Doripenem

Doripenem belongs to the pharmacological class of Carbapenem antibiotics.

Doripenem has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection, healthcare–associated or high-risk community-acquired infection, Meningitis, bacterial, Osteomyelitis, native vertebral due to P. aeruginosa, Pneumonia, Severe systemic or life-threatening infections, S. maltophilia infection, multidrug-resistant, Surgical prophylaxis, Urinary tract infection.

After intravenous administration, doripenem follows linear pharmacokinetics over the dosage range of 250 mg to 1000 mg. The drug has a volume of distribution of approximately 20 liters and is primarily eliminated by the kidneys. The plasma half-life of doripenem is approximately 1 hour, and the drug is excreted unchanged in the urine. Doripenem does not significantly bind to plasma proteins, and the drug is not metabolized by the liver. Renal impairment can affect the pharmacokinetics of doripenem, with reduced clearance and prolonged elimination half-life observed in patients with some moderate to severe renal impairment.

The common side effects involved in using Doripenem are Diarrhea, Nausea, Vomiting,Abdominal pain, Headache, Dizziness, Rash, and Itching. Doripenem is available in the form of Powder for Injection.

Doripenem is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Doripenem belongs to the pharmacological class of Carbapenem antibiotics.

Doripenem is a broad-spectrum carbapenem antibiotic that works by inhibiting bacterial cell wall synthesis. Specifically, it targets and binds to penicillin-binding proteins (PBPs), which are enzymes involved in the final stages of bacterial cell wall formation. This binding prevents the cross-linking of peptidoglycan chains, leading to a weakened bacterial cell wall and subsequent cell lysis. Doripenem has demonstrated efficacy against a wide range of gram-positive and gram-negative bacteria, including strains resistant to other antibiotics. Its broad-spectrum activity is due to its ability to penetrate the bacterial cell wall and reach the PBPs located in the periplasmic space. Overall, doripenem is an effective antibiotic for the treatment of serious infections caused by multidrug-resistant organisms.

Doripenem has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infections, Urinary tract infections.

Doripenem has a maximum concentration (Cmax) of approximately 23.3 µg/mL and a time to reach maximum concentration (Tmax) of about 1 hour after intravenous administration of a 500 mg dose. The onset of action is rapid, and the half-life is approximately 1 hour. The duration of action for doripenem is about 4-6 hours.

Doripenem is found to be available in the form of Powder for Injection.

Doripenem can be used in the following treatment:

• Intra-abdominal infection
• Urinary tract infection

Doripenem can help to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infections, Urinary tract infections.

Doripenem is approved for use in the following clinical indications:

• Intra-abdominal infection
• Urinary tract infection

For complicated intra-abdominal infections, a dose of 500 mg intravenous antibiotics every 8 hours is recommended. The total duration of treatment, which may involve switching to oral antibiotics, should be 4 to 5 days after achieving adequate source control.

In the case of complicated urinary tract infections such as pyelonephritis or infections accompanied by systemic signs or symptoms, a 500 mg intravenous dose of antibiotics every 8 hours is recommended.

Powder for injection: 500 mg/vial

Powder for Injection

• Dosage Adjustments in Kidney Patients:

If the creatinine clearance rate (CrCl) is greater than 50 mL/min, no dosage adjustment is needed. For CrCl rates between 30-50 mL/min, a 250 mg intravenous dose should be administered every 8 hours. For those with a CrCl rate of 10-30 mL/min, a 250 mg intravenous dose should be administered every 12 hours.

• Dosage Adjustments in Pediatric Patients:

There is insufficient evidence to confirm the safety and effectiveness of the product for individuals under the age of 18.

There are no specific dietary restrictions related to the use of doripenem. However, it is important to follow a healthy and balanced diet as part of overall health and wellness.

Doripenem may be contraindicated under the following conditions:

• In patients with known hypersensitivity to Doripenem, cephalosporin, penicillin, or any component of the formulation.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

Hypersensitivity Reactions

Patients receiving beta-lactam antibiotics like Doripenem may experience serious and also occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions. Such reactions are more likely to occur in the individuals with a history of sensitivity to multiple allergens. Before therapy with Doripenem is initiated, careful inquiry should be made to determine whether the patient have had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillins, or other allergens. If an allergic reaction to Doripenem occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions do require emergency treatment, as clinically indicated.

Seizures

Seizures had been reported during treatment with Doripenem, especially in patients with pre-existing central nervous system (CNS) disorders (e.g., stroke or history of seizures), patients with a compromised renal function, and also patients given doses greater than 500 mg every 8 hours. If a patient develops seizures while on Doripenem therapy, the drug should be discontinued.

Interaction with Valproic Acid

Due to a drug interaction, the patients with seizure disorders controlled with valproic acid or sodium valproate may be at an increased risk for breakthrough seizures when treated with Doripenem concomitantly. Alternative antibacterial therapies should be considered for these patients. If administration of Doripenem is necessary, supplemental anti-convulsant therapy should be considered.

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) had been reported with nearly all antibacterial agents and might range in severity from mild diarrhea to fatal colitis. If Clostridium difficile-associated diarrhea is suspected or confirmed, ongoing antibiotic use which is not directed against C. difficile might need to be discontinued. Appropriate fluid and also electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and also surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing the drug Doripenem in the absence of a proven or a strongly suspected bacterial infection is found to be unlikely to provide benefit to the patient and also increases the risk of the development of drug-resistant bacteria.

Pneumonitis with Inhalational Use

When Doripenem has been used investigationally via inhalation, pneumonitis has occurred. Therefore, it is advised that Doripenem should not be administered by this route.

When taking antibiotics, it is generally recommended to avoid consuming alcohol as it can increase the risk of certain side effects, such as stomach upset, nausea, dizziness, and headaches. Additionally, some antibiotics can interfere with the breakdown and elimination of alcohol, leading to higher blood alcohol levels and prolonging the effects of alcohol.

It is unknown whether the drug Doripenem is excreted in human milk. Caution should be exercised when administering Doripenem to a nursing woman due to the possibility of drug excretion in human milk.

Pregnancy Category B: Doripenem Use During Pregnancy

Animal studies have shown that Doripenem is not teratogenic and does not affect fetal weight, ossification, or developmental delays when administered intravenously during organogenesis at doses up to 1 g/kg/day in rats and 50 mg/kg/day in rabbits. However, the drug should be used during pregnancy only if clearly needed, as animal studies are not always predictive of human response. There are found to be no adequate and well-controlled studies available on pregnant women.

There are no known food warnings related to the use of Doripenem.

The adverse reactions related to Doripenem can be categorized as follows:

Common:

• Diarrhea
• Nausea
• Rash
• Vomiting
• Constipation
• Headache
• Insomnia
• Increased liver enzymes
• Phlebitis

Less Common:

• Pruritus
• Pyrexia
• Chills
• Hypotension
• Hypertension
• Anemia
• Leukopenia
• Thrombocytopenia
• Increased creatinine
• Increased blood urea nitrogen
• Hyperglycemia
• Hypoglycemia
• Increased alkaline phosphatase
• Increased bilirubin
• Dyspnea
• Chest pain

Rare:

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema multiforme
• Angioedema
• Anaphylaxis
• Pseudomembranous colitis
• Clostridium difficile-associated diarrhea
• Acute generalized exanthematous pustulosis
• Drug reaction along with eosinophilia and systemic symptoms (DRESS) syndrome
• Hepatitis
• Renal failure

The clinically relevant drug interactions of Doripenem is briefly summarized here:

Valproic Acid:

When Doripenem and valproic acid are co-administered, there is a risk of reduced serum concentrations of valproic acid, potentially resulting in breakthrough seizures. It is not fully understood how doripenem interacts with valproic acid, but in vitro and animal studies suggest that it may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g), leading to decreased plasma concentrations of valproic acid. Other carbapenems have also been associated with reduced serum concentrations of valproic acid upon co-administration. If Doripenem must be administered, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of doripenem are not affected by co-administration with valproic acid.

Probenecid:

When probenecid is co-administered with Doripenem, it interferes with the active tubular secretion of doripenem, leading to increased plasma concentrations of doripenem. Therefore, co-administration of probenecid with Doripenem is not recommended.

The following are the side effects involving Doripenem:

• Nausea
• Headache
• Diarrhea
• Rash
• Pain or redness at the injection site
• Elevated liver enzymes
• Decreased platelet count
• Increased white blood cell count

Pregnancy

Pregnancy Category B: Doripenem Use During Pregnancy

Animal studies have shown that Doripenem is not teratogenic and does not affect fetal weight, ossification, or developmental delays when administered intravenously during organogenesis at doses up to 1 g/kg/day in rats and 50 mg/kg/day in rabbits. However, the drug should be used during pregnancy only if clearly needed, as animal studies are not always predictive of human response. There are found to be no adequate and well-controlled studies available on pregnant women.

Nursing Mothers

It is unknown whether the drug Doripenem is excreted in human milk. Caution should be exercised when administering Doripenem to a nursing woman due to the possibility of drug excretion in human milk.

Pediatric Use

The safety and effectiveness of Doripenem in pediatric patients have not been established.

Geriatric Use

Clinical studies of Doripenem show that cure rates in complicated intra-abdominal and complicated urinary tract infections were found to be slightly lower in patients ≥65 years of age and in the subgroup of patients ≥75 years of age versus patients <65. However, these results were similar between the Doripenem and comparator treatment groups. The drug is excreted substantially by the kidney, so the risk of adverse reactions may be higher in patients with impaired renal function or pre-renal azotemia. Careful dose selection and monitoring of renal function may be necessary, particularly in elderly patients. Elderly subjects had higher Doripenem plasma concentrations than non-elderly subjects, primarily due to age-related changes in renal function. No significant safety differences were observed between older and younger subjects, although some older individuals may be more sensitive to the drug.

Physicians should be knowledgeable and vigilant about the treatment and identification of overdosage of Doripenem.

Overdosing on doripenem may lead to adverse effects, such as seizures and central nervous system toxicity. If an overdose is suspected, immediate medical attention should be sought. Standard supportive measures, such as monitoring vital signs and maintaining fluid and electrolyte balance, should also be implemented. Hemodialysis may be considered in patients with renal impairment to remove doripenem from the bloodstream. There is no specific antidote for doripenem overdose.

Pharmacodynamics

To establish the effectiveness of doripenem and other beta-lactam antimicrobial agents in animal models of infection, it has been demonstrated that the duration during which the unbound plasma concentration of doripenem exceeds the minimum inhibitory concentration (MIC) of the infecting organism is the most significant factor.

Pharmacokinetics

Pharmacokinetic Parameters:

• Absorption

When administered intravenously over 1 hour, the pharmacokinetics of doripenem, including its maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC), exhibit linearity across a dosage range of 500 mg to 1g. In individuals with normal renal function, there is no accumulation of doripenem after repeated intravenous infusions of either 500 mg or 1g administered every 8 hours for a duration of 7 to 10 days.

• Volume of distribution

The binding of doripenem to plasma proteins has an average value of approximately 8.1%, and it does not depend on the plasma drug concentrations. In healthy individuals, the median (range) volume of distribution at steady state is 16.8 L (8.09-55.5 L), which is similar to the volume of extracellular fluid (18.2 L).

Doripenem is capable of penetrating various body fluids and tissues, which including those at the site of infection for the approved indications. In both peritoneal and retroperitoneal fluids, the concentrations of doripenem either meet or exceed those required to inhibit most susceptible bacteria. However, the clinical significance of this discovery has not yet been established.

• Metabolism

The primary pathway for the metabolism of doripenem into a microbiologically inactive ring-opened metabolite called doripenem-M1 is through the action of dehydropeptidase-I. In healthy individuals, the mean (SD) plasma ratio of doripenem-M1 to doripenem AUC following a single 500 mg and 1 g doses is 18% (7.2%). In vitro experiments using pooled human liver microsomes indicate that doripenem is not metabolized by hepatic CYP450 enzymes.

• Route of elimination

Doripenem is mainly excreted unchanged by the kidneys. In healthy non-elderly adults, the average plasma elimination half-life for doripenem is approximately one hour, and the mean (SD) plasma clearance is 15.9 (5.3) L/hour. The mean (SD) renal clearance is 10.3 (3.5) L/hour, suggesting that doripenem undergoes both glomerular filtration and active tubular secretion. The considerable decrease in doripenem elimination with concomitant probenecid administration, coupled with the magnitude of renal clearance, suggests that active tubular secretion and glomerular filtration play significant roles in doripenem elimination. After a single 500 mg dose of Doripenem in healthy adults, about 71% and 15% of the dose was found to be recovered in urine as unchanged drug and ring-opened metabolite, respectively, within 48 hours, indicating renal excretion. Following a radiolabeled single 500 mg dose of doripenem administration to healthy adults, less than 1% of the total radioactivity was detected in feces after a week.

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