Acinetobacter baumannii: Emergence and Resistance
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Questions and Answers

What is the primary reason for the rapid increase of CRAB?

  • The inherent resistance of Acinetobacter
  • The lack of development of new antibiotics
  • The poor hygiene in hospitals
  • The abuse of a variety of antibiotics in clinical application (correct)

    • What is the main characteristic of Acinetobacter baumannii that makes it difficult to treat?

  • Its high minimum inhibitory concentration of certain drugs
  • Its ability to exchange genetic material (correct)
  • Its ability to adapt to changes in the environment
  • Its ability to metabolize antibiotics

    • 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 (correct)
  • It is a common cause of community-acquired infections
  • It is a rare cause of hospital-acquired infections
  • It is easily treated with available antibiotics

    • What is the consequence of Acinetobacter baumannii's ability to easily adapt to changes in the environment?

    <p>It leads to prolonged colonization in various parts of the human body and hospital wards</p> Signup and view all the answers

    What is the primary site of infection associated with high mortality in patients with A.baumannii infection?

    <p>Intensive care unit (ICU) with ventilator-associated pneumonia</p> Signup and view all the answers

    Why is Acinetobacter baumannii categorized as a superbug?

    <p>It has the potential to become resistant to a large variety of antibiotics, particularly carbapenems</p> Signup and view all the answers

    What is the main challenge in treating infections caused by CRAB?

    <p>The selection of effective antibiotics for treatment is difficult</p> Signup and view all the answers

    What is the focus of the present study?

    <p>The review of the newest studies on antibiotics and non-beta-lactam-based biologically active chemical compounds for the treatment of CRAB infections</p> Signup and view all the answers

    What is the primary function of resistance-associated genes in microorganisms?

    <p>To interact with the environment and protect themselves from other bacteria.</p> Signup and view all the answers

    What is the main challenge in treating infections with carbapenem-resistant Acinetobacter (CRA)?

    <p>The difficulty in detecting carbapenem resistance through phenotypic tests.</p> Signup and view all the answers

    What was the primary outcome of the study mentioned in the content?

    <p>30-day mortality</p> Signup and view all the answers

    What is the limitation of covalent inhibitors in treating CRAB infections?

    <p>They are not effective against serine-to-asparagine substituted β-lactamases.</p> Signup and view all the answers

    Which of the following antibiotics is associated with a favorable clinical outcome in the treatment of CRAB infections?

    <p>Tigecycline</p> Signup and view all the answers

    What is the mechanism of action of β-lactamases?

    <p>They hydrolyze the β-lactam ring, neutralizing the β-lactams' activity against bacteria.</p> Signup and view all the answers

    What is the most common adverse event occurring in hospitalized patients?

    <p>Nosocomial infections</p> Signup and view all the answers

    What is the purpose of β-lactamase inhibitors in treating bacterial infections?

    <p>To restore the activity of β-lactams against bacteria.</p> Signup and view all the answers

    What is the characteristic of non-covalent inhibitors?

    <p>They have a non-ligand displacement mechanism.</p> Signup and view all the answers

    What is the primary mechanism of antibiotic resistance in A. baumannii?

    <p>Beta-lactamase expression</p> Signup and view all the answers

    What is the frequency of carbapenem-hydrolyzing oxacillinase 23 beta-lactamase in A. baumannii?

    <p>66%</p> Signup and view all the answers

    What is the advantage of non-covalent inhibitors over covalent inhibitors?

    <p>They can overcome carbapenemase-inhibitor resistance.</p> Signup and view all the answers

    What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors?

    <p>They can restore the clinical potency of β-lactams against multidrug-resistant bacteria.</p> Signup and view all the answers

    What is the primary reason for the increasing antimicrobial resistance in A. baumannii?

    <p>Overuse of antibiotics</p> Signup and view all the answers

    What is the primary function of beta-lactam antibiotics?

    <p>Inhibition of cell wall-related enzyme function</p> Signup and view all the answers

    What is the global situation regarding the prevalence of carbapenem-resistant Acinetobacter baumannii (CRAB)?

    <p>The prevalence is high in some endemic and epidemic regions.</p> Signup and view all the answers

    What is the primary concern in treating CRAB infections in patients with comorbid conditions?

    <p>All of the above</p> Signup and view all the answers

    What is the significance of antimicrobial resistance genes in the environment?

    <p>They are always associated with mobile elements.</p> Signup and view all the answers

    What is the primary reason for the limited options for treating CRAB infections?

    <p>Extensive resistance to available antibiotics</p> Signup and view all the answers

    What is the year in which A. baumannii began to exhibit resistance to colistin?

    <p>2007</p> Signup and view all the answers

    What is the primary mechanism of action of most BL inhibitors?

    <p>By being used in combination with a suitable beta-lactam antibiotic</p> Signup and view all the answers

    What is the characteristic feature of boronic acid inhibitors?

    <p>They use the weaker, more accessible oxyanion hole as the specific discriminator</p> Signup and view all the answers

    What is the advantage of using non-beta-lactam beta-lactamase inhibitors?

    <p>They are less dependent on the specific reaction mediated by the serine-like hydrolytic activity of the beta-lactamase</p> Signup and view all the answers

    What is the significance of the study conducted by Lomovskaya O et al. in 2019?

    <p>It showed the potent in vitro activity of novel boronic β-lactamase inhibitors</p> Signup and view all the answers

    What is the characteristic feature of class D enzymes?

    <p>They use the weaker, more accessible oxyanion hole as the specific discriminator</p> Signup and view all the answers

    What is the mechanism of action of the sodium adduct of compound 17?

    <p>It has a good ADME profile and is suitable for i.v. dosing</p> Signup and view all the answers

    What is the significance of the potent non-beta-lactam-beta-lactamase inhibitors?

    <p>They could be a valuable treatment option for infections caused by both MDRE and PDR isolates of A. baumannii</p> Signup and view all the answers

    What is the mechanism of action of durlobactam?

    <p>It is a beta-lactamase inhibitor that covalently binds to a carbapenem antibiotic</p> Signup and view all the answers

    What is the advantage of using nitrile group in non-beta-lactam beta-lactamase inhibitors?

    <p>It increases the chances for induction of strong binding</p> Signup and view all the answers

    What is the mechanism of action of MSD Star?

    <p>It is a beta-lactamase inhibitor that is combined with a suitable beta-lactam antibiotic</p> Signup and view all the answers

    What is the reason behind the poor clinical outcomes in patients with CRAB infections?

    <p>Due to the mechanisms of resistance CRAB can acquire quickly</p> Signup and view all the answers

    What is the main location of the New Delhi Metallo-β-lactamase-1 gene in CRABs?

    <p>In the chromosome of CRABs</p> Signup and view all the answers

    What is the primary aim of the study mentioned in the content?

    <p>To show the effectiveness of β-lactam combination therapy</p> Signup and view all the answers

    What is the main driving force behind new investigations into the treatment of CRAB infection?

    <p>All of the above</p> Signup and view all the answers

    What is the main reason for the critical unmet need for new antibiotics with activity against CRAB?

    <p>All of the above</p> Signup and view all the answers

    What is the main function of antibiotic resistance in A. baumannii?

    <p>To have an environmental function and thus be beneficial for the organism</p> Signup and view all the answers

    What is the main reason behind the selection of empiric antibiotics in patients with hospital-associated infections?

    <p>All of the above</p> Signup and view all the answers

    What are the three antibiotics commonly utilized to treat patients with CRAB infections?

    <p>Meropenem, imipenem, and doripenem</p> Signup and view all the answers

    What is the current status of the antibiotic pipeline for novel antibiotics?

    <p>It is depleted</p> Signup and view all the answers

    What is the main challenge posed by the emergence of carbapenem-resistant Acinetobacter baumannii?

    <p>It poses unprecedented challenges for antimicrobial drug development</p> Signup and view all the answers

    What is the primary concern regarding Carbapenem-resistant A.baumannii (CRAB) infections?

    <p>The need for more potent and broad-spectrum antibiotics</p> Signup and view all the answers

    Which of the following beta-lactamases are the main beta-lactamases of CRAB?

    <p>Class D serine beta-lactamases</p> Signup and view all the answers

    What is the primary mechanism of action of non-beta-lactam beta-lactamase inhibitors?

    <p>Inhibiting the hydrolytic activity of beta-lactamases</p> Signup and view all the answers

    What is the primary concern regarding the development of new antibiotics for CRAB infections?

    <p>The minimal efforts to develop new antibiotics due to low return on investment</p> Signup and view all the answers

    What is the primary advantage of non-beta-lactam antibiotics in treating CRAB infections?

    <p>Their ability to overcome beta-lactamase-mediated resistance</p> Signup and view all the answers

    Which of the following is NOT a non-beta-lactam antibiotic used to treat CRAB infections?

    <p>Ampicillin</p> Signup and view all the answers

    What is the primary consequence of the widespread multiplicity of beta-lactamase-mediated resistance?

    <p>The increased use of combination therapies</p> Signup and view all the answers

    What is the primary challenge in treating CRAB infections?

    <p>The emergence of carbapenem non-susceptible Acinetobacter baumannii</p> Signup and view all the answers

    What is the primary mechanism of action of beta-lactamase inhibitors?

    <p>Inhibiting the hydrolytic activity of beta-lactamases</p> Signup and view all the answers

    Which of the following is a novel non-beta-lactam beta-lactamase inhibitor?

    <p>Diazabicyclooctane derivatives</p> Signup and view all the answers

    What is the primary concern regarding the use of combination treatment in the clinic?

    <p>Rapid development of resistance mechanisms</p> Signup and view all the answers

    What is the criterion for classifying CRAB according to the CDC?

    <p>Carbapenem minimal inhibitory concentration (MIC) of ≥ 8μg/mL</p> Signup and view all the answers

    What is the primary goal of developing non-beta-lactam molecules against A. baumannii?

    <p>To target A. baumannii beta-lactamases and efflux mechanisms</p> Signup and view all the answers

    What is the primary limitation of avibactam against A. baumannii?

    <p>High minimum inhibitory concentrations</p> Signup and view all the answers

    What is the purpose of developing beta-lactamase inhibitors with broad-spectrum activities?

    <p>To treat a wide range of infections</p> Signup and view all the answers

    What is the primary advantage of WXC210?

    <p>Its low pKa value due to the sulfonamide moiety</p> Signup and view all the answers

    What is the primary characteristic of the Zinc-Evolved Cyclic-DEPI-Lactamase Inhibitor?

    <p>It is a class B inhibitor specific to NDM-1</p> Signup and view all the answers

    What is the primary concern regarding the use of beta-lactamase inhibitors in a real clinical setting?

    <p>The side effects of higher doses are extremely limited</p> Signup and view all the answers

    What is the primary reason for the rapid increase in antibiotic resistance among pathogenic bacterial species?

    <p>The production of beta-lactamases by bacteria</p> Signup and view all the answers

    What is the primary goal of monitoring the inhibitory activities of serine-type beta-lactamase inhibitors against CRAB?

    <p>To determine the effectiveness of beta-lactamase inhibitors against CRAB infections</p> Signup and view all the answers

    What is the primary mechanism by which beta-lactam inhibitors inactivate beta-lactamases?

    <p>By forming an equilibrium to an acyl-enzyme intermediate</p> Signup and view all the answers

    What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors?

    <p>They offer a new mechanism of action against beta-lactamases</p> Signup and view all the answers

    What is the primary advantage of non-beta-lactam beta-lactamase inhibitors over beta-lactam inhibitors?

    <p>They have a different mechanism of action</p> Signup and view all the answers

    What is the primary reason for the development of new non-beta-lactam beta-lactamase inhibitors?

    <p>To overcome the limitations of beta-lactam inhibitors</p> Signup and view all the answers

    What is the expected outcome of the development of non-beta-lactam beta-lactamase inhibitors?

    <p>The renewal of the arsenal of antibiotics available for use</p> Signup and view all the answers

    What is the primary role of sulbactam in the sulbactam-clavulanate combination?

    <p>To inhibit the activity of beta-lactamases</p> Signup and view all the answers

    What is the significance of the pharmacokinetic value of sulbactam-clavulanate?

    <p>It enables the rationalization of bone and soft tissue infection dosing decisions</p> Signup and view all the answers

    What is the primary purpose of developing non-beta-lactam beta-lactamase inhibitors?

    <p>To mitigate resistance occurring in beta-lactamase-inhibitor deficient beta-lactam/beta-lactamase inhibitor fixed-dose combinations</p> Signup and view all the answers

    What is the primary goal of the development of new beta-lactamase inhibitors?

    <p>To preserve therapeutic options for the clinical management of infections</p> Signup and view all the answers

    What is the potential benefit of using clavulanate in implanting at laboratories?

    <p>To reposition beta-lactam/beta-lactamase inhibitor therapy</p> Signup and view all the answers

    What is the significance of the discovery of non-beta-lactam beta-lactamase inhibitors in the fight against CRAB?

    <p>It represents a major breakthrough in the fight against CRAB</p> Signup and view all the answers

    What is the primary advantage of orally bioavailable non-beta-lactam beta-lactamase inhibitors?

    <p>They can facilitate the discharge of patients on IV beta-lactam therapy after acute hospitalization</p> Signup and view all the answers

    What is the ultimate clinical utility of non-beta-lactam beta-lactamase inhibitors?

    <p>To facilitate oral administration for post-exposure prophylaxis in high-risk patients</p> Signup and view all the answers

    What is the characteristic of non-beta-lactam beta-lactamase inhibitors?

    <p>They are effective against intrinsically resistant, carbapenem-hydrolyzing beta-lactamase (CHDL)-expressing, multi-drug resistant Gram-negative pathogens</p> Signup and view all the answers

    Why are non-beta-lactam beta-lactamase inhibitors considered a novel class of antibacterial adjuvants?

    <p>Because they can restore the activity of beta-lactams against intrinsically resistant, carbapenem-hydrolyzing beta-lactamase (CHDL)-expressing, multi-drug resistant Gram-negative pathogens</p> Signup and view all the answers

    What is the potential benefit of using non-beta-lactam beta-lactamase inhibitors in the context of CRAB infections?

    <p>To facilitate source control or prophylaxis broadly</p> Signup and view all the answers

    What is the significance of clavulanate in the context of CRAB infections?

    <p>It is worthwhile for implanting at laboratories to reposition beta-lactam/beta-lactamase inhibitor therapy in a tertiary institution</p> Signup and view all the answers

    What is the primary advantage of the sulbactam-clavulanate combination?

    <p>It enables the reduction of resistance risks when considering beta-lactam therapy</p> Signup and view all the answers

    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.

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    Description

    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.

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