Doripenem
When ATH:
J01DH
Pharmacological action.
Synthetic carbapenem antibiotic from the group of broad-spectrum, similar in structure to other beta-lactam antibiotics. Дорипенем in vitro active against aerobic and anaerobic Gram-positive and Gram-negative bacteria.
As compared with imipenem and meropenem it is 2-4 times more active against Pseudomonas aeruginosa. Doripenem has a bactericidal effect by disrupting bacterial cell wall biosynthesis. It inactivates a number of important proteins penicillin (PSB), which leads to disruption of the synthesis of the bacterial cell wall and subsequent death of the bacterial cell. Doripenem has the greatest affinity with respect to PSB Staphylococcus aureus.
The cells of Escherichia coli and Pseudomonas aeruginosa doripenem binds strongly to DPM, which is involved in maintaining the shape of a bacterial cell. Experiments in vitro have shown, doripenem that reduces the activity of other antibiotics slightly, Other antibiotics do not reduce the activity of doripenem. Described additive activity or weak synergy with amikacin and levofloxacin against Pseudomonas aeruginosa, as well as with daptomycin, linezolid, levofloxacin and vancomycin against Gram-positive bacteria.
Pharmacokinetics
Distribution
Cmax and AUC values vary linearly with dosage range 500 mg-1 g at / in infusion for 1 or 4 no. FAQ plasma concentration (mg / l) doripenem after a 1-hour and 4-hour in / infusion 500 mg and a 4-hour infusion 1 g.
In patients with normal renal function were found signs of accumulation of doripenem following multiple in / infusion 500 mg or 1 g every 8 h for 7 – 10 days. The binding of doripenem to plasma proteins averages 8.1% and it does not depend on its concentration in blood plasma. Vd is approximately 16.8 l, which is close to the volume of extracellular fluid in humans (18.2 l). Doripenem penetrates well into the uterine tissue, prostate, gall bladder and urine, and retroperitoneal fluid, reaching concentrations there, exceeding the MIC.
Metabolism
Active substance biotransformed microbiologically inactive metabolite preferably under the action of dehydropeptidase-I. In vitro metabolism of doripenem observed under the action of CYP450 isozymes and other enzymes, in the presence, and in the absence of NADP (nikotinamiddinukleotidfosfata).
Deduction
Doripenem is derived mainly kidneys unchanged. In healthy young adults the final T1 / 2 is about doripenem 1 no, and clearance from plasma is approximately 15.9 l /. The average renal clearance of 10.3 l /. The value of this indicator, along with a significant decrease in the elimination of doripenem when administered concurrently with probenicid testifies, that doripenem undergoes both glomerular filtration, and renal secretion.
In healthy young adults after a single dose in the dose of doripenem 500 mg 71% dose was found in the urine as unchanged and doripenem 15% – a ring-opened metabolite, respectively. After the introduction of healthy young adults a single dose (500 mg) radiolabeled doripenem was found in the feces less 1% total activity.
Pharmacokinetics in special clinical situations
After the introduction of a dose of doripenem 500 mg dose to patients with impaired renal function increases AUC compared with AUC in healthy subjects with normal renal function (QC ≥80 ml / min). Doripenem dose should be reduced in patients with moderate and severe renal impairment. There is currently no data on the pharmacokinetics of doripenem in patients with impaired hepatic function. Doripenem hardly metabolized in liver, so it is assumed, liver disease that do not affect its pharmacokinetics.
Compared to young adults, elderly patients doripenem AUC was increased by 49%. This change is mainly due to age-related changes QC. In elderly patients with normal (for their age) renal function reduce the dose of doripenem not need. Women doripenem AUC was on 13% better, than men.
Men and women should enter the same dose of doripenem. In the application of the drug among the various racial groups was no significant difference in the clearance of doripenem, therefore adjust the dose is not recommended.
Testimony
Nosocomial (nosocomial) pneumonia, including pneumonia, associated with mechanical ventilation (IVL);
Complicated intra-abdominal infections;
Complicated urinary tract infection, including complicated and uncomplicated pyelonephritis, incl. with concomitant bacteremia.
Contraindications
Age to 18 years;
Hypersensitivity to the drug;
Hypersensitivity to other drugs of carbapenems, as well as beta-lactam antibiotics.
Dosage regimen
The drug is introduced into / in. For the treatment of patients with nosocomial pneumonia are recommended for infusion 1 no. If there is less risk of infection by susceptible microorganisms recommended infusion for 4 no.
The duration of therapy include the ability to switch to an appropriate oral therapy after, least, 3-x daily parenteral therapy, caused clinical improvement (the transition to oral therapy can be prescribed fluoroquinolones, broad-spectrum penicillins combined with clavulanic acid, as well as antibiotics any pharmacotherapeutic group).
Patients with concomitant bacteremia duration of therapy may reach 14 days.
Patients with impaired renal function in QA >50 ml / min dose adjustment is required.
In patients with moderate renal impairment (QC of ≥30 to ≤50 ml / min) preparation is administered in a dose of 250 mg every 8 no.
In patients with severely impaired renal function (KK from >10 to <30 ml / min) preparation is administered in a dose of 250 mg every 12 no. Doripenem is removed from the blood during dialysis; currently there is insufficient information to formulate recommendations for patients, dialysis.
Elderly patients, Kidney function that corresponds to their age, dose adjustment is required.
Patients with liver failure is no need for correction of the dose.
Drug Interactions
Probenetsid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. Probenecid increases the AUC of doripenem in the 75% and T1/2 plasma – on 53%. Therefore, it is not recommended to use both probenetsid and Doripeks®.
Doripenem does not inhibit the major cytochrome P450 isoenzymes, and therefore, probably, It does not interact with drugs, are metabolized by this enzyme system. According to the results of in vitro studies, doripenem is not capable of inducing enzyme activity.
In healthy volunteers doripenem reduces the concentration of valproic acid until subtherapeutic plasma levels (значение AUC уменьшалось на 63%), it is also consistent with the results, obtained for other carbapenems. The pharmacokinetics of doripenem are not changed. With simultaneous use of doripenem and valproic acid concentrations should be monitored and the latter to consider the possibility of appointing another treatment.
Pharmaceutically compatible
The drug should not be mixed with other drugs, except sterile water d / and, 0.9% sodium chloride solution for injection (saline solution) or 5% glucose solution.
