Ertapenem

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Ertapenem
Ertapenem.svg
Clinical data
Trade names Invanz
AHFS/Drugs.com Monograph
MedlinePlus a614001
License data
Pregnancy
category
Routes of
administration 		Intramuscular, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90% (intramuscular)
Protein binding Inversely proportional to concentration; 85 to 95%
Metabolism Hydrolysis of beta-lactam ring, CYP not involved
Elimination half-life 4 hours
Excretion Kidney (80%) and fecal (10%)
Identifiers
  • (4R,5S,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H25N3O7S
Molar mass 475.52 g·mol−1
3D model (JSmol)
  • O=C(O)c1cc(ccc1)NC(=O)[C@H]4NC[C@@H](S\C3=C(\N2C(=O)[C@H]([C@H](O)C)[C@H]2[C@H]3C)C(=O)O)C4
  • InChI=1S/C22H25N3O7S/c1-9-16-15(10(2)26)20(28)25(16)17(22(31)32)18(9)33-13-7-14(23-8-13)19(27)24-12-5-3-4-11(6-12)21(29)30/h3-6,9-10,13-16,23,26H,7-8H2,1-2H3,(H,24,27)(H,29,30)(H,31,32)/t9-,10-,13+,14+,15-,16-/m1/s1 Yes check.svgY
  • Key:JUZNIMUFDBIJCM-ANEDZVCMSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ertapenem, sold under the brand name Invanz, is a carbapenem antibiotic medication used for the treatment of infections of the abdomen, the lungs, the upper part of the female reproductive system, and the diabetic foot. [7] [8]

Contents

The most common side effects include diarrhoea, nausea (feeling sick), headache, and problems around the area where the medicine is infused. It can significantly reduce the concentrations of valproic acid, an anti-seizure medication, in the blood to the point where it loses its effectiveness. [6]

Ertapenem was approved for medical use in the United States in November 2001, [5] [9] and in the European Union in April 2002. [6] It is marketed by Merck. [5] [6]

Medical uses

Ertapenem is indicated for the treatment of intra-abdominal infections, community-acquired pneumonia, pelvic infections, and diabetic foot infections, with bacteria that are susceptible to this drug, or expected to be so. It can also be used to prevent infections after colorectal surgery. In the United States it is also indicated for the treatment of complicated urinary tract infections including pyelonephritis. [5] [7] [10] It is a potential effective alternative treatment for ceftriaxone-resistant gonorrhoea. [11] [12]

It is given as an intravenous infusion or intramuscular injection. The drug is not approved for children under three months of age. [5] [7] [10]

Contraindications

The drug is contraindicated in people with known hypersensitivity to ertapenem or other carbapenem type antibiotics, or with severe hypersensitivity reactions (such as anaphylaxis or severe skin reactions) to other beta-lactam antibiotics in the past. [5] [7] [10]

Side effects

Common side effects are diarrhoea (in 5% of people receiving ertapenem), nausea (in 3%) and vomiting, reactions at the injection site (5%, including pain and inflammation of the vein), and headache. Uncommon but possibly serious side effects include candida infections, seizures, skin reactions such as rashes (including nappy rash in children), and anaphylaxis. [10] [13] Hypersensitivity cross-reactions with penicillins are rare. [14]

Ertapenem also can have an effect on some blood tests such as liver enzymes and platelet count. [7] [10]

Overdose

Overdosing is unlikely. In adults receiving the threefold therapeutic dose over eight days, no significant toxicity was observed. [10]

Interactions

Ertapenem can reduce the concentrations of valproic acid, an epilepsy medication, by 70% and perhaps up to 95% within 24 hours; this can result in inadequate control of seizures. [13] [15] The effect is described for other carbapenem antibiotics as well, but seems to be most pronounced for ertapenem and meropenem. [15] This is likely caused by several mechanisms: carbapenems inhibit transport of valproic acid from the gut into the body; they may increase metabolization of valproic acid to its glucuronide; they may reduce enterohepatic circulation and recycling of valproic acid glucuronide by acting against gut bacteria; and they may block transporter proteins that pump valproic acid out of red blood cells into the blood plasma. [16] [17] The effect is also seen in reverse: in cases where ertapenem has been withdrawn blood concentrations of valproate have been reported to rise. [18] [19]

Drug interactions via the cytochrome P450 enzyme system or the P-glycoprotein transporter are considered unlikely, as these proteins are not involved in the metabolism of ertapenem. [10]

Pharmacology

Mechanism of action

Like all beta-lactam antibiotics, ertapenem is bactericidal. [14] It inhibits cross-linking of the peptidoglycan layer of bacterial cell walls by blocking a type of enzymes called penicillin-binding proteins (PBPs). When a bacterial cell tries to synthesize new cell wall in order to grow and divide, the attempt fails, rendering the cell vulnerable to osmotic disruption. Additionally, the surplus of peptidoglycan precursors triggers autolytic enzymes of the bacterium, which disintegrate the existing wall. [20]

Bacteria attempting to grow and divide in the presence of ertapenem shed their cell walls, forming fragile spheroplasts. Penicillin spheroplast generation horizontal.svg
Bacteria attempting to grow and divide in the presence of ertapenem shed their cell walls, forming fragile spheroplasts.

Susceptible bacteria

Bacteria that are normally susceptible to ertapenem treatment (at least in Europe) include: [10]

Resistance

Bacteria that show no clinically relevant response to ertapenem include methicillin-resistant Staphylococcus species (including MRSA) as well as Acinetobacter , Aeromonas , Enterococcus , and Pseudomonas . [10] [14]

Microorganisms can become resistant to ertapenem by producing carbapenemases, enzymes that inactivate the drug by opening the beta-lactam ring. Other mechanisms of resistance against carbapenems are development of efflux pumps that transport the antibiotics out of the bacterial cells, mutations of PBPs, and mutations of Gram-negative bacteria's porins which are necessary for carbapenems to enter the bacteria. [8]

Pharmacokinetics

The main metabolite in humans, which is pharmacologically inactive Ertapenem open-ring metabolite.svg
The main metabolite in humans, which is pharmacologically inactive

The route of administration has only a slight effect on the drug's concentrations in the bloodstream: when given as an intramuscular injection, its bioavailability is 90% (as compared to the 100% availability when given directly into a vein), and its highest concentrations in the blood plasma are reached after about 2.3 hours. In the blood, 85–95% of ertapenem are bound to plasma proteins, mostly albumin. Plasma protein binding is higher for lower concentrations, and vice versa. The drug is only partially metabolized, with 94% circulating in form of the parent substance and 6% as metabolites. The main metabolite is the inactive hydrolysis product with the ring opened. [7]

Ertapenem is mainly eliminated via the kidneys and urine (80%) and to a minor extent via the faeces (10%). Of the 80% found in the urine, 38% is excreted as the parent drug and 37% as the ring-opened metabolite. The biological half-life is about 3.5 hours in women, 4.2 hours in men and 2.5 hours in children up to 12 years of age. [7] [13]

Comparison with other antibiotics

Like all carbapenem antibiotics, ertapenem has a broader spectrum of activity than other beta-lactams like penicillins and cephalosporins. Similar to doripenem, meropenem and biapenem, ertapenem has slightly better activity against many Gram-negative bacteria than other carbapenems such as imipenem. In contrast to imipenem, doripenem and meropenem, it is not active against Enterococcus, Pseudomonas and Acinetobacter species. [8] [14]

For diabetic foot infections, ertapenem as a single treatment or in combination with vancomycin has been found to be more effective and have fewer side effects than tigecycline, but in severe cases it is less effective than piperacillin/tazobactam. [23] [24]

Regarding pharmacokinetics, imipenem, doripenem and meropenem have lower plasma protein bindings (up to 25%) and shorter half-lives (about one hour) than ertapenem. [14]

History

Ertapenem is marketed by Merck. It was approved for use by the US Food and Drug Administration in November 2001, [9] and by the European Medicines Agency in April 2002. [6] [25]

Related Research Articles

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Penicillin</span> Group of antibiotics derived from Penicillium fungi

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous β-lactam antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Imipenem/cilastatin</span> Combination antibiotic medication

Imipenem/cilastatin, sold under the brand name Primaxin among others, is an antibiotic useful for the treatment of a number of bacterial infections. It is made from a combination of imipenem and cilastatin. Specifically it is used for pneumonia, sepsis, endocarditis, joint infections, intra-abdominal infections, and urinary tract infections. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

<span class="mw-page-title-main">Imipenem</span> Carbapenem antibiotic

Imipenem is a synthetic β-lactam antibiotic belonging to the carbapenems chemical class. developed by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria, thus playing a key role in the treatment of infections not readily treated with other antibiotics. It is usually administered through intravenous injection.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

Ampicillin/sulbactam is a fixed-dose combination medication of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the brand name Unasyn, generic only outside the United States, is an intravenous antibiotic. The second, an oral form called sultamicillin, is marketed under the brand name Ampictam outside the United States, and generic only in the United States. Ampicillin/sulbactam is used to treat infections caused by bacteria resistant to beta-lactam antibiotics. Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.

<span class="mw-page-title-main">Flucloxacillin</span> Penicillin

Flucloxacillin, also known as floxacillin, is an antibiotic used to treat skin infections, external ear infections, infections of leg ulcers, diabetic foot infections, and infection of bone. It may be used together with other medications to treat pneumonia, and endocarditis. It may also be used prior to surgery to prevent Staphylococcus infections. It is not effective against methicillin-resistant Staphylococcus aureus (MRSA). It is taken by mouth or given by injection into a vein or muscle.

<span class="mw-page-title-main">Doripenem</span> Chemical compound

Doripenem is an antibiotic drug in the carbapenem class. It is a beta-lactam antibiotic drug able to kill Pseudomonas aeruginosa.

<span class="mw-page-title-main">Cefoxitin</span> Chemical compound

Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

<span class="mw-page-title-main">Thienamycin</span> Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae (CPE) are Gram-negative bacteria that are resistant to the carbapenem class of antibiotics, considered the drugs of last resort for such infections. They are resistant because they produce an enzyme called a carbapenemase that disables the drug molecule. The resistance can vary from moderate to severe. Enterobacteriaceae are common commensals and infectious agents. Experts fear CRE as the new "superbug". The bacteria can kill up to half of patients who get bloodstream infections. Tom Frieden, former head of the Centers for Disease Control and Prevention has referred to CRE as "nightmare bacteria". Examples of enzymes found in certain types of CRE are KPC and NDM. KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes, as well as the enzyme VIM have also been reported in Pseudomonas.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

References

  1. ↑ "Ertapenem (Invanz) Use During Pregnancy". Drugs.com. 24 January 2020. Retrieved 29 July 2020.
  2. ↑ "INVANZ ertapenem (as sodium) 1g powder for injection vial (81449)". Therapeutic Goods Administration (TGA). 12 August 2022. Retrieved 21 April 2023.
  3. ↑ "TGA eBS - Product and Consumer Medicine Information Licence".
  4. ↑ "Invanz 1g powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). Retrieved 29 July 2020.
  5. 1 2 3 4 5 6 7 "Invanz- ertapenem sodium injection, powder, lyophilized, for solution". DailyMed. 13 February 2020. Retrieved 29 July 2020.
  6. 1 2 3 4 5 "Invanz EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. 1 2 3 4 5 6 7 8 "Ertapenem Sodium Monograph for Professionals". Drugs.com. The American Society of Health-System Pharmacists. 29 June 2020. Retrieved 29 July 2020.
  8. 1 2 3 Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (November 2011). "Carbapenems: past, present, and future". Antimicrobial Agents and Chemotherapy. 55 (11): 4943–4960. doi: 10.1128/AAC.00296-11 . PMC   3195018 . PMID   21859938.
  9. 1 2 "Drug Approval Package: Invanz I.V. or I.M. (Ertapenem Sodium) NDA #21-337". U.S. Food and Drug Administration (FDA). 20 November 2001. Retrieved 29 July 2020.
  10. 1 2 3 4 5 6 7 8 9 "Invanz: EPAR – Product Information" (PDF). European Medicines Agency. 19 November 2019.
  11. ↑ de Vries HJ, de Laat M, Jongen VW, Heijman T, Wind CM, Boyd A, et al. (May 2022). "Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhoea (NABOGO): a randomised, non-inferiority trial". The Lancet. Infectious Diseases. 22 (5): 706–717. doi:10.1016/S1473-3099(21)00625-3. PMID   35065063. S2CID   246129045.
  12. ↑ "Antibiotic Ertapenem is alternative drug in treatment of gonorrhea". Amsterdam UMC. 20 January 2022. Retrieved 8 July 2022.
  13. 1 2 3 "Ertapenem". mediQ. Retrieved 29 July 2020.
  14. 1 2 3 4 5 Mutschler E (2013). Arzneimittelwirkungen (in German) (10th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 740, 753. ISBN   978-3-8047-2898-1.
  15. 1 2 Wu CC, Pai TY, Hsiao FY, Shen LJ, Wu FL (October 2016). "The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations". Therapeutic Drug Monitoring. 38 (5): 587–592. doi:10.1097/FTD.0000000000000316. PMID   27322166. S2CID   25445129.
  16. ↑ Mancl EE, Gidal BE (December 2009). "The effect of carbapenem antibiotics on plasma concentrations of valproic acid". The Annals of Pharmacotherapy. 43 (12): 2082–2087. doi:10.1345/aph.1M296. PMID   19934386. S2CID   207263641.
  17. ↑ Arzneimittel-Interaktionen (in German). Österreichischer Apothekerverlag. 2019. p. 760. ISBN   978-3-85200-254-5.
  18. ↑ Zaccara G (31 December 2012). "Antiepileptic drugs". In Aronson JK (ed.). Side Effects of Drugs Annual 34: A worldwide yearly survey of new data in adverse drug reactions. Newnes. p. 121. ISBN   978-0-444-59503-4.
  19. ↑ Liao FF, Huang YB, Chen CY (August 2010). "Decrease in serum valproic acid levels during treatment with ertapenem". American Journal of Health-System Pharmacy. 67 (15): 1260–1264. doi:10.2146/ajhp090069. PMID   20651316.
  20. ↑ "Beta lactam antibiotics". StatPearls. 2020. PMID   31424895.
  21. ↑ Cushnie TP, O'Driscoll NH, Lamb AJ (December 2016). "Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action". Cellular and Molecular Life Sciences. 73 (23): 4471–4492. doi:10.1007/s00018-016-2302-2. hdl: 10059/2129 . PMID   27392605. S2CID   2065821.
  22. ↑ CID 45105276 from PubChem . Accessed 30 July 2020.
  23. ↑ Selva Olid A, Solà I, Barajas-Nava LA, Gianneo OD, Bonfill Cosp X, Lipsky BA (September 2015). "Systemic antibiotics for treating diabetic foot infections". The Cochrane Database of Systematic Reviews. 2015 (9): CD009061. doi:10.1002/14651858.CD009061.pub2. PMC   8504988 . PMID   26337865.
  24. ↑ Tchero H, Kangambega P, Noubou L, Becsangele B, Fluieraru S, Teot L (September 2018). "Antibiotic therapy of diabetic foot infections: A systematic review of randomized controlled trials". Wound Repair and Regeneration. 26 (5): 381–391. doi:10.1111/wrr.12649. PMID   30099812. S2CID   51966152.
  25. ↑ "Invanz: EPAR – Summary for the public" (PDF). European Medicines Agency. 2 December 2016.
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