Ertapenem

Ertapenem
Names
Trade namesInvanz, others
IUPAC name
  • (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
Clinical data
Drug classCarbapenem[1]
Main usesPneumonia, diabetic foot infection, intra-abdominal infection[1][2]
Side effectsDiarrhea, nausea, headache, rash, pain at the site of delivery[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3[4]
  • US: N (Not classified yet)[4]
    Routes of
    use    		Intramuscular, intravenous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa614001
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability90% (intramuscular)
    Protein bindingInversely proportional to concentration; 85 to 95%
    MetabolismHydrolysis of beta-lactam ring, CYP not involved
    Elimination half-life4 hours
    ExcretionKidney (80%) and fecal (10%)
    Chemical and physical data
    FormulaC22H25N3O7S
    Molar mass475.52 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    • 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 checkY
    • Key:JUZNIMUFDBIJCM-ANEDZVCMSA-N checkY

    Ertapenem, sold under the brand name Invanz among others, is an antibiotic used for the treatment of infections in the abdomen, pneumonia, upper female reproductive system, urinary tract, and diabetic foot.[1][2] It is given by injection into a vein or muscle.[1]

    Common side effects include diarrhea, nausea, headache, rash, and pain at the site of delivery.[3] Other side effects may include Clostridium difficile-associated colitis, seizures, and allergic reactions including anaphylaxis.[1] Use during pregnancy and breastfeeding appears to be safe, but has not been well studied.[8] It is in the carbapenem family of medications, which usually results in the death of the bacteria.[1]

    Ertapenem was approved for medical use in the United States in 2001 and Europe in 2002.[1][3] It is avaliable as a generic medication.[2] In the United Kingdom it costs the NHS about £32 per dose.[2] In the United States it costs about 34 USD per dose as of 2021.[9]

    Medical uses

    Ertapenem is used 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.[7][10][11]

    It is given as an intravenous infusion or intramuscular injection. It is not approved for children under three months of age.[7][10][11]

    Dosage

    It is used at a dose of 1 gram once per day.[2]

    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.[7][10][11]

    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.[11][12] Hypersensitivity cross-reactions with penicillins are rare.[13]

    Ertapenem also can have an effect on some blood tests such as liver enzymes and platelet count.[10][11]

    Overdose

    Overdosing is unlikely. In adults receiving the threefold therapeutic dose over eight days, no significant toxicity was observed.[11]

    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.[12][14] The effect is described for other carbapenem antibiotics as well, but seems to be most pronounced for ertapenem and meropenem.[14] 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.[15][16] The effect is also seen in reverse: in cases where ertapenem has been withdrawn blood concentrations of valproate have been reported to rise.[17][18]

    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.[11]

    Pharmacology

    Mechanism of action

    Main article: β-lactam antibiotic § Mechanism of action

    Like all beta-lactam antibiotics, ertapenem is bactericidal.[13] 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.[19]

    Bacteria attempting to grow and divide in the presence of ertapenem shed their cell walls, forming fragile spheroplasts.[20]

    Susceptible bacteria

    Bacteria that are normally susceptible to ertapenem treatment (at least in Europe) include:[11]

    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.[11][13]

    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.[21]

    Pharmacokinetics

    The main metabolite in humans, which is pharmacologically inactive[10][22]

    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.[10]

    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.[10][12]

    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.[21][13]

    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.[13]

    History

    The drug is marketed by Merck. It was approved for use by the US Food and Drug Administration on 21 November 2001[25] and by the European Medicines Agency on 18 April 2002.[3][26]

    References

    1. 1 2 3 4 5 6 7 "Ertapenem Monograph for Professionals". Drugs.com. Archived from the original on 19 January 2021. Retrieved 23 July 2021.
    2. 1 2 3 4 5 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 548. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    3. 1 2 3 4 5 "Invanz EPAR". European Medicines Agency (EMA). Archived from the original on 12 November 2020. Retrieved 29 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    4. 1 2 "Ertapenem (Invanz) Use During Pregnancy". Drugs.com. 24 January 2020. Archived from the original on 24 September 2020. Retrieved 29 July 2020.
    5. ↑ "Summary for ARTG Entry:81449 Invanz ertapenem (as sodium) 1g powder for injection vial" (PDF). Retrieved 29 July 2020.
    6. ↑ "Invanz 1g powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 20 September 2020. Retrieved 29 July 2020.
    7. 1 2 3 4 5 "Invanz- ertapenem sodium injection, powder, lyophilized, for solution". DailyMed. 13 February 2020. Archived from the original on 24 February 2021. Retrieved 29 July 2020.
    8. ↑ "Ertapenem (Invanz) Use During Pregnancy". Drugs.com. Archived from the original on 24 September 2020. Retrieved 23 July 2021.
    9. ↑ "Ertapenem Prices and Ertapenem Coupons - GoodRx". GoodRx. Archived from the original on 3 May 2016. Retrieved 23 July 2021.
    10. 1 2 3 4 5 6 7 "Ertapenem Sodium Monograph for Professionals". Drugs.com. The American Society of Health-System Pharmacists. 29 June 2020. Archived from the original on 24 September 2020. Retrieved 29 July 2020.
    11. 1 2 3 4 5 6 7 8 9 "Invanz: EPAR – Product Information" (PDF). European Medicines Agency. 2019-11-19. Archived (PDF) from the original on 2021-08-28. Retrieved 2020-12-26.
    12. 1 2 3 "Ertapenem". mediQ. Archived from the original on 2020-07-30. Retrieved 2020-07-29.
    13. 1 2 3 4 5 Mutschler E (2013). Arzneimittelwirkungen (in German) (10 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 740, 753. ISBN 978-3-8047-2898-1.{{cite book}}: CS1 maint: unrecognized language (link)
    14. 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): 587–92. doi:10.1097/FTD.0000000000000316. PMID 27322166. S2CID 25445129.
    15. ↑ Mancl EE, Gidal BE (December 2009). "The effect of carbapenem antibiotics on plasma concentrations of valproic acid". The Annals of Pharmacotherapy. 43 (12): 2082–7. doi:10.1345/aph.1M296. PMID 19934386. S2CID 207263641.
    16. ↑ Arzneimittel-Interaktionen (in Deutsch). Österreichischer Apothekerverlag. 2019. p. 760. ISBN 978-3-85200-254-5.
    17. ↑ Zaccara G (2012-12-31). "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. Archived from the original on 2021-08-28. Retrieved 2020-12-26.
    18. ↑ 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): 1260–4. doi:10.2146/ajhp090069. PMID 20651316.
    19. ↑ Pandey N, Cascella M (2020). "Beta lactam antibiotics". StatPearls. PMID 31424895. Archived from the original on 2020-12-15. Retrieved 2020-12-26.
    20. ↑ 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. Archived from the original on 2019-08-05. Retrieved 2020-12-26.
    21. 1 2 Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (November 2011). "Carbapenems: past, present, and future". Antimicrobial Agents and Chemotherapy. 55 (11): 4943–60. doi:10.1128/AAC.00296-11. PMC 3195018. PMID 21859938.
    22. ↑ "Hydrolysed ertapenem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 28 August 2021. Retrieved 22 July 2021.
    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 (9): CD009061. doi:10.1002/14651858.CD009061.pub2. 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. ↑ "Drug Approval Package: Invanz I.V. or I.M. (Ertapenem Sodium) NDA #21-337". U.S. Food and Drug Administration (FDA). 20 November 2001. Archived from the original on 3 April 2021. Retrieved 29 July 2020.
    26. ↑ "Invanz: EPAR – Summary for the public" (PDF). European Medicines Agency. 2016-12-02. Archived (PDF) from the original on 2021-08-28. Retrieved 2020-12-26.
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