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]
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]
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of red blood cells into the blood plasma.[16][17] The effect is also seen in reverse: in cases where ertapenem has been withdrawn blood concentrations of valproate have been reported to rise.[18][19]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]
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.[21]
Susceptible bacteria
Bacteria that are normally susceptible to ertapenem treatment (at least in Europe) include:[10]
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[7][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.[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]
^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. PMID35065063. S2CID246129045.
^ abcdeMutschler E (2013). Arzneimittelwirkungen (in German) (10th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 740, 753. ISBN978-3-8047-2898-1.
^ abWu 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. PMID27322166. S2CID25445129.
^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. PMID19934386. S2CID207263641.
^Arzneimittel-Interaktionen (in German). Österreichischer Apothekerverlag. 2019. p. 760. ISBN978-3-85200-254-5.
^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. ISBN978-0-444-59503-4.
^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. PMID20651316.
^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. PMID27392605. S2CID2065821.
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