86 Questions
What is the primary reason for the rapid increase of CRAB?
The abuse of a variety of antibiotics in clinical application
What is the main characteristic of Acinetobacter baumannii that makes it difficult to treat?
Its ability to exchange genetic material
What is the significance of Acinetobacter baumannii being listed as one of the main targets for the treatment and development of new antibiotics by the World Health Organization?
Many pathogenic factors of Acinetobacter baumannii are associated with virulence-related factors
What is the consequence of Acinetobacter baumannii's ability to easily adapt to changes in the environment?
It leads to prolonged colonization in various parts of the human body and hospital wards
What is the primary site of infection associated with high mortality in patients with A.baumannii infection?
Intensive care unit (ICU) with ventilator-associated pneumonia
Why is Acinetobacter baumannii categorized as a superbug?
It has the potential to become resistant to a large variety of antibiotics, particularly carbapenems
What is the main challenge in treating infections caused by CRAB?
The selection of effective antibiotics for treatment is difficult
What is the focus of the present study?
The review of the newest studies on antibiotics and non-beta-lactam-based biologically active chemical compounds for the treatment of CRAB infections
What is the primary function of resistance-associated genes in microorganisms?
To interact with the environment and protect themselves from other bacteria.
What is the main challenge in treating infections with carbapenem-resistant Acinetobacter (CRA)?
The difficulty in detecting carbapenem resistance through phenotypic tests.
What was the primary outcome of the study mentioned in the content?
30-day mortality
What is the limitation of covalent inhibitors in treating CRAB infections?
They are not effective against serine-to-asparagine substituted β-lactamases.
Which of the following antibiotics is associated with a favorable clinical outcome in the treatment of CRAB infections?
Tigecycline
What is the mechanism of action of β-lactamases?
They hydrolyze the β-lactam ring, neutralizing the β-lactams' activity against bacteria.
What is the most common adverse event occurring in hospitalized patients?
Nosocomial infections
What is the purpose of β-lactamase inhibitors in treating bacterial infections?
To restore the activity of β-lactams against bacteria.
What is the characteristic of non-covalent inhibitors?
They have a non-ligand displacement mechanism.
What is the primary mechanism of antibiotic resistance in A. baumannii?
Beta-lactamase expression
What is the frequency of carbapenem-hydrolyzing oxacillinase 23 beta-lactamase in A. baumannii?
66%
What is the advantage of non-covalent inhibitors over covalent inhibitors?
They can overcome carbapenemase-inhibitor resistance.
What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors?
They can restore the clinical potency of β-lactams against multidrug-resistant bacteria.
What is the primary reason for the increasing antimicrobial resistance in A. baumannii?
Overuse of antibiotics
What is the primary function of beta-lactam antibiotics?
Inhibition of cell wall-related enzyme function
What is the global situation regarding the prevalence of carbapenem-resistant Acinetobacter baumannii (CRAB)?
The prevalence is high in some endemic and epidemic regions.
What is the primary concern in treating CRAB infections in patients with comorbid conditions?
All of the above
What is the significance of antimicrobial resistance genes in the environment?
They are always associated with mobile elements.
What is the primary reason for the limited options for treating CRAB infections?
Extensive resistance to available antibiotics
What is the year in which A. baumannii began to exhibit resistance to colistin?
2007
What is the primary mechanism of action of most BL inhibitors?
By being used in combination with a suitable beta-lactam antibiotic
What is the characteristic feature of boronic acid inhibitors?
They use the weaker, more accessible oxyanion hole as the specific discriminator
What is the advantage of using non-beta-lactam beta-lactamase inhibitors?
They are less dependent on the specific reaction mediated by the serine-like hydrolytic activity of the beta-lactamase
What is the significance of the study conducted by Lomovskaya O et al. in 2019?
It showed the potent in vitro activity of novel boronic β-lactamase inhibitors
What is the characteristic feature of class D enzymes?
They use the weaker, more accessible oxyanion hole as the specific discriminator
What is the mechanism of action of the sodium adduct of compound 17?
It has a good ADME profile and is suitable for i.v. dosing
What is the significance of the potent non-beta-lactam-beta-lactamase inhibitors?
They could be a valuable treatment option for infections caused by both MDRE and PDR isolates of A. baumannii
What is the mechanism of action of durlobactam?
It is a beta-lactamase inhibitor that covalently binds to a carbapenem antibiotic
What is the advantage of using nitrile group in non-beta-lactam beta-lactamase inhibitors?
It increases the chances for induction of strong binding
What is the mechanism of action of MSD Star?
It is a beta-lactamase inhibitor that is combined with a suitable beta-lactam antibiotic
What is the reason behind the poor clinical outcomes in patients with CRAB infections?
Due to the mechanisms of resistance CRAB can acquire quickly
What is the main location of the New Delhi Metallo-β-lactamase-1 gene in CRABs?
In the chromosome of CRABs
What is the primary aim of the study mentioned in the content?
To show the effectiveness of β-lactam combination therapy
What is the main driving force behind new investigations into the treatment of CRAB infection?
All of the above
What is the main reason for the critical unmet need for new antibiotics with activity against CRAB?
All of the above
What is the main function of antibiotic resistance in A. baumannii?
To have an environmental function and thus be beneficial for the organism
What is the main reason behind the selection of empiric antibiotics in patients with hospital-associated infections?
All of the above
What are the three antibiotics commonly utilized to treat patients with CRAB infections?
Meropenem, imipenem, and doripenem
What is the current status of the antibiotic pipeline for novel antibiotics?
It is depleted
What is the main challenge posed by the emergence of carbapenem-resistant Acinetobacter baumannii?
It poses unprecedented challenges for antimicrobial drug development
What is the primary concern regarding Carbapenem-resistant A.baumannii (CRAB) infections?
The need for more potent and broad-spectrum antibiotics
Which of the following beta-lactamases are the main beta-lactamases of CRAB?
Class D serine beta-lactamases
What is the primary mechanism of action of non-beta-lactam beta-lactamase inhibitors?
Inhibiting the hydrolytic activity of beta-lactamases
What is the primary concern regarding the development of new antibiotics for CRAB infections?
The minimal efforts to develop new antibiotics due to low return on investment
What is the primary advantage of non-beta-lactam antibiotics in treating CRAB infections?
Their ability to overcome beta-lactamase-mediated resistance
Which of the following is NOT a non-beta-lactam antibiotic used to treat CRAB infections?
Ampicillin
What is the primary consequence of the widespread multiplicity of beta-lactamase-mediated resistance?
The increased use of combination therapies
What is the primary challenge in treating CRAB infections?
The emergence of carbapenem non-susceptible Acinetobacter baumannii
What is the primary mechanism of action of beta-lactamase inhibitors?
Inhibiting the hydrolytic activity of beta-lactamases
Which of the following is a novel non-beta-lactam beta-lactamase inhibitor?
Diazabicyclooctane derivatives
What is the primary concern regarding the use of combination treatment in the clinic?
Rapid development of resistance mechanisms
What is the criterion for classifying CRAB according to the CDC?
Carbapenem minimal inhibitory concentration (MIC) of ≥ 8μg/mL
What is the primary goal of developing non-beta-lactam molecules against A. baumannii?
To target A. baumannii beta-lactamases and efflux mechanisms
What is the primary limitation of avibactam against A. baumannii?
High minimum inhibitory concentrations
What is the purpose of developing beta-lactamase inhibitors with broad-spectrum activities?
To treat a wide range of infections
What is the primary advantage of WXC210?
Its low pKa value due to the sulfonamide moiety
What is the primary characteristic of the Zinc-Evolved Cyclic-DEPI-Lactamase Inhibitor?
It is a class B inhibitor specific to NDM-1
What is the primary concern regarding the use of beta-lactamase inhibitors in a real clinical setting?
The side effects of higher doses are extremely limited
What is the primary reason for the rapid increase in antibiotic resistance among pathogenic bacterial species?
The production of beta-lactamases by bacteria
What is the primary goal of monitoring the inhibitory activities of serine-type beta-lactamase inhibitors against CRAB?
To determine the effectiveness of beta-lactamase inhibitors against CRAB infections
What is the primary mechanism by which beta-lactam inhibitors inactivate beta-lactamases?
By forming an equilibrium to an acyl-enzyme intermediate
What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors?
They offer a new mechanism of action against beta-lactamases
What is the primary advantage of non-beta-lactam beta-lactamase inhibitors over beta-lactam inhibitors?
They have a different mechanism of action
What is the primary reason for the development of new non-beta-lactam beta-lactamase inhibitors?
To overcome the limitations of beta-lactam inhibitors
What is the expected outcome of the development of non-beta-lactam beta-lactamase inhibitors?
The renewal of the arsenal of antibiotics available for use
What is the primary role of sulbactam in the sulbactam-clavulanate combination?
To inhibit the activity of beta-lactamases
What is the significance of the pharmacokinetic value of sulbactam-clavulanate?
It enables the rationalization of bone and soft tissue infection dosing decisions
What is the primary purpose of developing non-beta-lactam beta-lactamase inhibitors?
To mitigate resistance occurring in beta-lactamase-inhibitor deficient beta-lactam/beta-lactamase inhibitor fixed-dose combinations
What is the primary goal of the development of new beta-lactamase inhibitors?
To preserve therapeutic options for the clinical management of infections
What is the potential benefit of using clavulanate in implanting at laboratories?
To reposition beta-lactam/beta-lactamase inhibitor therapy
What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors in the fight against CRAB?
It represents a major breakthrough in the fight against CRAB
What is the primary advantage of orally bioavailable non-beta-lactam beta-lactamase inhibitors?
They can facilitate the discharge of patients on IV beta-lactam therapy after acute hospitalization
What is the ultimate clinical utility of non-beta-lactam beta-lactamase inhibitors?
To facilitate oral administration for post-exposure prophylaxis in high-risk patients
What is the characteristic of non-beta-lactam beta-lactamase inhibitors?
They are effective against intrinsically resistant, carbapenem-hydrolyzing beta-lactamase (CHDL)-expressing, multi-drug resistant Gram-negative pathogens
Why are non-beta-lactam beta-lactamase inhibitors considered a novel class of antibacterial adjuvants?
Because they can restore the activity of beta-lactams against intrinsically resistant, carbapenem-hydrolyzing beta-lactamase (CHDL)-expressing, multi-drug resistant Gram-negative pathogens
What is the potential benefit of using non-beta-lactam beta-lactamase inhibitors in the context of CRAB infections?
To facilitate source control or prophylaxis broadly
What is the significance of clavulanate in the context of CRAB infections?
It is worthwhile for implanting at laboratories to reposition beta-lactam/beta-lactamase inhibitor therapy in a tertiary institution
What is the primary advantage of the sulbactam-clavulanate combination?
It enables the reduction of resistance risks when considering beta-lactam therapy
Study Notes
Acinetobacter baumannii (A. baumannii)
- A. baumannii is a predominantly nosocomial pathogen, capable of adapting to changes in the environment, leading to prolonged colonization in various parts of the human body and hospital wards.
- It is a superbug, posing a significant threat to the development of microbial therapy due to its potential to become resistant to a large variety of antibiotics, particularly carbapenems.
History of A. baumannii
- In the 1970s, A. baumannii began to exhibit resistance to streptomycin and tetracycline.
- In 2007, it became resistant to colistin, forcing the recycling of old antibiotics to treat A. baumannii infections.
- Since the 1950s, β-lactam antibiotics have been widely used in clinics due to their specific inhibition of cell wall-related enzyme function.
Beta-Lactamases in A. baumannii
- β-lactamases are the main mechanism of antibiotic resistance in A. baumannii.
- There are 89 specific β-lactamase genes and subtypes for A. baumannii in the Lahey Beta-Lactamase Database.
- The most common types of β-lactamases are carbapenem-hydrolyzing oxacillinase (66%), cefotaximase and its derivatives (17%), and broad-spectrum β-lactamases (15%).
Carbapenem-Resistant A. baumannii (CRAB)
- CRAB is a major concern in nosocomial and healthcare-associated infections.
- Infections with CRAB often require toxic second-line therapies with poor outcomes.
- The number of known types of β-lactamases in CRAB is increasing.
- Oxacillinases (class D serine β-lactamases) are the main β-lactamases of CRAB, conferring marked hydrolytic resistance to penicillins and carbapenems.
Treatment Challenges
- The antibiotic pipeline is depleted, and there is a critical unmet need for new antibiotics with activity against CRAB.
- Current treatment options are limited, and clinical outcomes are not satisfactory.
- The mortality rate in patients with CRAB bacteremia is still high.
- Non-beta-lactam beta-lactamase inhibitors, such as diazabicyclooctane derivatives, offer a promising solution to treat CRAB infections.
Emergence of Multidrug-Resistant Strains
- A. baumannii has a natural antibiotic resistance, which is beneficial for the organism.
- Antibiotic resistance genes are always associated with mobile elements in the environment.
- The widespread occurrence of mobile elements has permitted the rapid international spread of the antimicrobial resistome and obligate human and animal pathogens.
Importance of Non-Beta-Lactam Beta-Lactamase Inhibitors
-
Non-beta-lactam beta-lactamase inhibitors are essential for restoring the activity of carbapenems and penicillins against CRAB.
-
These inhibitors offer a promising solution to overcome carbapenemase-inhibitor resistance and provide a superior substrate compared to existing covalent inhibitors.
-
Non-covalent inhibitors could restore the clinical potency of most antimicrobials from β-lactamase activity, thus offering great promise for the treatment of multidrug-resistant (MDR) A. baumannii.### Non-Beta-Lactam Beta-Lactamase Inhibitors
-
Non-beta-lactam beta-lactamase inhibitors are a new class of antibacterial adjuvants that can restore the activity of beta-lactams against multi-drug resistant Gram-negative pathogens.
-
These inhibitors are effective against class A and class C beta-lactamases, but not serine carbapenemases.
-
Examples of non-beta-lactam beta-lactamase inhibitors include WXC220 and WXC240, which have shown inhibitory activity against Enterobacteriaceae, A. baumannii, and P. aeruginosa.
Mechanisms of Action
- One strategy for inducing good binding with serine beta-lactamases involves the initial binding of the proposed inhibitor compounds to the serine-enzyme intermediate formed.
- The currently most popular inhibitor class is the Boronic Acids, which have the same general reaction at the active site but with different pendant groups.
- Three mechanisms for rationally designed non-beta-lactam beta-lactamase inhibitors are recognized: covalently trapping the enzyme-bound intermediate, encouraging suicide inactivation of the active enzyme, and binding to an alternate site that facilitates deacylation to form an inactive complex.
Examples of Non-Beta-Lactam Inhibitors
- In 2019, Lomovskaya O et al. conducted a study on potent non-beta-lactam beta-lactamase inhibitors, which showed significant in vivo activity when combined with PEN.
- MSD Star showed good solubility, enabling i.v. dosing, and had a good ADME profile.
- The compound was best in class and had a good ADME profile.
Clinical Development and Future Directions
- The non-BL BLIs are still in early stages, some barely reaching preclinical stages and some already in clinical trials.
- In the future, we can expect new drugs that will prove to be effective in inhibiting the β-lactamases and potentially satisfying the same role that a substance as tried and tested as Avibactam fulfills to perfection in the present.
- These substances will offer an alternative to the joint use of β-lactams, overcoming the intrinsic limitations in the use of the MP's associated with the small family of hydrolyze-resistant β-lactam groups, such as cephamycins and 3-GCs.
Drug Development Pipeline
- Based on the published medical evidence level, the activity and pharmacokinetic value that we highlighted invites intravenous sulbactam-clavulanate tests to enable the rationalization of bone and soft tissue infection dosing decisions with linezolid.
- The antacid clavulanic acid, augmented by sulbactam, a unique bilactam derivative targeting NDM-1, is of interest in the reduction of resistance risks when considering beta-lactam therapy.
Challenges and Opportunities in Clinical Translation
- Non-beta-lactam beta-lactamase inhibitors are developed for the primary purposes of mitigating resistance occurring in beta-lactamase-inhibitor deficient beta-lactam/beta-lactamase inhibitor fixed-dose combinations (FDCs) and of expanding the indication of existing beta-lactams to include resistant pathogens.
- These agents may not offer novel antimicrobial activity or the ability to shorten the course of therapy, particularly for infections that already respond well to existing beta-lactam or beta-lactam/beta-lactamase inhibitor regimens.
- The ultimate clinical utility of these agents would include oral administration not only for post-exposure prophylaxis in high-risk patients but also to facilitate the discharge of patients on IV beta-lactam therapy after acute hospitalization.
Learn about the emergence of Acinetobacter baumannii as a pathogen, its multiple-drug resistance, and the rapid increase of CRAB due to antibiotic abuse. Understand the role of the World Health Organization in addressing this issue.
Make Your Own Quizzes and Flashcards
Convert your notes into interactive study material.
Get started for free
