Invanz Sandbox

From Proteopedia

Revision as of 13:16, 19 November 2016

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 that can be administered intramuscularly (Merck, Sharpe, and Dohme Corporation).

Function

Function: Invanz is used to treat a range of bacterial infections caused by Gram positive and Gram negative bacteria 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 (Merck, Sharp, and Dohme Corporation). 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 ^[1]. The unique structural features of Invanz equip this drug with some of the widest spectrum and most potent antimicrobial activity of carbapenem antibiotics today ^[2].

Structural highlights

Structure: Invanz 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 ^[3]. Antibiotic resistance to carbapenems largely results from ability of the bacterial species to secrete beta-lactamase enzymes that can degrade the antimicrobial. Invanz has resistance to many beta-lactamases since it has a trans-1-hydroxyethyl group that confers resistance of the antibiotic to degradation by most beta-lactamases ^[4]. The beta lactam ring 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 ^[5]. By inactivating PBPs and inhibiting cell wall synthesis, bacterial cell death will occur as the cells lyse due to osmotic pressure (Page, 1984).

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 1-beta-methyl substituent that shields the beta-lactam carbonyl from DHP-1 degradation ^[7]. The meta-substituted benzoic acid substituent increases the molecular weight and makes the drug more soluble in nonpolar solvents. Additionally, the carboxylic acid substituent becomes ionized at physiological pH, so the ertapenem has a net negative charge. Increased solubility in nonpolar 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 (Hammond et al., 2007). Invanz largely travels in the bloodstream bound to the human plasma protein albumin (Merck, Sharp, and Dohm).

Image:Invanz.jpg

Microbial Action

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 (Merck, Sharp, and Dohme).

Adverse Drug Reactions

Hypersensitivity 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 (United States National Institutes of Health).

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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

6. 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).

7. Page, M.L. The mechanisms of reactions of beta lactam antibiotics. Accounts of Chemical Research, 1984, 17(4), 144-151.

8. 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).