Doripenem, powder 500 mg

Pharmacotherapeutic group:

Antibiotic – carbapenem

CodeATH: J01DH04

Pharmacological properties

Pharmacodynamics

Doripenem is a synthetic carbapenem antibiotic of broad spectrum action, structurally similar to other beta-lactam antibiotics. Doripenem has pronounced in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria. Compared with imipenem and meropenem it is 2-4 times more active against Pseudomonas aeruginosa.

The mechanism of action

Doripenem has a bactericidal effect by disrupting the biosynthesis of the bacterial cell wall. It inactivates many important penicillin-binding proteins (PBPs), and this leads to disruption of bacterial cell wall synthesis and subsequent bacterial cell death. Doripenem has the greatest affinity against Staphylococcus aureus PBP.

In Escherichia coli and Pseudomonas aeruginosa cells, doripenem binds firmly to BPS, which are involved in maintaining the shape of the bacterial cell. In vitro experiments have shown that doripenem weakly inhibits the action of other antibiotics, and its action is also not inhibited by other antibiotics.

Additive activity or weak synergism with amikacin and levofloxacin against Pseudomonas aeruginosa and with daptomycin, linezolid, levofloxacin and vancomycin against gram-positive bacteria has been described.

Resistance mechanisms

The mechanisms of bacterial resistance to doripenem include its inactivation by carbapenem hydrolyzing enzymes as well as by mutant or acquired PSBs, reduction of outer membrane permeability and active release of doripenem from bacterial cells. Doripenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria; the exception is a relatively rare beta-lactamase capable of hydrolyzing Doripenem.

The prevalence of acquired resistance of individual species may vary in different geographic regions and at different times, and therefore information on local resistance patterns is very useful, especially when treating severe infections. If necessary, advice should be sought from microbiologists if the local resistance patterns are such that the use of a particular drug, at least for certain types of infection, is questionable.

Doripenem susceptible species

Gram-positive: Enterococcus faecalis, Staphylococcus aureus (methicillin-sensitive strains). Staphylococcus epidermidis (strains sensitive to methicillin), Staphylococcus haemolyticus (strains sensitive to methicillin). Streptococcus agalactiae (including macrolide-resistant strains4), Staphylococcus saprophytics, Streptococcus intermedius, Streptococcus conste/latus, Streptococcus pneumoniae (including strains resistant to penicillin or ceftriaxone), Streptococcus pyogenes; Streptococcus viridans (including moderately sensitive and penicillin-resistant strains).

Gram-negative aerobes: Citrobacter diversus, Citrobacter freundii (including strains insensitive to ceftazidime), Enterobacter aerogenes, Entero-bacter cloacae (including strains insensitive to ceftazidime), Haemophilus influenzae (including beta-lactamase-producing strains or ampicillin-resistant strains that do not produce beta-lactamases), Escherichia coli, including strains, resistant to levofloxacin and extended spectrum beta-lactamase (ESBL)-producing strains, Klebsiella pneumoniae (including ESBL-producing strains), Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (including ESBL-producing strains), Proteus vulgaris, Providencia rettgeri, Providencia stuartii Pseudomonas aeruginosa (including ceftazidime-resistant strains), Salmonella spp., Serratia marcescens (including strains insensitive to ceftazidime), species of the genus Shigella. Anaerobes: Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophila wadsworthia, species of Clostridium genus, Peptostreptococcus magnus, Peptostreptococcus micros, species of Porphyromonas genus, Prevotella species, Sutterella wadsworthenis.

Resistant microorganisms

Gram-positive aerobes: Staphylococcus aureus, resistant to methicillin; Enterococcus faecium.

Gram-negative aerobes: Stenotrophomonas maltophiNA, Legionella spp.

Acquired resistance can have: Burkholderia cepacia, Acinetobacter baumannii Acinetobacter spp., Pseudomonas aeruginosa.

Pharmacokinetics

The pharmacokinetics of doripenem (Cmax, maximum plasma concentration, and AUC, area under the concentration-time curve) are linear over the 500 mg-1 g dose range when infused intravenously for 1 or 4 h. Patients with normal renal function showed no evidence of doripenem cumulation after multiple intravenous infusions of 500 mg or 1 g every 8 h for 7-10 days.

The pharmacokinetics of doripenem are linear over a dose range of 500 mg to 2 g when administered as an intravenous infusion of 1 h and 500 mg to 1 g when administered as an intravenous infusion of 4 h. The pharmacokinetic characteristics of Doripenem when administered once [after a 4-hour infusion] in adults with cystic fibrosis are consistent with those of adults without cystic fibrosis. There have been no adequately controlled studies of the safety and efficacy of Doripenem in patients with cystic fibrosis.

Distribution: The average degree of binding of Doripenem to plasma proteins was 8.1% and was independent of its plasma concentration. The volume of distribution is approximately 16.8 liters, which is close to the volume of extracellular fluid in humans (18.2 liters). Doripenem penetrates well into a number of tissues and body fluids, such as uterine tissue, retroperitoneal fluid, prostate tissue, gallbladder tissue and urine, reaching concentrations exceeding the MIC (minimum inhibitory concentration) there.

Metabolism: Doripenem biotransformation to microbiologically inactive metabolite occurs mainly under the action of dehydropeptidase-I. In vitro metabolism of Doripenem was observed under the action of CYP450 system isoenzymes and other enzymes, both in the presence and absence of nicotinamide adenine dinucleotide phosphate (NADPH).

Elimination: Doripenem is eliminated mainly by the kidneys unchanged. In healthy young adults, the average final plasma elimination half-life of doripenem is about 1 h, and plasma clearance is approximately 15.9 L/h. Average renal clearance is 10.3 l/h. The magnitude of this figure, along with a significant decrease in elimination of doripenem when administered simultaneously with probenecid, indicates that doripenem is subject to both glomerular filtration and renal secretion. In healthy young adults who received a single dose (500 mg) of doripenem, 71% of the dose was detected in the urine as unchanged doripenem and 1 5% as an open ring metabolite, respectively. After a single dose (500 mg) of radioactively labeled doripenem in young healthy adults, less than 1% total radioactivity was detected in the feces.

Patients with renal insufficiency: After administration of a single dose (500 mg) of doripenem to patients with mild (creatinine clearance 51-79 ml/min), moderate (creatinine clearance 31-50 ml/min), and severe (creatinine clearance <30 ml/min) renal impairment, AUC increased by 1.6 times, 2.8 times, and 5.1 times, respectively, compared with AUC in healthy subjects with normal renal function (creatinine clearance >80 ml/min). The dose of Doripenem should be reduced in patients with moderate to severe renal impairment.

Patients with hepatic impairment: There are currently no data on the pharmacokinetics of doripenem in patients with hepatic impairment. Doripenem undergoes little or no metabolism in the liver, and therefore it is assumed that impaired function of this organ should not affect its pharmacokinetics.

Elderly patients: Compared with young adults, the AUC of doripenem was increased by 49% in older adults. These changes are mainly due to age-related changes in creatinine clearance. In elderly patients with normal (for their age) renal function the dose of Doripenem does not need to be reduced.

Gender differences: In women the AUC of Doripenem was 13% higher than in men. It is recommended that men and women be given the same dose of doripenem.

Raciality: There was no significant difference in doripenem clearance among diverse racial groups when doripenem was used, so no dose adjustment is recommended.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to doripenem:

– hospital-acquired (nosocomial) pneumonia, including pneumonia associated with artificial ventilation (ALV);

– complicated intra-abdominal infections;

– complicated infections of the urinary system, including complicated and uncomplicated pyelonephritis and cases with concomitant bacteremia.

Pharmacological effect

Pharmacotherapeutic group:

antibiotic – carbapenem

ATX code: J01DH04

Pharmacological properties

Pharmacodynamics

Doripenem is a synthetic carbapenem antibiotic with a broad spectrum of action, structurally similar to other beta-lactam antibiotics. Doripenem has pronounced in vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Compared to imipenem and meropenem, it is 2-4 times more active against Pseudomonas aeruginosa.

Mechanism of action

Doripenem has a bactericidal effect by disrupting the biosynthesis of the bacterial cell wall. It inactivates many important penicillin-binding proteins (PBPs), and this leads to disruption of bacterial cell wall synthesis and subsequent death of bacterial cells. Doripenem has the greatest affinity against Staphylococcus aureus PSB.

In Escherichia coli and Pseudomonas aeruginosa cells, doripenem binds tightly to PBPs, which are involved in maintaining the shape of the bacterial cell. In vitro experiments have shown that doripenem weakly inhibits the action of other antibiotics, and also its action is not inhibited by other antibiotics.

Additive activity or weak synergism has been described with amikacin and levofloxacin against Pseudomonas aeruginosa, as well as with daptomycin, linezolid, levofloxacin and vancomycin against gram-positive bacteria.

Mechanisms of resistance

The mechanisms of bacterial resistance to doripenem include its inactivation by enzymes that hydrolyze carbapenems, as well as mutant or acquired PBPs, a decrease in the permeability of the outer membrane, and the active release of doripenem from bacterial cells. Doripenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases, which are produced by gram-positive and gram-negative bacteria; The exception is relatively rare beta-lactamases that can hydrolyze doripenem.

The prevalence of acquired resistance in individual species may vary across geographic regions and over time, and information on local resistance patterns is therefore very useful, especially in the treatment of severe infections. If necessary, advice should be sought from microbiologists if the structure of local resistance is such that the use of a particular drug, at least for some types of infection, is doubtful.

Sensitive to doripenem:

Usually sensitive species

Gram-positive: Enterococcus faecalis, Staphylococcus aureus (strains sensitive to methicillin). Staphylococcus epidermidis (strains sensitive to methicillin), Staphylococcus haemolyticus (strains sensitive to methicillin). Streptococcus agalactiae (including strains4 resistant to macrolides), Staphylococcus saprophytics, Streptococcus intermedius, Streptococcus conste/latus, Streptococcus pneumoniae (including strains resistant to penicillin or ceftriaxone), Streptococcus pyogenes; Streptococcus viridans (including strains moderately sensitive and resistant to penicillin).

Gram-negative aerobes: Citrobacter diversus, Citrobacter freundii (including strains nonsusceptible to ceftazidime), Enterobacter aerogenes, Enterobacter cloacae (including strains nonsusceptible to ceftazidime), Haemophilus influenzae (including strains producing beta-lactamases or resistant to ampicillin strains that do not produce beta-lactamases), Escherichia coli, including strains resistant to levofloxacin and strains producing extended spectrum beta-lactamases (ESBL), Klebsiella pneumoniae (including strains producing ESBL), Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (including strains producing ESBL), Proteus vulgaris, Providencia rettgeri, Providencia stuartii Pseudomonas aeruginosa (including strains resistant to ceftazidime), Salmonella spp., Serratia marcescens (including strains insensitive to ceftazidime), species of the genus Shigella. Anaerobes: Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophila wadsworthia, species of the genus Clostridium, Peptostreptococcus magnus, Peptostreptococcus micros, species of the genus Porphyromonas, species of the genus Prevotella, Sutterella wadsworthenis.

Resistant microorganisms

Gram-positive aerobes: Staphylococci resistant to methicillin; Enterococcus faecium.

Gram-negative aerobes: Stenotrophomonas maltophiHa, Legionella spp.

The following may have acquired resistance: Burkholderia cepacia, Acinetobacter baumannii Acinetobacter spp., Pseudomonas aeruginosa.

Pharmacokinetics

The pharmacokinetics of doripenem (Cmax – maximum concentration in plasma and AUC – area under the concentration-time curve) is linear in the dose range of 500 mg-1 g with intravenous infusion over 1 or 4 hours. In patients with normal renal function, no signs of accumulation of doripenem were found after repeated intravenous infusions of 500 mg or 1 g every 8 hours 7-10 days.

The pharmacokinetics of doripenem is linear in the dose range of 500 mg – 2 g when administered as an intravenous infusion lasting 1 hour and 500 mg – 1 g when administered as an intravenous infusion lasting 4 hours. Pharmacokinetic characteristics of doripenem with a single dose [after a 4-hour infusion] in adults with cystic fibrosis are similar to those for adults without cystic fibrosis. There have been no adequate, well-controlled studies of the safety and effectiveness of doripenem in patients with cystic fibrosis.

Distribution: The average degree of binding of doripenem to plasma proteins was 8.1% and did not depend on its concentration in the blood plasma. The volume of distribution is approximately 16.8 L, which is close to the volume of extracellular fluid in humans (18.2 L). Doripenem penetrates well into a number of tissues and biological fluids, such as uterine tissue, retroperitoneal fluid, prostate tissue, gallbladder tissue and urine, reaching concentrations there that exceed the MIC (minimum inhibitory concentration).

Metabolism: Biotransformation of doripenem into a microbiologically inactive metabolite occurs mainly under the action of dehydropeptidase-I. Metabolism of doripenem by CYP450 isoenzymes and other enzymes, both in the presence and absence of nicotinamide adenine dinucleotide phosphate (NADP), has been observed in vitro.

Elimination: Doripenem is eliminated mainly unchanged by the kidneys. In healthy young adults, the mean terminal plasma half-life of doripenem is approximately 1 hour and plasma clearance is approximately 15.9 L/hour. The average renal clearance is 10.3 l/h. The magnitude of this indicator, along with a significant decrease in the elimination of doripenem when administered simultaneously with probenecid, indicates that doripenem undergoes both glomerular filtration and renal secretion. In healthy young adults receiving a single dose (500 mg) of doripenem, 71% of the dose was found in urine as unchanged doripenem and 15% as the open-ring metabolite, respectively. Following administration of a single dose (500 mg) of radiolabeled doripenem to young healthy adults, less than 1% of total radioactivity was detected in feces.

Patients with renal impairment: Following the administration of a single dose (500 mg) of doripenem to patients with mild (creatinine clearance 51-79 ml/min), moderate (creatinine clearance 31-50 ml/min) and severe (creatinine clearance 80 ml/min). The dose of doripenem should be reduced in patients with moderate to severe renal impairment.

Patients with hepatic impairment: There are currently no data on the pharmacokinetics of doripenem in patients with hepatic impairment. Doripenem is practically not metabolized in the liver, and it is therefore expected that dysfunction of this organ should not affect its pharmacokinetics.

Elderly: Compared with younger adults, the AUC of doripenem was increased by 49% in older adults. These changes are explained mainly by age-related changes in creatinine clearance. In elderly patients with normal (for their age) renal function, the dosage dose does not need to be reduced.

Sex differences: In women, the AUC of doripenem was 13% greater than in men. It is recommended that men and women receive the same dose of doripenem.

Race: No significant differences in clearance of doripenem have been observed among different racial groups when doripenem is used, and dosage adjustments are not recommended.

Special instructions

Patients receiving beta-lactam antibiotics may experience serious and sometimes fatal hypersensitivity reactions (anaphylactic reactions). Before starting treatment with doripenem, the patient should be carefully questioned about whether he or she has previously experienced hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics.

If a hypersensitivity reaction occurs to doripenem, it should be discontinued immediately and appropriate treatment administered.

Serious hypersensitivity reactions (anaphylactic shock) require emergency treatment including corticosteroids and pressor amines (epinephrine), as well as other measures including oxygen therapy, intravenous fluids and, if necessary, antihistamines, and maintaining a patent airway.

Cases of seizures have been reported during therapy with caroapenems, including doripenem (see section “Side effects”). In clinical studies of doripenem, seizures were observed more frequently in patients with underlying central nervous system diseases (eg, stroke, history of seizures), impaired renal function, and when doses exceeding 500 mg were used.

Pseudomembranous colitis caused by Clostridium difficile can appear both during long-term use and 2-3 weeks after stopping treatment; manifested by diarrhea, leukocytosis, fever, abdominal pain (sometimes accompanied by the release of blood and mucus with feces).

If these phenomena occur, in mild cases, it is sufficient to discontinue treatment and use ion exchange resins (colestyramine, colestipol); in severe cases, replacement of the loss of fluid, electrolytes and protein, and the appointment of oral vancomycin or metronidazole are indicated. You cannot use medications that inhibit intestinal motility.

Long-term treatment with doripenem should be avoided to prevent excessive proliferation of doripenem-resistant microorganisms. Before using the drug, it is recommended to conduct a bacteriological study.

It is necessary to select appropriate samples for bacteriological testing in order to isolate pathogens, identify them and determine their sensitivity to doripenem. In the absence of such data, empirical selection of drugs should be based on local epidemiological data and local susceptibility patterns of microorganisms.

Long-term renal replacement therapy

The exposure of the doripenem-M-1 metabolite in patients on long-term renal replacement therapy may be reduced to a level for which there is no data on the safety of the drug in vivo.

This metabolite does not exhibit microbiological activity, and other possible pharmacological effects are unknown. Therefore, careful monitoring of side effects is recommended for patients on long-term renal replacement therapy.

In a clinical trial in patients with ventilator-associated pneumonia, a 7-day course of doripenem (1 g over 4-hour infusions every 8 hours) was not effective compared with 10-day courses of imipenem-cilastatin (1 g over 1-hour infusions every 8 hours). The usual duration of treatment for patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7 to 14 days and should depend on the severity of the disease, the location of the infection, and the patient’s clinical response to treatment.

Impact on the ability to drive vehicles and machinery

Studies on the effect of doripenem on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions have not been conducted, but given the safety profile of the drug and the presence of side effects from the nervous system, attention should be paid to the possible effect of the drug on the above functions.

Active ingredient

Doripenem

Composition

For 1 bottle:

Active ingredient:

Doripenem monohydrate – 521.4 mg (in terms of doripenem) – 500 mg.

Pregnancy

Pregnancy

There are limited clinical data on the use of doripenem in pregnant women. The potential risk to the fetus is unknown. During pregnancy, it is used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Lactation

If it is necessary to use doripenem during lactation, breastfeeding must be stopped.

Contraindications

Hypersensitivity to doripenem or other carbapenems. as well as beta-lactam antibiotics.
Children under 18 years of age.

Side Effects

The frequency of adverse effects was classified as follows: very common >1/10; often >1/100- 1/1000 – 1/10,000- 1/100,000 –< 1/10,000. The following undesirable effects have been noted:

From the nervous system:

very common: headache

frequency unknown: seizures

From the cardiovascular system:

often: phlebitis

From the gastrointestinal tract:

often: nausea, diarrhea;

uncommon: pseudomembranous colitis

From the skin and subcutaneous tissue: often: itching, rash

Allergic reactions:

uncommon: hypersensitivity reactions (anaphylactic reactions);

very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome

From the hepatobiliary system:

often: increased activity of liver enzymes

From the circulatory and lymphatic system:

Uncommon – neutropenia, thrombocytopenia

Others:

often: candidiasis of the oral mucosa, vaginal candidiasis.

Interaction

Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. Probenecid increases the AUC of ripenem by 75% and the plasma half-life by 53%. Therefore, it is not recommended to use probenecid and doripenem simultaneously.

Doripenem does not inhibit the main isoenzymes of the cytochrome P450 system, and therefore, most likely, does not interact with drugs that are metabolized by these enzymes. Doripenem, based on in vitro studies, does not have the ability to induce enzyme activity.

In healthy volunteers, doripenem reduced plasma valproic acid concentrations to subtherapeutic levels (valproic acid AUC decreased rapidly by 63%), which is also consistent with results obtained with other carbapenems.

The pharmacokinetics of dori-penem did not change. When taking doripenem and valproic acid or semisodium valproate concomitantly, the concentrations of the latter should be monitored and the possibility of prescribing other treatment should be considered.

The drug cannot be mixed with other drugs and solutions, with the exception of 0.9% sodium chloride solution, 5% dextrose solution and water for injection.

Overdose

There have been cases of the appearance of a papulo-erythematous rash when doripenem was administered intravenously at a dose of 2 g every 8 hours for 10-14 days. The papuloerythematous rash resolved within 10 days after discontinuation of doripenem.

In case of overdose, doripenem should be discontinued and maintenance therapy should be carried out until it is completely eliminated from the body by the kidneys. Treatment of overdose consists of general supportive symptomatic therapy, including monitoring of basic physiological parameters and monitoring the clinical condition of the patient.

Doripenem is removed from the body by hemodialysis or long-term renal replacement therapy, but there is currently insufficient information on the use of hemodialysis or long-term renal replacement therapy for doripenem overdose.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Shelf life

3 years.

Manufacturer

Biokhimik JSC, Russia