Invanz (Ertapenem) is a 1-beta-methyl carbapenem antibiotic that is designed to treat multi drug resistant bacterial infections such as intra-abdominal infections, skin and skin suture infections, community-acquired pneumonia, complicated urinary tract infections including pyelonephritis, acute pelvic infections, and can be used as a prophylactic measure prior to colorectal surgery. Invanz is an injectable antibiotic, which can be administered intramuscularly. It is generally known to be an antibiotic to treat mostly life-threatening infections and is used sparingly [1][2].
Function
Invanz is used to treat a range of bacterial infections caused by Gram positive bacteria, Gram negative bacteria, and as well as a range of both aerobic and anaerobic bacteria. Invanz works by inhibiting cell wall synthesis via binding to penicillin binding proteins (PBPs). Invanz is stable against hydrolysis from many beta-lactamases including penicillinases and cephalosporinases, but is unstable against metallo-beta-lactamases [2]. Beta-lactamases are secreted by bacteria to provide resistance to antibiotics; however, Invanz is relatively unaffected by these beta-lactamases and thus is an effective treatment for various bacterial infections [3]. The unique structural features of Invanz equip this drug with some of the widest spectrum and most potent antimicrobial activity of carbapenem antibiotics today [4].
Structural highlights
is a carbapenem which is a beta-lactam antibiotic (contains a beta lactam ring) that has antimicrobial action via inhibition of cell wall synthesis. This class of antibiotics is known for its broad spectrum of activity, and its structure allows it to bind penicillin binding proteins (PBPs) to inhibit bacterial cell wall synthesis in a variety of bacterial types [5][6]. Antibiotic resistance to carbapenems largely results from ability of the bacterial species to secrete beta-lactamase enzymes that prevent the antimicrobial from accomplishing its job. Beta-lactamases work by attacking and cleaving the beta-lactam ring of antibiotics before the antibiotic reaches its target such as the penicillin binding proteins [7]. Invanz has resistance to many beta-lactamases since it has a (shown in pink) that confers resistance of the antibiotic to degradation by most beta-lactamases [8] [9]. The (shown in purple) is a four-membered, nitrogen-containing ring that binds to PBPs, thus making them unable to continue bacterial cell wall synthesis. PBPs are enzymes found in the cell membrane that aid in cross-linking of peptidoglycan during cell wall synthesis [10]. By inactivating PBPs and inhibiting cell wall synthesis, bacterial cell death will occur since the bacterial cells will lyse due to osmotic pressure [11]. There are various crystal structures of Invanz that help to elucidate its mechanism of action and effectiveness against some species of bacteria that are able to resist inhibition by other classes of antibiotics. The is a crystallized structure of Invanz bound to the GES-2 beta-lactamase in Pseudomonas aeruginosa. The GES enzymes are the Guina Extended Spectrum beta-lactamases that help some bacteria resist attack of antibiotics [12]. This crystal structure complex is important for illustrating the acylation event between the GES-2 enzyme and the Ertapenem. While Ertapenem is a broad spectrum antibtiotic, it has reduced efficacy in inhibiting Pseudomonas aeruginosa. In this study, the kinetic activity of GES-1, GES-2, and GES-5 beta-lactamases were examined in order to better understand how these enzymes could confer resistance to carbapenems such as Invanz. In these types of beta-lactamases, a catalytic Serine at position 70 attacks the β-lactam ring of the antibiotic to form an acyl-enzyme intermediate. The Glu-166 acts as a general base to activate a water molecule for deacylation of the enzyme, and the Cys-69 and Cys-238 amino acid residues form a disulfide bond thought to be important for the stability and carbapenemase activity of the beta-lactamase enzyme. This study concluded that GES-1 is the weakest beta-lactamase in conferring resistance to carbapenem antibiotics, while GES-5 is the strongest beta-lactamase and GES-2 is intermediate in its resistance. The deacylating water molecule is retained in the active site of GES-2 due primarily to the presence of an asparagine at position 170, and this structural difference in the GES-2 active site accounts for the tightly bound deacylating water molecule. The hydrogen bonding between the acyl-enzyme complex and this water molecule weakens the GES-2 beta-lactamase’s activation for deacylation. Consequently, this deacylation step is less efficient in GES-2 when compared to GES-5, and thus the carbapenem such as Invanz is able to escape hydrolysis by some but not all the beta-lactamases within P. aeruginosa [13]. The shows was used to better characterize the mechanism of action of by carbapenem antibiotics. PBPs vital for peptidoglycan synthesis are replaced by l,d-transpeptidases (ltds) in an ampicillin-resistant strain of E. faecium and in M. tuberculosis. This structure shows that bacterial strains such as E. faecium and M. tuberculosis are successfully inhibited by ertepenem through acylation of the ltd which prevents the ltd from continuing further cell wall synthesis.Specifically, the beta-lactam ring of the ertapenem acylates the nucleophilic serine that normally catalyzes the transpeptidation reaction during cross-linking of the bacterial cell wall. Ldts are inactivated by β–lactam antibiotics, the carbapenems, via formation of a thioester bond with the active–site cysteine [14]. The and the are structures from a publication that attempted to netter characterize the efficacy of beta-lactam antibiotics such as Invanz in treating M. tuberculosis. Beta-lactam antibiotics are not used often to treat M. tuberculosis since the BlaC enzyme (a beta-lactamase enzyme found in M. tuberculosis) has shown resistance to antibiotics such as Invanz. Like other beta-lactamases, BlaC catalyzes the opening of the β-lactam ring through nucleophilic attack via an active site serine that causes formation of the acylenzyme, followed by the hydrolysis of the ester bond to open the beta-lactam ring and inactive the antibiotic [15].
Ltd Acylation by Ertapenem Mechanism
There are various structural features of Invanz that make make administration of the drug easy. Older carbapenems required patients to take a dehydropeptidase-1 (DHP-1) inhibitor since the DHAP enzyme found in the human renal system could interfere with the action of the carbapenem by degrading the antibiotic [6]. Invanz is a unique antibiotic because it has a (shown in yellow) that shields the beta-lactam carbonyl from DHP-1 degradation [9]. The (shown in green) increases the molecular weight and makes the drug more soluble in non polar solvents. Additionally, the carboxylic acid substituent becomes ionized at physiological pH, so the ertapenem has a net negative charge. Increased solubility in non polar solvents and the net negative charge allows the drug to bind human plasma proteins with an extended half-life in the blood stream, and thus the drug only has to be administered once daily [9]. Invanz largely travels in the bloodstream bound to the human plasma protein albumin [2].
Microbial Action
Invanz can be used to effectively treat the following Gram Positive bacteria: Staphylococcus aureus (methicillin susceptible strains only), Streptococcus agalactiae
Streptococcus pneumoniae (penicillin susceptible strains only), Streptococcus pyogenes, Staphylococcus epidermidis (methicillin susceptible strains only), and Streptococcus pneumoniae (penicillin-intermediate strains). Invanz is effective against the following Gram Negative bacteria: Escherichia coli, Haemophilus influenzae (beta-lactamase negative strains only), Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenzae (beta-lactamase positive strains only), Haemophilus parainfluenzae, Klebsiella oxytoca (not including ESBL producing strains), Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens. Invanz can be used to treat the following anaerobic bacterial species: Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vulgatus, and Clostridium perfringens [2].
Adverse Drug Reactions
Patients with a history of anaphylactic reaction after treatment with beta lactam antibiotics, as well as patients affected by multiple allergens are more susceptible to adverse drug reactions after taking Invanz. Before beginning therapy with Invanz, such individuals should consult with an allergist in regards to any hypersensitivity to other beta-lactams, penicillins and cephalosporins.
Drug-Resistant Bacteria
As with many other antibiotics, extended use of Invanz can lead to the development of drug-resistant bacteria. In order to ensure the effectiveness of the drug, Invanz should only be prescribed to treat a strongly-suspected bacterial infection.
Seizure Potential
Although rare, some adult patients treated with the drug experienced seizures. Seizures are most common in patients with central nervous system (CNS) disorders. In case of seizures, anticonvulsant therapy should be instituted or continued in patients with known seizure disorder. The dosage of the drug should also be re-examined and re-adjusted, accordingly.
Interaction with Valproic Acid
Valproic acid is used to treat patients with bipolar disorders, to prevent migraines, and for different types of seizures. Taking Invanz lowers the concentration of the valproic acid, therefore increasing the risk of seizures and other diseases used to treat the patient. For patients dependent on valproic acid, Invanz is not recommended [16].
References
- ↑ Merck, Sharp, and Dohme Corporation. Highlight of Prescribing Information: Invanz. http://www.merck.com/product/usa/pi_circulars/i/invanz/invanz_pi.pdf (accessed November, 12 2016)
- ↑ 2.0 2.1 2.2 2.3 ...
- ↑ Shaikh S, Fatima J, Shakil S, Rizvi SM, Kamal MA. Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment. Saudi J Biol Sci. 2015 Jan;22(1):90-101. doi: 10.1016/j.sjbs.2014.08.002. Epub, 2014 Aug 17. PMID:25561890 doi:http://dx.doi.org/10.1016/j.sjbs.2014.08.002
- ↑ Shah PM, Isaacs RD. Ertapenem, the first of a new group of carbapenems. J Antimicrob Chemother. 2003 Oct;52(4):538-42. Epub 2003 Sep 1. PMID:12951340 doi:http://dx.doi.org/10.1093/jac/dkg404
- ↑ Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, Noreddin AM, Karlowsky JA. Comparative review of the carbapenems. Drugs. 2007;67(7):1027-52. PMID:17488146
- ↑ 6.0 6.1 ...
- ↑ Stewart NK, Smith CA, Frase H, Black DJ, Vakulenko SB. Kinetic and Structural Requirements for Carbapenemase Activity in GES-Type beta-Lactamases. Biochemistry. 2014 Dec 22. PMID:25485972 doi:http://dx.doi.org/10.1021/bi501052t
- ↑ Hammond ML. Ertapenem: a Group 1 carbapenem with distinct antibacterial and pharmacological properties. J Antimicrob Chemother. 2004 Jun;53 Suppl 2:ii7-9. PMID:15150178 doi:http://dx.doi.org/10.1093/jac/dkh203
- ↑ 9.0 9.1 9.2 ...
- ↑ Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008 Mar;32(2):234-58. doi: 10.1111/j.1574-6976.2008.00105.x., Epub 2008 Feb 11. PMID:18266856 doi:http://dx.doi.org/10.1111/j.1574-6976.2008.00105.x
- ↑ Page, M.L. The mechanisms of reactions of beta lactam antibiotics. Accounts of Chemical Research, 1984, 17(4), 144-151 DOI: 10.1021/ar00100a005
- ↑ Weldhagen GF, Prinsloo A. Molecular detection of GES-2 extended spectrum Beta-lactamase producing Pseudomonas aeruginosa in Pretoria, South Africa. Int J Antimicrob Agents. 2004 Jul;24(1):35-8. PMID:15225858 doi:http://dx.doi.org/10.1016/j.ijantimicag.2003.12.012
- ↑ Kalp M, Carey PR. Carbapenems and SHV-1 beta-lactamase form different acyl-enzyme populations in crystals and solution. Biochemistry. 2008 Nov 11;47(45):11830-7. doi: 10.1021/bi800833u. Epub 2008 Oct, 16. PMID:18922024 doi:http://dx.doi.org/10.1021/bi800833u
- ↑ Lecoq L, Dubee V, Triboulet S, Bougault C, Hugonnet JE, Arthur M, Simorre JP. Structure of Enterococcus faeciuml,d-Transpeptidase Acylated by Ertapenem Provides Insight into the Inactivation Mechanism. ACS Chem Biol. 2013 Apr 12. PMID:23574509 doi:10.1021/cb4001603
- ↑ Lecoq L, Dubee V, Triboulet S, Bougault C, Hugonnet JE, Arthur M, Simorre JP. Structure of Enterococcus faeciuml,d-Transpeptidase Acylated by Ertapenem Provides Insight into the Inactivation Mechanism. ACS Chem Biol. 2013 Apr 12. PMID:23574509 doi:10.1021/cb4001603
- ↑ United States National Institutes of Health. Current Medication Information for INVANZ (Ertapenem sodium) injection, powder, lyphilized for solution. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=33f3b99b-fa82-42e0-26bf-f49891ae3d22 (accessed November 17, 2016)
