What Is Ertapenem?

Ertapenem chemical name is (4R, 5R, 6S) -3-[(3S, 5S) -5-[(3-carboxyphenyl) carbamoyl] pyrrolidin-3-yl] sulfur-6- ( 1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, the molecular formula is C22H25N3O7S, its relative molecular weight is 475.51500, and its density is 1.55 g / cm3. It is clinically used to treat complex abdominal infections, complex skin and soft tissue infections, community-acquired pneumonia, complex urinary tract infections, acute pelvic infections, and severe enterobacteriaceae bacterial infections.

Chinese name: Ertapenem
Foreign name: ertapenem

CAS number: 153832-46-3
Molecular formula: C22H25N3O7S

Introduction to urtapenem compounds

Ertapenem Basic Information

Chinese name: Ertapenem

Chinese alias: (4R, 5R, 6S) -3-[(3S, 5S) -5-[(3-carboxyphenyl) carbamoyl] pyrrolidin-3-yl] sulfur-6- (1-hydroxyethyl ) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; meropenem core;

English name: ertapenem

English alias: Ertapenem; AC-6814; (4R, 5S, 6S) -3-[(3S, 5S) -5-[(3-carboxyphenyl) carbamoyl] pyrrolidin-3-yl] sulfanyl-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; UNII-G32F6EID2H;

CAS number: 153832-46-3

Molecular formula: C ₂₂ H ₂₅ N ₃ O ₇ S

Structural formula:

Molecular weight: 475.51500

Exact mass: 475.14100

PSA: 181.57000

LogP: 1.28040

Physicochemical properties of Ertapenem

Density: 1.55 g / cm ³

Boiling point: 813.9ºC at 760 mmHg

Flash point: 446ºC

Refractive index: 1.7 ^[1]

Ertapenem Pharmacology and Toxicology

This product is a new type of carbapenem antibiotics. By combining with penicillin-binding protein (PBP), it interferes with the synthesis of bacterial cell walls, resulting in the inhibition of bacterial growth and reproduction, and a few cells lysed. The product has high antibacterial activity against methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and other Gram-positive bacteria and Enterobacteriaceae; Haemophilus, Moraxella catarrhalis, Neisseria meningitidis Highly sensitive to this product, but resistant to methicillin-resistant Staphylococcus, Enterococcus, Pseudomonas aeruginosa, Acinetobacter and other bacteria. This product is stable to most penicillinase, cephalosporinase, and extended-spectrum & szlig; -lactamase, but can be hydrolyzed by metalloenzymes. This product is stable to human renal dehydropeptidase-I, and does not need to be used in combination with cilastatin. ^[2]

Ertapenem Toxicology Study

Genotoxicity: In the following in vitro tests, including alkaline elution / rat hepatocyte test, Chinese hamster ovary cell chromosome aberration test, TK6 human lymphoblast-like cell mutagenesis test, and in vivo micronucleus test in mice, None of ertapenem had mutagenic activity or genotoxicity.

Reproductive toxicity: When mice and rats were injected intravenously with ertapenem at a dose of up to 700 mg / kg / day, it had no effect on mating behavior, fertility, fertility, or embryo survival. Calculated based on body surface area, this dose given to mice is roughly equivalent to 3 times the recommended human dose of 1 g; calculated based on plasma AUCs, this dose given to rats is equivalent to approximately 1.2 times the recommended dose given to humans. Times.

When mice and rats were injected intravenously with ertapenem at a dose of up to 700 mg / kg / day, the fetal appearance, internal organs and bones were examined, and no developmental toxicity was found. Calculated based on body surface area, this dose given to mice is approximately three times the recommended human dose of 1 g; in terms of plasma AUCs, this dose given to rats is approximately equivalent to the recommended human dose of 1 g 1.2 times. However, when the mice were given a dose of 700 mg / kg / day, a slight decrease in the average fetal weight and a corresponding decrease in the number of sacrococcygeal ossification were observed.

In rats, Ertapenem passes through the placental barrier.

Carcinogenicity: Long-term studies evaluating the potential carcinogenicity of ertapenem have not been performed in animals. ^[3]

Ertapenem pharmacokinetics

After intravenous infusion of 0.5g, 1g and 2g, the peak plasma concentration (Cmax) was reached within 30min, which was 71.3mg / L, 137.0mg / L and 255.9mg / L, respectively. After intramuscular injection of this product, the bioavailability is about 90%, the peak time is 2.3h, and the Cmax is 67mg / L.

The plasma protein binding rate of this product is 92% to 95%, and the protein binding rate is higher when the concentration is low. It is mainly excreted by the kidney, and its plasma half-life is 4.3 to 4.6 hours. After intravenous application of isotopically labeled 1g of this product to healthy young volunteers, the drug elimination rates in urine and bile were 80% and 10%, respectively, and the drug prototype and metabolites in urine accounted for 40% each. ^[2]

Ertapenem absorption

Ertapenem was dissolved with 1% lidocaine hydrochloride injection (dissolved in normal saline, no adrenaline) in accordance with US Pharmacopeia standards. After intramuscular injection of the recommended dose of 1 g, Ertapenem was almost completely absorbed. The average bioavailability is about 90%. When calculated at a daily intramuscular dose of 1 g, the average time (Tmax) required to reach the peak plasma concentration (Cmax) is about 2.3 hours.

Ertapenem distribution

Ertapenem is highly bound to human plasma proteins, mainly albumin. In healthy young adults, when the plasma concentration increases, the binding of ertapenem to protein decreases, and the binding rate decreases from about 95% when the plasma concentration is less than 100 g / mL to approximately 300 g / mL. Around 85%.

Ertapenem metabolism

In healthy young adults, after intravenous infusion of 1 g of radioisotope-labeled ertapenem, the radioactivity in plasma was mainly from ertapenem (94%). Ertapenem's main metabolite is a ring-opening derivative formed by hydrolysis of an inactive -lactam ring. In vitro studies using human liver microsomes have shown that Ertapenem has no inhibitory effect on metabolism mediated by the six major isozymes of cytochrome P450 (CYP) (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) (See Drug Interactions).

In vitro studies have shown that Ertapenem has no inhibitory effect on P-glycoprotein-mediated digoxin or vinblastine transport. Ertapenem is not a substrate for P-glycoprotein-mediated transport (see Precautions, Drug Interactions).

Ertapenem Clear

Ertapenem is cleared primarily through the kidneys. In healthy young adults and patients 13 to 17 years of age, the average plasma half-life is approximately 4 hours, and in pediatric patients 3 months to 12 years of age, the average plasma half-life is approximately 2.5 hours.

After intravenous infusion of 1 g of radioisotope-labeled ertapenem to healthy young adults, approximately 80% are excreted from the urine, of which approximately 38% are excreted as prototypes and 37% are excreted as open-loop metabolites. Another 10% is excreted from feces.

Intravenous infusion of 1 g of ertapenem to healthy young adults, the average amount of urtapenem excreted in the urine during the 0 to 2 hours after administration was 17.4% of the drug dose, and 4 to 6 after administration It was 5.4% during the hour and 2.4% during the 12 to 24 hour period after dosing.

Ertapenem special population

Renal insufficiency: The pharmacokinetics of the total and unbound portion of Ertapenem were studied in 26 adult subjects (aged 31 to 80 years) with varying degrees of renal impairment. After a single intravenous infusion of Ertapenem 1g, the unbound drug was used in patients with mild renal insufficiency (Clcr 60-90 mL / min / 1.73m) and patients with moderate renal insufficiency (Clcr 31-59mL / min / 1.73 The AUC in m) was 1.5 and 2.3 times that of healthy young subjects (aged 25 to 45 years). For patients with creatinine clearance 31mL / min / 1.73m, no dose adjustment is required. Compared with healthy young subjects, the AUC of unbound drugs in patients with severe renal insufficiency (Clcr 5-30mL / min / 1.73m) and patients with end-stage renal insufficiency (Clcr <10mL / min / 1.73m) respectively Increased 4.4 times and 7.6 times. Renal insufficiency has a smaller effect on the AUC of all drugs. For patients with creatinine clearance 30 mL / min / 1.73m, the recommended dose of ertapenem is 0.5 g / day. Five patients with end-stage renal insufficiency were treated with a single intravenous infusion of 1 g of ertapenem immediately after 4 hours of hemodialysis, and about 30% of the administered amount was recovered from the dialysate. If ertapenem is used within 6 hours before hemodialysis, it is recommended to increase the drug dose by 150 mg. (See usage and dosage)

Hepatic insufficiency: The pharmacokinetics of ertapenem in patients with liver insufficiency have not been studied. However, since only about 10% of the drug can be detected in feces, combined with in vitro studies, Ertapenem does not appear to be metabolized by the liver. (See notes and usage)

Gender: The effect of gender on the pharmacokinetics of ertapenem was evaluated in 8 healthy male and 8 female subjects. Although some differences were observed, they can be attributed to differences in body weight. There is no need to adjust the dose of the drug according to gender.

Elderly patients: The effect of age on the pharmacokinetics of ertapenem was evaluated in 7 healthy male and 7 female subjects aged 65 years and older. Compared with young adult subjects, the AUCs of the above-mentioned elderly subjects for all drugs and unbound drugs increased by 37% and 67%, respectively. This change was attributed to changes in age-related creatinine clearance. If elderly patients have normal kidney function that matches their age, there is no need to adjust the dosage.

Pediatric patients: The pharmacokinetics of urtapenem in pediatric patients has not been studied. ^[3]

Ertapenem indications:

This product is suitable for the treatment of the following moderate to severe infections caused by sensitive strains of the following bacteria in adults.

Secondary celiac infection: Caused by Escherichia coli, Clostridium bacillus, Eubacillus flavus, Digestive streptococcus, Bacteroides fragile, Bacteroides jejuni, B. ovale, B. polymorpha or B. monomorpha By.

Complex skin and appendage infections: Caused by Staphylococcus aureus (only strains susceptible to methicillin), Streptococcus pyogenes, Escherichia coli, and Digestive Streptococcus.

Community-acquired pneumonia: Caused by Streptococcus pneumoniae (only strains that are sensitive to penicillin, including cases of combined bacteremia), Haemophilus influenzae (only -lactamase negative strains), or catarrhalis .

Complex urinary tract infections, including pyelonephritis: Caused by Escherichia coli or Klebsiella pneumoniae.

Acute pelvic infections, including postpartum endometritis, abortion infections and post-gynecological infections: by Streptococcus agalactiae, Escherichia coli, Bacteroides fragile, Porphyromonas glycolytics, Peptostreptococcus Caused by two-way Prevotella.

Bacteremia: In order to isolate and identify pathogenic bacteria and determine their sensitivity to urtapenem, specimens for bacteriological examination should be taken correctly. Before obtaining the results of these tests, you can start using this product for empirical treatment; once the test results are obtained, the antibiotic treatment plan should be adjusted accordingly.

In order to reduce the formation of bacterial resistance and ensure the efficacy of this product and other antibacterial drugs, this product can only be used to treat or prevent infections that have been clearly or highly suspected to be caused by sensitive bacteria. After obtaining the results of bacterial culture and drug sensitivity testing, antibiotic treatment options should be selected and adjusted accordingly. Before the above test results are obtained, empirical treatment options can be selected based on local bacterial epidemiological data and drug sensitivity characteristics. ^[3]

Ertapenem Usage and Dosage

1g each time, once a day, intravenous or intramuscular injection. Intravenous infusion time should be greater than 30min. Intramuscular injection can be used for sequential treatment of intravenous medication. The creatinine clearance rate 30ml / min is adjusted to 0.5g each time, once a day; if hemodialysis is performed within 6 hours after administration, a supplementary dose of 0.15g is given after dialysis. Every 1g of Ertapenem should be dissolved in more than 50ml of normal saline for intravenous infusion, and the time of each intravenous infusion should be greater than 30min. Each 1g of intramuscular injection should be dissolved in 1% lidocaine solution for deep intramuscular injection. ^[2]

Ertapenem contraindications

1. Allergic to urtapenem or other carbapenems is prohibited.

2. Intramuscular injection of ertapenem is diluted with lidocaine solution, and should not be used for intravenous administration, nor for patients with allergic lidocaine or patients with other lidocaine contraindications such as severe shock and atrioventricular block. . ^[2]

Ertapenem adverse reactions

The most common drug-related adverse events during the treatment of patients with parenteral administration of Ertapenem were diarrhea (4.3%), complications of intravenous infusion (3.9%), nausea (2.9%), and headache ( 2.1%).

Immune system: allergic reactions, including allergic-like reactions

Mental disorders: changes in mental state (including agitation, aggressiveness, delirium, disorientation, changes in mental state)

Neurological disorders: decreased consciousness, dyskinesias, hallucinations, myoclonus, tremors

Disorders of skin and subcutaneous tissue: urticaria, drug rash with erythrocytosis and systemic symptoms (DRESS syndrome).

Pediatric patient

The total number of pediatric patients treated with ertapenem in clinical studies was 384. The overall safety profile is similar to that of adult patients. In clinical trials, the most common drug-related clinical adverse events reported during parenteral administration were diarrhea (5.5%), infusion site pain (5.5%), and erythema at the infusion site (2.6%). ^[3]

Urtapenem notes

Serious and occasional lethal allergic reactions have been reported in patients receiving beta-lactam antibiotics. Patients with a previous history of allergies to multiple allergens are more likely to develop these reactions. There have been reports of severe allergic reactions in patients with a history of penicillin allergy when treated with another beta-lactam antibiotic. Before starting treatment with this product, patients must be carefully asked about their allergies to penicillin, cephalosporins, other beta-lactam antibiotics, and other allergens. If an allergic reaction to this product occurs, the drug must be discontinued immediately. Serious allergic reactions require immediate first aid.

It has been reported in the literature that combined carbapenem drugs, including ertapenem, patients receiving valproic acid or sodium valproate will cause a decrease in valproic acid concentration. Because of drug interactions, valproic acid levels are lower than the therapeutic range and therefore the risk of seizures increases. Increasing the dose of valproic acid or sodium valproate is not sufficient to overcome this type of interaction. Simultaneous administration of ertapenem and valproic acid / divalproate is generally not recommended. When seizures are well controlled by valproic acid or sodium valproate, other antibiotics other than carbapenems should be considered for the treatment of infections. If this product is necessary, supplementary anticonvulsant therapy should be considered (see Drug Interactions).

Like other antibiotics, prolonging the use of this product may cause excessive growth of non-sensitive bacteria. It is necessary to repeatedly evaluate the condition of the patient. If a double infection occurs during treatment, appropriate measures should be taken.

Almost all antibacterials, including ertapenem, have been reported to cause pseudomembranous colitis, with severity ranging from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients with diarrhea after administration of antimicrobials. Studies have shown that toxins produced by Clostridium difficile are the main cause of "antibiotic-associated colitis".

Caution should be used when injecting this product intramuscularly to avoid accidental injection of the drug into a blood vessel

Regardless of drug relevance, seizures occurred in 0.2% of adult patients treated with ertapenem (1 g, once daily) in clinical studies. This phenomenon occurs most often in patients with neurological conditions (such as brain disorders or a history of seizures) and / or impaired renal function. The recommended dosing regimen should be strictly followed, especially for patients with known convulsive factors.

Medications for pregnant women and lactating women:

There are no adequate well-controlled studies in pregnant women. Use this product during pregnancy only when the potential benefits outweigh the potential dangers to the mother and fetus.

Ertapenem is secreted into human milk (see Pharmacokinetics, Distribution). Caution should be exercised when using this product for nursing women.

Urtapenem medication for children:

Data from well-controlled adult studies, pharmacokinetic data from pediatric patients, and controlled studies in pediatric patients from 3 months to 17 years of age with the following infections have confirmed that this product is between 3 months and 17 Safety and effectiveness in aged paediatric patients (see Indications and Clinical Studies, Pediatric Patients).

· Secondary abdominal infections

Complex skin and appendage infections

Community acquired pneumonia

· Complex urinary tract infection

· Acute pelvic infection

· Bacterial sepsis

This product is not recommended for infants under 3 months of age and no data are currently available.

Ertapenem medications for the elderly:

In clinical studies, the efficacy and safety of this product in the elderly (65 years) are comparable to those of younger patients (<65 years). ^[3]

Ertapenem Drug Interactions

When both probetazone and probenecid were administered at the same time, probenecid and ertapenem competed for active secretion of the renal tubules, thereby inhibiting renal excretion of the latter. This results in a small but statistically significant increase in clearance half-life (19%) and an increased degree of systemic drug exposure (25%). When probenecid is administered at the same time, there is no need to adjust the dose of ertapenem. Because of its small effect on half-life, it is not recommended to use probenecid to extend the half-life of ertapenem.

In vitro studies have shown that Ertapenem does not inhibit P-glycoprotein-mediated digoxin or vinblastine transport, and Ertapenem is not a substrate for P-glycoprotein-mediated transport. In vitro studies in human liver microsomes have shown that Ertapenem has no inhibitory effect on cytochrome 6 major P450 (CYP) isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) -mediated metabolism. Ertapenem is unlikely to cause drug-drug interactions by inhibiting P-glycoprotein or CYP-mediated drug clearance (see Pharmacokinetics).

With the exception of probenecid, no interaction with specific clinical drugs has been studied.

Some literature shows that combined carbapenem drugs, including ertapenem, patients receiving valproic acid or sodium valproate will cause a decrease in valproic acid concentration. Because of drug interactions, valproic acid levels are lower than the therapeutic range and therefore the risk of seizures increases. Although the mechanism of drug interaction is not clear, in vitro and animal data show that carbapenems can inhibit the hydrolysis of valproic acid glucuronide metabolism (VPA-g) to valproic acid and reduce the serum concentration of valproic acid . (See note) ^[3]

Ertapenem overdose

There is no specific data on the treatment of this drug overdose. It is generally unlikely that a deliberate overdose of this product will occur. In healthy adult volunteers, intravenous infusion of this product at 3g / day for 8 days did not cause significant toxicity. In adult clinical studies, inadvertent administration of up to 3 g of this product within one day did not cause clinically significant adverse events. In clinical studies in children, single dose intravenous infusion of this product 40mg / kg (body weight), up to a maximum dose of 2g, did not cause toxicity. In pediatric clinical studies, single dose intravenous infusion of this product 40mg / kg (body weight) to the maximum dose of 2g, no toxic effect was found.

When overdose occurs, the use of this product should be stopped and general supportive treatment should be given until the clearance of the kidneys takes effect.

This product can be removed by hemodialysis. There are no data on the use of hemodialysis for overdose. ^[3]