Invanz Mechanism of Action

INVANZ (Ertapenem for Injection) is a sterile, synthetic, long-acting, parenteral, 1-β methyl-carbapenem that is structurally related to beta-lactam antibiotics, such as penicillins and cephalosporins, with activity against a wide range of gram-positive and gram-negative aerobic and anaerobic bacteria.
Pharmacology: Mechanism of Action: Ertapenem has in vitro activity against a wide range of gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has strong affinity toward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3. Ertapenem has significant stability to hydrolysis by most classes of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases.
Pharmacodynamics: SUSCEPTIBILITY TESTS: When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
The following are the MIC ranges for some organisms: (See Table 1.)

Click on icon to see table/diagram/image

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method† (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 6.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ertapenem to test the susceptibility of microorganisms to ertapenem. The disk diffusion interpretive criteria are provided in Table 2.
Anaerobic Techniques: For anaerobic bacteria, susceptibility to ertapenem as MICs can be determined by a standardized test method. The MIC values obtained should be interpreted according to the criteria provided in Table 2. (See Table 2.)

Click on icon to see table/diagram/image

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard ertapenem powder should provide the following range of values noted in Table 3. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. (See Table 3.)

Click on icon to see table/diagram/image

Pharmacokinetics: Absorption: Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is well absorbed following IM administration at the recommended dose of 1 g. The mean bioavailability is approximately 92%. Following 1 g daily IM administration, mean peak plasma concentrations (C_max) are reached in approximately 2 hours (T_max).
Distribution: Ertapenem is highly bound to human plasma proteins. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of <100 mcg/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL.
Average plasma concentrations (mcg/mL) of ertapenem following a single 30 minute IV infusion of a 1 or 2 g dose and IM administration of a single 1 g dose in healthy young adults are presented in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

Area under the plasma concentration curve (AUC) of ertapenem in adults increases nearly dose-proportionally over the 0.5 to 2 g dose range.
There is no accumulation of ertapenem in adults following multiple IV doses ranging from 0.5 to 2 g daily or IM doses of 1 g daily.
Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 5. (See Table 5.)

Click on icon to see table/diagram/image

The volume of distribution (V_dss) of ertapenem in adults is approximately 8 liters (0.11 liter/kg) and approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.
Ertapenem penetrates into suction-induced skin blisters. Concentrations of ertapenem achieved in skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 6. The ratio of AUC in skin blister fluid to AUC in plasma is 0.61. (See Table 6.)

Click on icon to see table/diagram/image

The level of ertapenem in breast milk of 5 lactating women was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy. The measured concentration of ertapenem in breast milk on the last day of therapy (5 to 14 days postpartum) in all 5 women was < 0.38 mcg/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and was detected at trace levels (< 0.13 mcg/mL) in 1 woman.
In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport (see INTERACTIONS).
Metabolism: In healthy young adults, after IV infusion of radiolabeled 1 g ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the ring-opened derivative formed by hydrolysis of the beta-lactam ring.
In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the six major cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (see INTERACTIONS).
Elimination: Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults and patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age.
Following administration of a 1 g radiolabeled IV dose of ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.
In healthy young adults given a 1 g IV dose, average concentrations of ertapenem in urine exceed 984 mcg/mL during the period 0 to 2 hours postdose and exceed 52 mcg/mL during the period 12 to 24 hours postdose.
Characteristics in Patients: Gender: The plasma concentrations of ertapenem are comparable in men and women.
Elderly: Plasma concentrations following a 1 g and 2 g IV dose of ertapenem are slightly higher (approximately 39% and 22%, respectively) in elderly adults (≥ 65 years) relative to young adults (<65 years). No dosage adjustment is necessary in elderly patients.
Pediatric Patients: Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose.
Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age were generally comparable to those in healthy young adults. Three out of six patients 13 to 17 years of age received less than a 1 g dose. To provide an estimate of the pharmacokinetic data if all patients in this age group were to receive a 1 g dose, the pharmacokinetic data were calculated adjusting for a 1 g dose, assuming linearity. A comparison of results show that a 1 g once daily dose of ertapenem achieves a pharmacokinetic profile in patients 13 to 17 years of age comparable to that of adults. The ratios (13 to 17 years/adults) for AUC, the end of infusion concentration and the concentration at the midpoint of the dosing interval were 0.99, 1.20, and 0.84, respectively.
Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the midpoint of the dosing interval following a 1 g once daily IV dose in adults (see Distribution as previously mentioned). The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem.
Hepatic Insufficiency: Since the pharmacokinetics of ertapenem sodium in hepatic insufficiency has not been established, it is to be used with caution in patients with hepatic impairment.
Renal Insufficiency: Following a single 1 g IV dose of ertapenem in adults, AUC is similar in patients with mild renal insufficiency (Cl_cr 60-90 mL/min/1.73 m²) compared with healthy subjects (ages 25 to 82 years). AUC is increased in patients with moderate renal insufficiency (Cl_cr 31-59 mL/min/1.73 m²) approximately 1.5-fold compared with healthy subjects. AUC is increased in patients with advanced renal insufficiency (Cl_cr 5-30 mL/min/1.73 m²) approximately 2.6-fold compared with healthy subjects. AUC is increased in patients with end-stage renal insufficiency (Cl_cr <10 mL/min/1.73 m²) approximately 2.9-fold compared with healthy subjects. Following a single 1 g IV dose given immediately prior to a hemodialysis session, approximately 30% of the dose is recovered in the dialysate. There are no data in pediatric patients with renal insufficiency.
A dosage adjustment is recommended for patients with advanced or end-stage renal insufficiency (see DOSAGE & ADMINISTRATION).
Microbiology: Ertapenem has in vitro activity against a wide range of gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has strong affinity toward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3. Ertapenem has significant stability to hydrolysis by most classes of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases.
INVANZ has been shown to be active against most strains of the following microorganisms in vitro and in clinical infections (see INDICATIONS): AEROBIC AND FACULTATIVE GRAM-POSITIVE MICROORGANISMS: Staphylococcus aureus (including penicillinase-producing strains), Streptococcus agalactiae, Streptococcus pneumoniae (penicillin susceptible isolates only), Streptococcus pyogenes.
Note: Methicillin-resistant staphylococci and Enterococcus spp are resistant to INVANZ.
AEROBIC AND FACULTATIVE GRAM-NEGATIVE MICROORGANISMS: Escherichia coli, Haemophilus influenzae (Beta-lactamase negative isolates only), Klebsiella pneumoniae, Moraxella catarrhalis.
ANAEROBIC MICROORGANISMS: Bacteroides fragilis and other species in the B. fragilis Group, Clostridium species (excluding C. difficile), Eubacterium species, Peptostreptococcus species, Porphyromonas asaccharolytica, Prevotella species.
The following in vitro data are available, but their clinical significance is unknown.
INVANZ exhibits in vitro minimum inhibitory concentrations (MICs) of ≤ 1 mcg/mL against most (≥ 90%) strains of Streptococcus species including Streptococcus pneumoniae, ≤ 0.5 mcg/mL against most (≥ 90%) strains of Haemophilus species, ≤ 2 mcg/mL against most (≥ 90%) strains of the other aerobic and facultative anaerobic microorganisms and ≤ 4 mcg/mL against most (≥ 90%) strains of the strict anaerobic microorganisms in the following list; however, the safety and effectiveness of INVANZ in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical studies: AEROBIC AND FACULTATIVE GRAM-POSITIVE MICROORGANISMS: Staphylococcus species, coagulase negative, methicillin susceptible, Streptococcus pneumoniae (penicillin-intermediate isolates only).
AEROBIC AND FACULTATIVE GRAM-NEGATIVE MICROORGANISMS: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenzae (beta-lactamase positive isolates), Haemophilus parainfluenzae, Klebsiella oxytoca (excluding ESBL producing isolates), Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Serratia marcescens.
ANAEROBIC MICROORGANISMS: Bacteroides vulgatus, Clostridium perfringens, Fusobacterium species.