Beta-Lactamase Inhibitors
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 in Kucers’ The Use of Antibiotics, 2017
Beta-lactamase inhibitors are used in combination with beta-lactam antibiotics to prevent their destruction by various beta-lactamases. Clavulanic acid is a potent inhibitor of many beta-lactamases (Reading et al., 1983). The drug binds initially beta-lactamases and functions as a competitive inhibitor; this is followed by acylation of these enzymes through the beta-lactam carbonyl part of the clavulanic acid molecule. This mechanism is similar to the reaction between a beta-lactamase and a labile beta-lactam antibiotic, such as penicillin G. In the latter case, the acyl enzyme undergoes rapid hydrolysis to release active enzyme, again together with penicillin-degradation products. By contrast, the acyl enzyme formed by reaction with clavulanic acid is hydrolyzed only very slowly, and therefore the enzyme is transiently inhibited. Beta-lactamases differ in their susceptibility to inhibition by clavulanic acid. Those that are readily inhibited include staphylococcal and E. faecalis beta-lactamases and the plasmid-mediated enzymes (e.g. TEM-1), which are widespread among the Enterobacteriaceae, P. aeruginosa, H. influenzae, N. gonorrhoeae, and M. catarrhalis. Clavulanic acid is a more potent inhibitor compared to sulbactam for both conventional- and extended-spectrum beta-lactamases (Payne et al., 1994). Overall, clavulanic acid and tazobactam had similar potency against both sets of enzymes.
Evidence-Based Approach to Therapy
Mark A. Richardson, Norman R. Friedman in Clinician’s Guide to Pediatric Sleep Disorders, 2016
Al-Ghamdi et al. (72) performed an open-label pilot study of five days of oral prednisone on nine children with OSA. There was no improvement in symptomatology, sleep-study indices or tonsil and adenoid size. There have been two studies evaluating oral antibiotics. Sclafani et al. (73) performed a prospective, randomized, double-blind, placebo-controlled trial of 30 days of amoxicillin/clavulanate potassium in 168 children with obstructive symptoms. Sleep studies were not performed. Treatment with the antibiotic significantly reduced the need for T&A at one-month follow-up as compared to placebo (37.5% vs. 62.7%). By 24 months, most of the children in both groups had undergone T&A (83.3% of the study group vs. 98.0% of the placebo group). Don et al. (74) performed a randomized, double-blind, placebo-controlled trial of 30 days of azithromycin in 22 children with OSA documented by PSG. There were no significant differences in sleep-study indices, tonsil size, or symptoms in the azithromycin group as compared to the placebo group. These preliminary studies suggest that these therapies are not indicated for children with severe OSA, but may have a role in the treatment of milder SDB or for temporary relief of symptoms.
Surgical infection
Professor Sir Norman Williams, Professor P. Ronan O’Connell, Professor Andrew W. McCaskie in Bailey & Love's Short Practice of Surgery, 2018
Ampicillin and amoxicillin are b-lactam penicillins and can be taken orally or may be given parenterally. Both are effective against Enterobacteriaceae, Enterococcus faecalis and the majority of group D streptococci, but not species of Klebsiella or Pseudomonas. Clavulanic acid has no antibacterial activity itself, but it does inactivate P-lactamases, so can be used in conjunction with amoxicillin. The combination is known as co-amoxiclav and is useful against P-lactamase producing bacteria that are resistant to amoxicillin on its own. These include resistant strains of Staphylococcus aureus, E. coli, Haemophilus influenzae, Bacteroides and Klebsiella.
A review on the mechanistic details of OXA enzymes of ESKAPE pathogens
Published in Pathogens and Global Health, 2023
Fatma Gizem Avci, Ilgaz Tastekil, Amit Jaisi, Pemra Ozbek Sarica, Berna Sariyar Akbulut
The alarming increase in the transmission of multidrug-resistant (MDR) pathogenic bacteria, especially those expressing extended-spectrum β-lactamases, makes it very difficult to cope with such bacteria using existing drugs and approaches. Furthermore, the most widely used β-lactamase inhibitors of combinatorial treatments in the clinic are commonly ineffective against class B, C, and D enzymes. Prudent support for the development of new antibiotics and alternative solutions are required to avoid antibacterial agents exhibiting cross-resistance [92]. In this context, the focus is turned to nature, which serves as a rich source for untapped novel bioactive compounds. Indeed, clavulanic acid, the first β-lactamase inhibitor introduced into clinical medicine, is a natural product [3]. These compounds can be administered alone or in combinatorial therapies to fight against increased incidences of antibiotic resistance. Thus, natural products obtained from different sources, which are not limited to microbial and plant cells, play key roles in the discovery of new molecules with distinct antimicrobial mechanisms and multi-target properties [93].
Iatrogenic factors of Helicobacter pylori eradication failure: lessons from the frontline
Published in Expert Review of Anti-infective Therapy, 2023
Jinliang Xie, Dingwei Liu, Jianxiang Peng, Shuang Wu, Dongsheng Liu, Yong Xie
In addition, amoxicillin-clavulanate potassium and other uncommonly used or ineffective antibiotics were used in H. pylori eradication. It was irrational for some patients to treat H. pylori infection using amoxicillin-clavulanate potassium instead of amoxicillin. In an RCT study, bismuth quadruple therapy with amoxicillin-clavulanate and tetracycline showed 17.4% eradication rate by per-protocol analyses [31]. Clavulanate potassium is known as a β-lactamase inhibitor, while H. pylori do not produce β- lactamase, the addition of clavulanate potassium agent in the H. pylori treatment is maybe ineffective. Secondly, clavulanate potassium will exceed the normal dosage to meet the amoxicillin standard dose and increase the risk of drug-induced liver damage consequently. Otherwise, an insufficient dose of amoxicillin may reduce the efficacy and lead to eradication failure. At present, there is no consensus to recommend amoxicillin-clavulanate potassium to treat H. pylori infection. Besides, some patients used other not recommended or ineffective antibiotics, such as gentamicin, azithromycin, roxithromycin, etc. These antibiotics are not verified by clinical trials so they may affect the efficacy [9,22]. Moreover, some other not recommended treatments were used, such as non-high dual dose therapy, only one antibiotic therapy, etc. These informal treatments with an insufficient dose of regimens should be avoided to reduce the risk of treatment failure.
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
Vaborbactam (Scheme 2) is an example of a synthetic β-lactamase inhibitor that is used in combination with meropenem, an intravenous β-lactam antibiotic susceptible to degradation by metallo-β-lactamases. The FDA-approved meropenem-vaborbactam combination complements other β-lactamase inhibitors, such as clavulanic acid, a secondary metabolite of Streptomyces clavuligerus. The Klebsiella pneumoniae β-lactamase is only weakly inhibited by clavulanic acid, which therefore has no clinically relevant use against infections caused by K. pneumoniae7. Vaporbactam is a potent inhibitor of K. pneumonia carbapenemase with no observable concomitant off-target inhibition of mammalian serine proteases. However, vaborbactam does not inhibit class B metallo-β-lactamases, thus, further search for compounds with even wider β-lactamase spectrum is warranted. The key steps in the vaborbactam synthesis involve iridium (I)-catalyzed regioselective hydroboration of an allyl precursor, stereoselective chloromethylation of pinanediol boronate, and a stereospecific substitution of the chloro substituent with lithium hexamethylsilazide8.
Related Knowledge Centers
- Antibiotic
- Antimicrobial Resistance
- Bacteria
- Suicide Inhibition
- Amoxicillin
- Beta-Lactam Antibiotics
- Β-Lactamase Inhibitor
- Beta-Lactamase
- Amoxicillin/Clavulanic Acid
- Veterinary Medicine