Invanz Mechanism of Action

Therapeutic Class: 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.
Pharmacokinetics: Absorption: Ertapenem, reconstituted with 1% lidocaine HCl injection (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 hrs (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 1.

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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 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 2.

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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 3. The ratio of AUC in skin blister fluid to AUC in plasma is 0.61. (See Table 3.)

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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 hrs and approximately 2.5 hrs 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.
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 ANAEROBIC GRAM-POSITIVE MICROORGANISMS: Staphylococcus aureus (including penicillinase-producing strains), Streptococcus agalactiae, Streptococcus pneumoniae and Streptococcus pyogenes.
Note: Methicillin-resistant staphylococci are resistant to INVANZ. Many strains of Enterococcus faecalis and most strains of Enterococcus faecium are resistant.
AEROBIC AND FACULTATIVE ANAEROBIC GRAM-NEGATIVE MICROORGANISMS: Escherichia coli, Haemophilus influenzae (including beta-lactamase producing strains), Klebsiella pneumoniae, Moraxella catarrhalis and Proteus mirabilis.
ANAEROBIC MICROORGANISMS: Bacteroides fragilis and other species in the B. fragilis Group, Clostridium sp (excluding C. difficile), Eubacterium species, Peptostreptococcus species, Porphyromonas asaccharolytica and 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 ANAEROBIC GRAM-POSITIVE MICROORGANISMS: Staphylococcus species, coagulase-negative, methicillin-susceptible Streptococcus pneumoniae, penicillin-resistant Viridans streptococci.
Note: Methicillin-resistant staphylococci are resistant to INVANZ. Many strains of Enterococcus faecalis and most strains of Enterococcus faecium are resistant.
AEROBIC AND FACULTATIVE ANAEROBIC GRAM-NEGATIVE MICROORGANISMS: Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli producing ESBLs, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae producing ESBLs, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Note: Many strains of these organisms that are multiply resistant to other antibiotics, e.g., penicillins, cephalosporins (including third-generation) and aminoglycosides are susceptible to INVANZ.
ANAEROBIC MICROORGANISMS: Fusobacterium species.