What is the action of beta-lactamase?
MECHANISM OF ACTION β-Lactam antibiotics are bactericidal agents that interrupt bacterial cell-wall formation as a result of covalent binding to essential penicillin-binding proteins (PBPs), enzymes that are involved in the terminal steps of peptidoglycan cross-linking in both Gram-negative and Gram-positive bacteria.
What do beta-lactamase inhibitors do?
Beta-lactamase inhibitors are drugs that are co-administered with beta-lactam antimicrobials to prevent antimicrobial resistance by inhibiting serine beta-lactamases, which are enzymes that inactivate the beta-lactam ring, which is a common chemical structure to all beta-lactam antimicrobials.
What is beta-lactamase and why is it important?
β-Lactams represent one of the most important groups of antibiotics prescribed for antibacterial treatment today. They stop bacterial growth by inhibiting PBPs that are indispensable for the cross-linking process during cell wall biosynthesis.
What is the beta-lactamase test used for?
To detect the enzyme beta-lactamase, which confers penicillin resistance to various bacterial organisms.
How do β lactamases contribute to antibiotic resistance?
β-Lactamases (BLs) represent one of the most common causes of bacterial resistance to β-lactam antibiotics, particularly in Gram-negative bacteria [18]. These enzymes can inactivate almost all β-lactam antibiotics by binding covalently to their carbonyl moiety and hydrolyzing the β-lactam ring.
How do beta-lactamases disrupt antibiotics?
β-Lactams. β-Lactam antibiotics inhibit bacteria by binding covalently to PBPs in the cytoplasmic membrane. These target proteins catalyze the synthesis of the peptidoglycan that forms the cell wall of bacteria. Alterations of PBPs can lead to β-lactam antibiotic resistance.
Why do the beta-lactam drugs affect bacteria?
Beta-lactam antibiotics inhibit bacterial cell wall biosynthesis, consequently leading to cell lysis and death. Specifically, beta-lactam antibiotics bind and acylate active site of penicillin-binding protein (PBP), the enzyme essential for the biosynthesis of bacteria cell wall.
Does beta-lactamase destroy penicillin?
Bacteria generate antibiotic resistance through a number of mechanisms. Some bacteria can become resistant to penicillin by producing beta-lactamase, which is a bacterial enzyme that destroys the beta-lactam ring of penicillin and makes it ineffective.
What is a beta-lactamase infection?
What is an ESBL infection? ESBL stands for extended spectrum beta-lactamase. It's an enzyme found in some strains of bacteria. ESBL-producing bacteria can't be killed by many of the antibiotics that doctors use to treat infections, like penicillins and some cephalosporins. This makes it harder to treat.
How do the β-lactamase inhibitors work quizlet?
These substances were developed to inhibit beta-lactamase and improve the antibacterial spectrum of the antibiotics. Bind irreversibly through the beta lactam ring to the enzyme, and in that way they provide irreversible inhibition of the enzyme.
Why do the beta-lactam drugs affect bacteria?
Beta-lactam antibiotics inhibit bacterial cell wall biosynthesis, consequently leading to cell lysis and death. Specifically, beta-lactam antibiotics bind and acylate active site of penicillin-binding protein (PBP), the enzyme essential for the biosynthesis of bacteria cell wall.
What are beta-lactamases encoded on?
Some beta-lactamases are encoded on mobile genetic elements (eg, plasmids); others are encoded on chromosomes. There are numerous different types of beta-lactamases. They are not all active against all beta-lactam antibiotics and so are broadly classified into several main groups based on their affinity for particular beta-lactams: ...
Which organisms produce beta-lactamases?
AmpC beta-lactamases are generally chromosomally encoded and commonly produced by Enterobacter, Serratia, Citrobacter, Providencia, Morganella, and Pseudomonas aeruginosa. AmpC production is variable and inducible by beta-lactam exposure, so some of these organisms may appear to be falsely susceptible to 3rd-generation cephalosporins by minimum inhibitory concentration (MIC) testing.
What are the metallo-beta-lactamases?
Metallo-beta-lactamases: Carbapenems plus all other beta-lactams, except the monobactam aztreonam (note, these enzymes are not inhibited by beta-lactamase inhibitors)
What are the extended spectrum beta-lactamases?
Extended-spectrum beta-lactamases: Extended-spectrum penicillins (eg, piperacillin), most cephalosporins, monobactams. Metallo-beta-lactamases: Carbapenems plus all other beta-lactams, except the monobactam aztreonam (note, these enzymes are not inhibited by beta-lactamase inhibitors)
Which drugs block penicillinases?
Clavulanate, sulbactam, tazobactam: These drugs block penicillinases but not AmpC or carbapenemases. They also block some ESBLs in vitro, but most combinations that include these drugs are not reliable against ESBL producers clinically.
What is a beta lactam?
Beta-lactams are antibiotics that have a beta-lactam ring nucleus. Subclasses include. All beta-lactams bind to and inactivate enzymes required for bacterial cell wall synthesis.
Which drugs block ESBLs?
Avibactam, relebactam, vaborbactam: These drugs block ESBLs, most serine carbapenemases including KPC, and AmpC but not the metallo-beta-lactamases. Avibactam: This drug also blocks some OXA carbapenemases.
What are some examples of beta-lactamase inhibitors?
Examples of beta-lactamase inhibitors are FPI-1465, metallopolymer, NagZ inhibitor, cobaltocenium containing polymers, avibactam, clavulanic acid, sulbactam, and tazobactam.
Which enzymes cleave the beta-lactam ring of penicillin?
Beta-lactamases are an important group of bacterial enzymes, which preferentially cleave the beta-lactam ring of penicillins, cephalosporins, or other medically important beta-lactam antibiotics (Fig. 1 ).
Which beta-lactamases are able to hydrolyze penicillins?
Metallo beta-lactamases exhibit the broadest spectrum and are able to hydrolyze penicillins, cephalosporins, and even carbapenems, and they are not inhibited by clavulanic acid or tazobactam Rasmussen and Bush (1997), Bush (2001). Metallo beta-lactamases able to hydrolyze the otherwise stable carbapenems have recently spread and are now found in a variety of species such as P. aeruginosa, Acinetobacter spp., Klebiella spp., and others.
What is the gene cluster for -lactamase?
The gene cluster encoding regulated production of β-lactamase in Staphylococcus aureus is usually found on a plasmid or a transposon. The cluster include a repressor gene blaI, an anti-repressor gene blaR1, and the β-lactamase gene blaZ. They were first identified by genetic studies ( Richmond, 1966, 1967 ).
Which enzymes are inhibited by clavulanate?
Other group 2 enzymes are generally inhibited by clavulanate, with the exception of the rare TEM-1 β-lactamase derivatives, the inhibitor-resistant TEM (IRT) enzymes, which have reduced affinity for the inhibitor, and many of the class D oxacillin-hydrolyzing enzymes. Group 2a enzymes are penicillinases; group 2b enzymes have a broader spectrum of activity, hydrolyzing penicillins and early cephalosporins almost equally well. Group 2be enzymes, the extended-spectrum β-lactamases (ESBLs), may be derived from group 2b enzymes, but exhibit enhanced hydrolytic properties that enable them to hydrolyze extended-spectrum cephalosporins and monobactams. Group 2c enzymes hydrolyze carbenicillin, and group 2d enzymes hydrolyze isoxazolyl penicillins such as cloxacillin or oxacillin. The 2d enzymes, the only β-lactamases that belong to molecular class D, may be further subdivided according to the ability to hydrolyze extended-spectrum cephalosporins (group 2de) or carbapenems (group 2df). Group 2f enzymes are carbapenem-hydrolyzing enzymes that are class A serine β-lactamases rather than metalloenzymes. The group 3 metallo-β-lactamases are readily distinguished from other β-lactamases because they can hydrolyze carbapenems and are not inhibited by clavulanic acid, but are inhibited by metal-ion chelators such as EDTA.
Do bacteria produce more than one beta-lactamase?
Bacteria often produce more than one beta-lactamase, which may complement each other in their substrate profiles.
What is the -lactamase?
β -Lactamases hydrolyse the cyclic amide bond in susceptible β -lactam molecules so that antibiotics are unable to bind to PBPs [179]. In Gramnegative bacteria, β -lactamases are intracellular with a periplasmic location, whereas in Gram-positive bacteria they are mainly excreted from the cell and thus are extracellular [180]. Extended-spectrum β -lactamases are plasmid-enclosed enzymes that confer resistance on those β -lactams (e.g. cefotaxime, cefrazidine and aztreonam) that were designed to resist such enzyme attack [180].
What is a class 3 -lactamase?
Class 3 β -lactamases exhibit zinc-dependent activity and are sometimes referred to as ‘carbapenemases’ because they hydrolyse carbapenems (37) as well as penams (38), on which the penicillin structure is based, and cephems (39), on which the cephalosporins are based. Sign in to download full-size image.
What are the four groups of bacterial -lactamases?
A more modern general classification scheme for bacterial β -lactamases [181] places the enzymes into four groups: 1, active against cephalosporins and consisting of chromosomally encoded enzymes from Gram-negative bacteria; 2 a, Gram-positive penicillinases, 2b,TEM-1 and TEM-2 enzymes, 2b′TEM-3 and TEM-5 enzymes, 2c PSE-1, PSE-3 and PSE-4 β -lactamases, 2d OXA-1 and PSE-2 enzymes, 2e cephalosporinases produced by Proteus vulgaris; 3, enzymes with variable substrate activity; and 4, penicillinases as exemplified by the enzymes produced by Burkholderia (formerly Pseudomonas) cepacia. The β -lactamases may be constitutive or inducible, extracellular or intracellular (q.v.) and plasmid- or chromosomally-encoded. Many, but not all, types of β -lactamases are inhibited by clavulanic acid (36), usually at a concentration of 10 μ M, but few types are inhibited by EDTA. Class 3 β -lactamases exhibit zinc-dependent activity and are sometimes referred to as ‘carbapenemases’ because they hydrolyse carbapenems (37) as well as penams (38), on which the penicillin structure is based, and cephems (39), on which the cephalosporins are based.
Which enzyme cleaves the beta ring of penicillin?
Beta-lactamases are an important group of bacterial enzymes, which preferentially cleave the beta-lactam ring of penicillins, cephalosporins, or other medically important beta-lactam antibiotics (Fig. 1 ). Fig. 1. Hydrolysis of benzylpenicillin by beta-lactamase to form penicilloic acid.
Which antibiotic is more effective against Gram negative bacteria?
Ampicillin was the first broad-spectrum penicillin and has a broader antibacterial range of action than that of penicillin G. Ampicillin is effective against many Gram-negative bacilli including Escherichia coli, Haemophilus, Shigella and Proteus.
Which penicillins have anti-pseudomonal activity?
Some semi-synthetic pe nicillins have anti-pseudomonal activity; carbenicillin and piperacillin are included in this type. 1,10,14,15,18,19 These agents generally possess the same spectrum of activity as ampicillin with additional activity against aerobic Gram-negative bacteria, including Klebsiella, Enterobacter and Pseudomonas, although they are not stable to penicillinase.
What is beta lactam used for?
Beta-lactam antibiotics are used in the management and treatment of bacterial infections. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of an interprofessional healthcare ...
Which agents are used to treat carbapenemase?
These agents include the first-generation beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and the newer avibactam and vaborbactam that are active against carbapenemase such as Klebsiella pneumoniae carbapenemase (KPC). Mechanism of Action.
Is Aztreonam effective against Gram negative bacteria?
Aztreonam (IV). It is effective only against aerobic gram-negative organisms but shows no activity against gram-positive bacteria or anaerobes.
Is beta lactam a public health problem?
Resistance to beta-lactams is an alarming and growing phenomenon and, in turn, a public health challenge. It concerns, above all, Streptococcus pneumoniaeand individual gram-negative bacilli such as Pseudomonas aeruginosa. With emerging resistance for antibiotics, it makes sense to look into mechanisms of resistance as it can help decide which drugs to prescribe in different scenarios and ways to overcome the same. Although bacterial resistance to beta-lactams mostly expresses through the production of beta-lactamases, other mechanisms are involved. Following are the mechanisms of resistance[2]:
Beta-lactamases
Beta-lactamases are enzymes produced by bacteria that break open the beta-lactam ring, inactivating the beta-lactam antibiotic. Some beta-lactamases are encoded on mobile genetic elements (eg, plasmids); others are encoded on chromosomes.
Merck and the Merck Manuals
Merck & Co., Inc., Kenilworth, NJ, USA is a global healthcare leader working to help the world be well. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world. The Merck Manual was first published in 1899 as a service to the community.
Why are beta-lactamase inhibitors used?
Beta-lactamase inhibitors are medications that are used ubiquitously in modern medicine due to their ability to combat bacterial antimicrobial resistance mechanisms. Antimicrobial resistance poses an enormous global public health challenge.[32] Therefore, careful monitoring and prescribing of patients taking Beta-lactamase inhibitors in combination with beta-lactam antimicrobials are of paramount importance. Interprofessional health teams of doctors, nurses, pharmacists, and other healthcare professionals must work together to determine the necessity of treatment, as well as to counsel patients regarding the proper administration of this class of medications. Patients must complete their entire course of medication and must not share this medication with others. By working together, members of an interprofessional healthcare team can strive to prevent adverse outcomes for the patient and antimicrobial resistance in the community.
How to administer beta-lactamase inhibitor?
The administration of many beta-lactamase inhibitor medications is via intravenous infusion over several hours. Each drug has different dosage scheduling options, allowing care providers to tailor a patient’s medication regime according to his or her unique needs. Given the potential for nephrotoxicity, dosage adjustment is a recommendation for patients with renal disease. Ceftazidime-avibactam administration is intravenous.[4] Sulbactam-ampicillin administration may be parenteral or oral.[21] Tazobactam-piperacillin administration is parenteral.[21] Clavulanic acid-amoxicillin administration is either parenteral or oral.[21] Relebactam-imipenem-cilastatin administration is intravenous via intravenous infusion, as is vaborbactam-meropenem.[6] Tebipenem is administered orally.[22] Poor medication adherence is noted among pediatric populations, particularly for dosing regimens greater than twice per day.[21] This factor merits consideration when designing a treatment regimen for pediatric patients. It is also vital to regularly counsel patients and their caregivers regarding the importance of patient adherence.
How much tazobactam is in plasma?
The mean concentrations of tazobactam in plasma at 4 hrs are 1.2 micrograms per milliliter with piperacillin and 0.6 micrograms per milliliter alone. The clearance of tazobactam alone is 203.5 ml/min, while that with piperacillin is 134.2 ml/min. There appears to be no significant difference in the volume of distribution, elimination half-life, the volume of distribution, or AUC from 0 to infinity hours between tazobactam alone and tazobactam with piperacillin. The total renal clearance is 73 micrograms/milliliter, the half-life is 1 hr, and the AUC from 0 to infinity is 237 micrograms*hours/ml. The maximum concentrations of tazobactam is 6.4 micrograms/ml alone and 11.3 micrograms/ml with piperacillin. Tazobactam is excreted renally, both alone and with piperacillin. The mean 24-hour urinary excretion of tazobactam is 63.7% alone and 56.8% with piperacillin. [17]
How long does Avibactam last?
Avibactam has a half-life of approximately 2 hours, and administration is in combination with ceftazidime in a 1:4 combination. It is cleared renally with dose adjustment for patients with renal disease. The ceftazidime MIC is 8 mg/L at 4 mg/L avibactam concentrations. A dosing regimen of 2/0.5g ceftazidime/avibactam is used every 8 hours with a 2 hour infusion period for patients with normal kidney function. [12]
How long does sulbactam stay in your system?
Sulbactam has a half-life of one hour and a volume of distribution of 12 liters. Seventy-five percent of the dose is excreted unchanged in the urine. The pharmacokinetics of sulbactam are not significantly impacted by the co-administration of sulbactam with beta-lactam antimicrobials.[15] Sulbactam is approximately 38% bound to plasma proteins. Sulbactam has demonstrated greater efficacy with prolonged infusion strategies. [16]
What are the side effects of beta-lactamase inhibitors?
Adverse reactions associated with beta-lactamase inhibitors include gastrointestinal side effects, such as diarrhea, nausea, and constipation; nervous system effects such as headaches, insomnia, and seizures; hematological effects such as impaired platelet function; allergic reactions including anaphylaxis; pain at the injection site; and dermatologic side effects including Ste vens-Johnson syndrome, toxic epidermal necrol ysis, and drug-induced eosinophilia and systemic symptoms. Gastrointestinal side effects can be less severe if the patient takes the medication with food and/or water. Beta-lactamase inhibitor use is also associated with Candidaalbicansand Clostridioides(Clostridium) difficileinfections. [23][24][25] It is important for clinicians to monitor patients for adverse effects routinely and discontinue therapy immediately if severe side effects occur.
Does vaborbactam accumulate?
Vaborbactam concentration has been shown to increase in a dose-dependent manner, suggesting first-order kinetics, and does not accumulate with multiple doses. The terminal half-life of vaborbactam is 2.25 hours. Both the volume of distribution and the plasma clearance is independent of dose. With a 2000 mg dose, the plasma clearance is 7.95 liters/hour, the AUC from 0 h to infinity is 835 mg*h/liter, and the Vss is 18.6 liters. Vaborbactam undergoes renal excretion, and urinary recovery was 80% or greater over 48 h across all dose groups.[18] Vaborbactam does not undergo hepatic first-pass metabolism. [19]
Types of beta Lactamases
β-Lactamase can be classified into four molecular classes according to the Ambler scheme.
Introduction
ESBL stands for Extended-spectrum β- lactamase. In modern medical practice, newer antimicrobials drugs have been used extensively resulting in the emergence and rapid dissemination of resistant bacterial strains.
Details of ESBL
ESBLs are β- lactamases containing serine at the active site and belong to Ambler’s molecular class -A (majority of them). They hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include Cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino- monobactam aztreonam.
Treatment option
ESBL producing isolates typically show greater than average resistance to other agents including aminoglycosides and fluoroquinolones. These relationships were illustrated in a review of 85 episodes of bacteremia due to ESBL production from 12 hospitals in seven countries.
Clinical outcome due to ESBL
ESBL producing bacteria are typically associated with MDR. The antibacterial choice is often complicated by multi-drug resistance. Thus, infection due to ESBL producing bacteria can result in avoidable failure of treatment and increased cost in patients who have received inappropriate antibiotic treatment.
Worldwide pattern of ESBL
The prevalence of ESBLs among clinical isolates varies from country to country and from institution to institution.
For detection of MBL
MBL stands for Metallo β- lactamase and according to Ambler, the scheme comes under class B. This class of β -lactamases is characterized by the ability to hydrolyze carbapenems and by its resistance to the commercially available β- lactamase inhibitors (clavulanic acid and tazobactam) but susceptibility to inhibition by metal ion chelators.
Types
Mechanism of action
Mechanism
Introduction
Structure
Evolution
Genetics
Summary
- Class D β-lactamases (also called OXA-type enzymes after their efficient hydrolysis of oxacillin) are found as resident chromosomally-encoded enzymes in several bacterial species, and also as plasmid-encoded enzymes. They were originally considered to be less important due to their overall lower diffusion and narrow substrate profile (including pen...
Research
Treatment