness
Common
- Abdominal or stomach cramps, pain, or tenderness
- bloody urine
- diarrhea
- redness, pain, or swelling at the injection site
- decreased frequency or amount of urine
- fever
- increased blood pressure
- increased thirst
- itching or pain of the vagina or genital area
- loss of appetite
- lower back or side pain
- nausea or vomiting
- sore mouth or tongue
- swelling of the face, fingers, or lower legs
- thick, white vaginal discharge with mild or no odor
- troubled breathing
- watery and severe diarrhea, which may also be bloody
- weight gain
- white patches in the mouth or on the tongue
Rare
- Blistering, peeling, or loosening of the skin
- chills
- cough
- difficulty with swallowing or sore throat
- dizziness
- fast heartbeat
- itching
- joint or muscle pain
- loss of bladder control
- muscle spasm or jerking of extremities
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- red skin lesions, often with a purple center
- red, irritated eyes
- skin rash or hives
- sores, ulcers, or white spots in the mouth or on the lips
- sudden loss of consciousness
- tightness in the chest
Drugs Interactions of Doripenem
- BCG
- cholera vaccine, live
- divalproex sodium
- entecavir
- estradiol
- ethinyl estradiol
- indium oxyquinoline in-111
- mycophenolate mofetil
- mycophenolic acid
- pemetrexed
- probenecid
- typhoid vaccine, live
- valproic acid
Pregnancy Category of Doripenem
FDA Pregnancy Category – B
No information is available on the clinical use of doripenem during breastfeeding. Its excretion into breastmilk is likely similar to that of imipenem and meropenem, which produce low levels of milk that are not expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant’s gastrointestinal flora, resulting in diarrhea or thrush has been reported with beta-lactams, but these effects have not been adequately evaluated. Doripenem is acceptable in nursing mothers.
Before Taking This medication
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% receiving 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.
Before using doripenem injection
- tell your doctor and pharmacist if you are allergic to doripenem injection; other carbapenem antibiotics such as imipenem/cilastatin (Primaxin) or meropenem (Merrem); penicillins; cephalosporin antibiotics such as cefaclor, cefadroxil, cefuroxime (Ceftin, Zinacef), or cephalexin (Keflex); aztreonam (Azactam); or any other medications.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the following: probenecid (Probalan, in Col-Probenecid) and valproic acid (Depakene). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you have any allergies and if you have or have ever had a stroke, seizures or kidney disease.
- tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using doripenem injection, call your doctor.
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