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Beta-Lactamase Inhibitors
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
Pascalis Vergidis, Matthew E. Falagas
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.
Hydrolytic activity of KPC-producing Klebsiella pneumoniae clinical isolates
Published in Journal of Chemotherapy, 2022
Vincent H. Tam, Cole S. Hudson, Paul R. Merlau, Ryan K. Shields
Carbapenem-resistant Enterobacterales is an urgent antibiotic resistance threat [1]. In the U.S., carbapenem resistance in Enterobacterales is primarily due to the production of serine-based carbapenemase (e.g. KPC). Clinical isolates expressing KPC could be resistant to a broad range of antimicrobial agents, limiting effective treatment options. Notably, the hydrolytic activity of these isolates varies as a function of bacterial density at the site of infection (e.g. empyema vs. uncomplicated urinary tract infection), enzyme variants (e.g. KPC-2 vs. KPC-3), presence of other beta-lactamases and their transcriptional levels, as well as substrate stability. Novel beta-lactamase inhibitors (e.g. avibactam, vaborbactam, relebactam) have been used to restore the activity of beta-lactam agents, when they are used in combination [2]. These beta-lactamase inhibitors are expected to reduce enzymatic degradation of the partnering beta-lactam agents and preserve their therapeutic effect. Theoretically, the effective concentration needed for a beta-lactamase inhibitor should match (or exceed) the hydrolytic activity of the target isolates. Where available, molecular testing in microbiology laboratories aims to detect the presence of target beta-lactamase genes, but not the functional capacity quantitatively. Accordingly, routine testing may not be very informative to guide dosing of beta-lactamase inhibitors. We examined the hydrolytic activity of several KPC-positive isolates to provide insights on the utility of this approach.
Lemierre’s syndrome with muscle necrosis and chronic osteomyelitis
Published in Baylor University Medical Center Proceedings, 2021
Azka Latif, Muhammad Junaid Ahsan, Amman Yousaf, Asim Tameezuddin, Akshat Sood, Joseph Thirumalareddy
The management of LS warrants an integrated approach from different specialties. Antibiotics are the mainstay of treatment, but there is a lack of consensus on specific agents. Ideally, antibiotic therapy should include at least one beta-lactamase inhibitor. As a combination drug, metronidazole has shown promising results in LS, but our patient had progression of myositis even on metronidazole. Different antibiotics, including beta-lactam drugs and clindamycin, can be employed as single-agent regimens. We used a combination of piperacillin/tazobactam and daptomycin to counter the infection. As an antipseudomonal drug, piperacillin/tazobactam was used for Fusobacterium. Daptomycin was added against the gram-positive bacteria, as the patient had a positive nasal swab test. The duration of antibiotic therapy is prolonged—at least 3 to 6 weeks.11
Synthesis and evaluation of polymeric micelle containing piperacillin/tazobactam for enhanced antibacterial activity
Published in Drug Delivery, 2019
Milani Morteza, Salehi Roya, Hamishehkar Hamed, Zarebkohan Amir, Akbarzadeh Abolfazl
Antibiotic treatment of this pathogen is extremely difficult due to multiple resistance mechanisms, such as b-lactamases, efflux pumps, and the impermeability of the outer membrane (Bassetti et al., 2018). In fact, this leads to a serious limitation of the options for the treatment of P. aeruginosa infections. Nowadays several antibiotics are used to treat P. aeruginosa infections. Piperacillin is a potent, broad-spectrum ureidopenicillin that is used against gram-negative, gram-positive and anaerobic bacteria. When combined with beta-lactamase inhibitors such as tazobactam, it demonstrates a broader spectrum of activity against lactamase-producing bacteria. For its spectrum of activity, Piperacillin/tazobactam is a β-lactam/β-lactamase inhibitor combination widely employed in first-line therapy, particularly for nosocomial infections (Grant et al., 2002; Fonseca et al., 2004; Lodise et al., 2007). Based on some studies, treatment with subinhibitory concentrations of antibiotics may be effective on bacterial virulence factors, such as adherence, motility and biofilm formation (Wolter & McCormack, 1998; Wilson et al., 2002; Fonseca et al., 2004). The emergence of multidrug-resistant pathogens including cephalosporins and fluoroquinolones has led to the use of Piperacillin/Tazobactam. On the other hand, Piperacillin/Tazobactam is considered a safe antimicrobial agent and has fewer side effects than penicillin derivatives.