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.
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.
Antibiotics: The Need for Innovation
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
For these penicillin analogues, susceptibility to β-lactamase is an issue. However, when used in combination with clavulanic acid, the scope of antibiotics such as amoxicillin is greatly improved. Administered to the patient as Augmentin, the dose level of amoxicillin can be greatly decreased when used in combination with clavulanic acid because clavulanic acid is an irreversible inhibitor of most β-lactamases. It was first isolated from Streptomyces clavuligerus by Beechams in 1976.
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].
Pharmacotherapeutic advances for recurrent urinary tract infections in women
Published in Expert Opinion on Pharmacotherapy, 2020
Mohamad Moussa, Mohamed Abou Chakra, Athanasios Dellis, Yasmin Moussa, Athanasios Papatsoris
Currently, PV alone is the available therapeutic option to treat uncomplicated UTIs by ESBL producers. However, in vitro data suggest that combinations with a β-lactamase inhibitor (e.g. clavulanic acid) are likely to result in a better result [124]. A trial was done to analyze the sensitivity rates of ESBL-producing Enterobacteriaceae to mecillinam from urine samples and to document if PV is a suitable alternative option in the treatment of UTIs. E. Coli was the most common organism, followed by Klebsiella species and other Enterobacteriaceae. Mecillinam sensitivity was found in 96% of E. Coli, 83% of Klebsiella species and 88% of other Enterobacteriaceae. Overall 95% of ESBL-producing urinary isolates were sensitive to mecillinam. PV appears to be a suitable option to treat ESBL-producing Enterobacteriaceae causing uncomplicated UTIs [127]. In a prospective, multi-center, observational cohort study PV given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production [128].
Appropriateness of empirical antibiotic therapy and added value of adjunctive gentamicin in patients with septic shock: a prospective cohort study in the ICU
Published in Infectious Diseases, 2021
Rob G. H. Driessen, Rald V. M. Groven, Johan van Koll, Guy J. Oudhuis, Dirk Posthouwer, Iwan C. C. van der Horst, Dennis C. J. J. Bergmans, Ronny M. Schnabel
Patients receiving gentamicin were more often treated with amoxicillin/clavulanic acid than patients receiving monotherapy in this study (44 vs 24%, p = .002). We believe this can be explained by the fact that in the gentamicin group, more patients are admitted directly from the emergency department (40 vs 21%). Amoxicillin/clavulanic acid is the first choice antibiotic therapy for patients admitted from out-of-hospital according to the antibiotic treatment protocol in our centre. Although more patients in the monotherapy group received meropenem, this difference was not statistically different between both groups (10 vs 5%, p = .175). The fact that less patients in the combination group received broad spectrum antibiotics, could also be explained as an advantage of gentamicin combination therapies.
Related Knowledge Centers
- Antibiotic
- Antimicrobial Resistance
- Bacteria
- Suicide Inhibition
- Beta-Lactam Antibiotics
- Β-Lactamase Inhibitor
- Beta-Lactamase
- Amoxicillin
- Amoxicillin/Clavulanic Acid
- Veterinary Medicine