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.
Peritonitis (General Considerations)
Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams in Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
A single antibiotic can be chosen that will have activity against all targeted pathogens. Selected β-lactam antibiotics may have a β-lactamase inhibitor added to the formulation to expand the antimicrobial activity to cover anticipated pathogens. Many clinicians prefer to use an antibiotic combination with one drug specific for the gram-negative rods and enterococci and a second drug (usually metronidazole) with specific activity against Bacteroides fragilis. The recommended antibiotic choices by the Surgical Infection Society guidelines for the treatment of intraabdominal infection are presented in Table 77.3.70 No one drug or drug combination has been demonstrated to have accepted superiority in clinical outcomes, but all have been shown to meet the test of non-inferiority in clinical trials. Cefoxitin, cefotetan, clindamycin, ampicillin-sulbactam and the aminoglycosides have commonly been used for the treatment of peritonitis in past years, but problems of emerging resistance have led to these choices no longer being recommended. It should also be emphasised that many of these antibiotic choices have been studied in clinical trials where perforated appendicitis has been the major infection. Rigorous evaluation of many of these choices are lacking in data for the management of severe faecal peritonitis from rectosigmoid perforations. Continued comparative clinical trials in patients with severe peritonitis are needed to evaluate outcomes, dosing and duration of therapy.
Problematic Beta-Lactamases: An Update
Robert C. Owens, Lautenbach Ebbing in Antimicrobial Resistance, 2007
Class C beta-lactamases remain an important source of antimicrobial resistance in specific pathogens like C. freundii, E. aerogenes and E. cloacae, Morganella morganii, Pseudomonas aeruginosa (PSDA), and Serratia marcescens. In addition, plasmid-mediated AmpC enzymes have found their way into organisms such as Klebsiella spp., E. coli, and Salmonella spp., and may be mistakenly identified as ESBLs (20). Class C beta-lactamases are cephalosporinases by nature, due to their naturally larger active site that can more easily accommodate the bulky R1 sidechains of third-generation cephalosporins. The Class A beta-lactamase inhibitors, clavulanic acid, tazobactam, and sulbactam, are not clinically effective against the bacteria that produce Class C beta-lactamases. In general, beta-lactams such as carbapenems, monobactams such as aztreonam, and the advanced generation cephalosporin, cefepime, can be used to treat patients with Class C producers. Sometimes, bacteria will restrict entry of antibiotics through the loss of OMPs; coupled with Class C beta-lactamase production, this can lead to carbapenem and cefepime resistance.
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.
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
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
Pertinent isolate characteristics are shown in Table 1. Three isolates (KP1438, KP1491 and KP1587) from the same institution were deemed to be related (data not shown). In contrast to common belief, the presence of multiple beta-lactamase genes did not result in a higher hydrolytic activity. It appeared that not all genes were expressed to the maximal extent and thus they did not contribute additively to the overall hydrolytic activity. Lysates from all isolates susceptible to ceftazidime/avibactam (MIC ≤ 4/4 mg/L) were found to have a similar hydrolytic activity against ceftazidime. However, a higher degradation rate was noted for an isolate resistant to ceftazidime/avibactam (KP 1491, Appendix 1). In this isolate, a higher avibactam concentration was needed to restore ceftazidime MIC to the susceptible range (data not shown). These insights are important and will be used to develop a quantitative method guiding optimal beta-lactamase inhibitor dosing.
Related Knowledge Centers
- Antimicrobial Resistance
- Enzyme
- Enzyme Inhibitor
- Serine Protease
- Beta-Lactamase
- Beta-Lactam Antibiotics
- Gram-Negative Bacteria
- Gram-Positive Bacteria
- Penicillin-Binding Proteins
- Methicillin-Resistant Staphylococcus Aureus