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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Imipenem (IMP) and meropenem (MRP) are highly water-soluble weak acids (log P −3.9 and −4.4, pKa 3.2 and 3.47–9.39, MW 299.3 and 383.15). Both are synthetic derivatives of thienamycin, a natural product of Streptomyces cattleya. Carbapenems target multiple transpeptidases (penicillin-binding proteins) involved in bacterial cell-wall synthesis including the unique l,d-transpeptidases characteristic of mycobacteria.270 However, M. tuberculosis possesses an extended spectrum class A β-lactamase (BlaC), which must be inactivated for in vitro activity of the drugs.271 Clavulanic acid is the most potent inhibitor of BlaC among licensed β-lactamase inhibitors.272 MIC99s of meropenem–clavulanate in wild-type MDR and XDR strains range from 0.125 to 2 μg/mL.273
Ultraviolet and Light Absorption Spectrometry
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Zoltan M. Dinya, Ferenc J. Sztaricskai
Thienamycin [(27), R = NH+3], shows absorbance at 296.5 nm in aqueous solution (ε = 790 m2/mol) [44], assignable to a π→π* type of absorption of β-thioalkyl-α, β-unsaturated carboxylic acids [111].
Imipenem–Cilastatin and Imipenem–Relebactam
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Yoshiro Hayashi, David L. Paterson
In the 1970s Beecham Research Laboratories identified a carbapenem group called olivanic acids, which were beta-lactamase inhibitors and broad spectrum antibiotics (Butterworth et al., 1979). At about the same time, Merck, Sharp and Dohme Research Laboratories independently identified thienamycin, derived from Streptomyces cattleya. This had the same carbapenem nucleus but different side chains, which increased its antibacterial potency (Cassidy et al., 1981). Its chemical instability in concentrated solution was overcome by crystallization of the N-formimidoyl derivative of thienamycin, called imipenem. Urinary recovery In vivo was less than expected due to extensive renal tubular metabolism by a brush border dipeptidase enzyme, dehydropeptidase I. A selective competitive antagonist of this enzyme was then developed and named cilastatin, which has similar pharmacokinetics to imipenem. Imipenem and cilastatin are marketed in combination in a 1:1 ratio (Kahan et al.,1983). Cilastatin not only prevents the degradation of imipenem but may also protect the kidneys against potential toxic effects exerted by higher doses of imipenem (Rodloff et al., 2006). The chemical structure of imipenem is shown in Figure 37.1.
Selected strategies to fight pathogenic bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Aiva Plotniece, Arkadij Sobolev, Claudiu T. Supuran, Fabrizio Carta, Fredrik Björkling, Henrik Franzyk, Jari Yli-Kauhaluoma, Koen Augustyns, Paul Cos, Linda De Vooght, Matthias Govaerts, Juliana Aizawa, Päivi Tammela, Raivis Žalubovskis
Doripenem is a new thienamycin-inspired antibiotic, which can be used parenterally. Thienamycin, isolated from Streptomyces cattleya in 1976, was found highly activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase, however, this compound was too metabolically unstable to be further developed9. The thienamycin analogue doripenem has an enhanced metabolic stability to renal dehydropeptidase-1 due to the 1β-methyl substituent in the carbapenem skeleton10. Doripenem is a broad-spectrum antibiotic against many pathogenic bacteria, including the Gram-negative Pseudomonas aeruginosa. The key synthetic step (Scheme 3) is a coupling between the 4-nitrobenzyl-protected enol phosphate and substituted 3-mercaptopyrrolidine11.
A plethora of carbapenem resistance in Acinetobacter baumannii: no end to a long insidious genetic journey
Published in Journal of Chemotherapy, 2021
Abolfazl Vahhabi, Alka Hasani, Mohammad Ahangarzadeh Rezaee, Behzad Baradaran, Akbar Hasani, Hossein Samadi Kafil, Faeze Abbaszadeh, Leila Dehghani
Carbapenem resistance is an on-going concern as carbapenems, including imipenem and meropenem, had a potent activity against A. baumannii and were often used as the last resort for the treatment of infections caused by MDR A. baumannii. Carbapenems have a good bactericidal activity, are stable towards a range of β-lactamases, possess broad-spectrum activity and a good safety profile.20,21 The first carbapenem discovered was olivanic acid produced by Streptomyces olivaceus. This was followed by the discovery of thienamycin in 1976. Years later, a more stable thienamycin derivative known as imipenem was synthesized and approved for use in 1984. Other carbapenems for parenteral administration were discovered later and included biapenem, panipenem, lenapenem and ertapenem. Carbapenems are recommended for the empirical treatment of a variety of severe infections and they are generally well tolerated in the human body except certain treatable allergic reactions.21,22 In parallel with the increase in carbapenem use and increase in A. baumannii infections there has been an increase in the rise of not only carbapenem resistance, but also resistance towards majority of other antibiotics (except the polymyxins or tigecycline). Imipenem resistance was first described in 1985 and since then carbapenem resistance in A. baumannii became increasingly common.20–22
Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections
Published in Expert Opinion on Pharmacotherapy, 2020
S.G. Kuiper, E. Leegwater, E.B. Wilms, C. van Nieuwkoop
Imipenem is, like all carbapenems, a derivate of thienamycin. Thienamycin is produced by Streptomyces cattleya, as well as penicillin. Carbapenems contain a β-lactam structure but differ to penicillin by having a double-bond link between carbon atoms in positions 2 and 3 and having a carbon atom instead of sulfur in position 1. Imipenem is the N-formimidoyl derivate of thienamycin and in contrast to thienamycin, has a formamidine sidechain at carbon 2 instead of cysteamine [6,7]. This improves the chemical stability of imipenem. Imipenem is a substrate for renal dehydropeptidase-1 (DHP-1). Therefore, it is needed to add cilastatin (a DHP-1 inhibitor) to increase the urinary concentration and renal recovery rate [8].