-
Journal of Global Antimicrobial... Dec 2023This work aimed to describe the in vitro performance of the combined activity of ceftazidime-avibactam (CZA) plus aztreonam (ATM) against carbapenemase-producing...
OBJECTIVE
This work aimed to describe the in vitro performance of the combined activity of ceftazidime-avibactam (CZA) plus aztreonam (ATM) against carbapenemase-producing Enterobacterales (CPE).
METHODS
We studied 44 CPE clinical isolates: NDM-1 (31), KPC-2 (5), KPC-3 (3), VIM-2 (2), NDM-1+KPC-2 (2), and OXA-48 (1). The efficacy of CZA in combination with were determined by two methods: (i) Kirby-Bauer's double disk synergy test and; (ii) Determination of the minimum inhibitory concentration to CZA by E-test, in either Mueller-Hinton agar alone or, supplemented with ATM 4 mg/L. Additionally, the Fractional inhibitory concentration index (FICI) was determined; values of ≤ 0.5 were interpreted as synergistic, while FICI > 0.5 were considered indifferent.
RESULTS
All isolates were carbapenem-resistant, 14 were resistant to CZA and ATM, 15 were only CZA resistant, 12 were only ATM resistant, and three were susceptible to both. 34/44 isolates presented positive double disk synergy tests between CZA and ATM regardless of their susceptibility profile, the isolates with negative synergy tests were susceptible to at least one of the agents. On the other hand, the 21 isolates selected to compare the MIC to CZA alone and CZA plus 4 mg/L ATM of exhibited FICI values between 0.016 and 0.125, indicating a synergistic effect.
CONCLUSIONS
This method is available to clinical laboratories and would provide valuable information to guide the treatment of infections with CZA and ATM. In this sense, the use of CZA together with ATM is a potentially suitable combination for the treatment of carbapenemase-producing microorganisms.
Topics: Aztreonam; Anti-Bacterial Agents; Ceftazidime
PubMed: 37611893
DOI: 10.1016/j.jgar.2023.08.010 -
The Journal of Allergy and Clinical... Aug 2023A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive β-lactam antibiotics increased β-lactam receipt...
BACKGROUND
A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive β-lactam antibiotics increased β-lactam receipt at a large northeastern US health care system.
OBJECTIVE
To report outcomes of implementing a similar guideline and electronic order set (OS) at an independent academic health care system.
METHODS
Penicillin/cephalosporin receipt (percentage of inpatients receiving full doses) and alternative antibiotic use (days of therapy per 1000 patient-days [DOT/1000PD]) were compared over 3 periods before (February 1, 2017, to January 31, 2018) and after guideline implementation (February 1, 2018, to January 31, 2019), and after OS implementation (February 1, 2019, to January 31, 2020) among inpatients with PCAAL admitted on medical services with access to guideline/OS and education (Medical-PCAAL, n = 8721), surgical services with access to guideline/OS without education (Surgical-PCAAL, n = 5069), and obstetrics/gynecology services without interventions (Ob/Gyn-PCAAL, n = 798) and inpatients without PCAAL admitted on the same services (Medical-No-PCAAL, n = 50,840; Surgical-No-PCAAL, n = 29,845; Ob/Gyn-No-PCAAL, n = 6109). χ tests were used to compare categorical variables, and analysis of variance was used to compare continuous and interrupted time series analyses (ITSA) to investigate the guideline/OS implementation effect on penicillin/cephalosporin receipt.
RESULTS
In the Medical-PCAAL group, penicillin/cephalosporin receipt increased (58%-68%, P < .001), specifically for cefazolin (8%-11%, P = .02) and third- to fifth-generation cephalosporins (43%-48%, P = .04), and aztreonam use decreased (12 DOT/1000PD, P = .03). In the Medical-No-PCAAL group, penicillin/cephalosporin receipt increased (88%-90%, P = .004), specifically for penicillin (40%-44%, P < .001), without changes in aztreonam use. Significant changes were not observed in these outcomes on surgical or obstetrics/gynecology services. Per ITSA, guideline/OS implementation was associated with increased penicillin/cephalosporin receipt in the Medical-PCAAL group only.
CONCLUSION
Guideline and OS implementation was associated with improved antibiotic stewardship on inpatient services that also received allergy education.
Topics: Humans; Anti-Bacterial Agents; beta-Lactams; Inpatients; Aztreonam; Penicillins; Cephalosporins; Drug Hypersensitivity; Hypersensitivity; Retrospective Studies
PubMed: 37182569
DOI: 10.1016/j.jaip.2023.04.051 -
Antibiotics (Basel, Switzerland) Mar 2024Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop... (Review)
Review
Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop resistance to β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems by producing β-lactamases. Therefore, a combination of β-lactam antibiotics with β-lactamase inhibitors has been a promising approach to controlling β-lactam-resistant bacteria. The discovery of novel β-lactamase inhibitors (BLIs) is essential for effectively treating antibiotic-resistant bacterial infections. Therefore, this review discusses the development of innovative inhibitors meant to enhance the activity of β-lactam antibiotics. Specifically, this review describes the classification and characteristics of different classes of β-lactamases and the synergistic mechanisms of β-lactams and BLIs. In addition, we introduce potential sources of compounds for use as novel BLIs. This provides insights into overcoming current challenges in β-lactamase-producing bacteria and designing effective treatment options in combination with BLIs.
PubMed: 38534695
DOI: 10.3390/antibiotics13030260 -
Antimicrobial Agents and Chemotherapy Nov 2023- complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted...
- complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted β-lactam/β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by , including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-β-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.
Topics: Sulbactam; Acinetobacter baumannii; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Monobactams; Microbial Sensitivity Tests
PubMed: 37843305
DOI: 10.1128/aac.00665-23 -
PLoS Pathogens Jul 2023Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of...
Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.
Topics: Methicillin-Resistant Staphylococcus aureus; Pentose Phosphate Pathway; Anti-Bacterial Agents; Oxacillin; Cell Wall; Monobactams; beta-Lactam Resistance; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 37486930
DOI: 10.1371/journal.ppat.1011536 -
Biological Research Mar 2024The convergence of hypervirulence and carbapenem resistance in the bacterial pathogen Klebsiella pneumoniae represents a critical global health concern. Hypervirulent K....
BACKGROUND
The convergence of hypervirulence and carbapenem resistance in the bacterial pathogen Klebsiella pneumoniae represents a critical global health concern. Hypervirulent K. pneumoniae (hvKp) strains, frequently from sequence type 23 (ST23) and having a K1 capsule, have been associated with severe community-acquired invasive infections. Although hvKp were initially restricted to Southeast Asia and primarily antibiotic-sensitive, carbapenem-resistant hvKp infections are reported worldwide. Here, within the carbapenemase production Enterobacterales surveillance system headed by the Chilean Public Health Institute, we describe the isolation in Chile of a high-risk ST23 dual-carbapenemase-producing hvKp strain, which carbapenemase genes are encoded in a single conjugative plasmid.
RESULTS
Phenotypic and molecular tests of this strain revealed an extensive resistance to at least 15 antibiotic classes and the production of KPC-2 and VIM-1 carbapenemases. Unexpectedly, this isolate lacked hypermucoviscosity, challenging this commonly used hvKp identification criteria. Complete genome sequencing and analysis confirmed the K1 capsular type, the KpVP-1 virulence plasmid, and the GIE492 and ICEKp10 genomic islands carrying virulence factors strongly associated with hvKp. Although this isolate belonged to the globally disseminated hvKp clonal group CG23-I, it is unique, as it formed a clade apart from a previously reported Chilean ST23 hvKp isolate and acquired an IncN KPC-2 plasmid highly disseminated in South America (absent in other hvKp genomes), but now including a class-I integron carrying bla and other resistance genes. Notably, this isolate was able to conjugate the double carbapenemase plasmid to an E. coli recipient, conferring resistance to 1st -5th generation cephalosporins (including combinations with beta-lactamase inhibitors), penicillins, monobactams, and carbapenems.
CONCLUSIONS
We reported the isolation in Chile of high-risk carbapenem-resistant hvKp carrying a highly transmissible conjugative plasmid encoding KPC-2 and VIM-1 carbapenemases, conferring resistance to most beta-lactams. Furthermore, the lack of hypermucoviscosity argues against this trait as a reliable hvKp marker. These findings highlight the rapid evolution towards multi-drug resistance of hvKp in Chile and globally, as well as the importance of conjugative plasmids and other mobile genetic elements in this convergence. In this regard, genomic approaches provide valuable support to monitor and obtain essential information on these priority pathogens and mobile elements.
Topics: Humans; Klebsiella pneumoniae; Chile; Escherichia coli; Klebsiella Infections; Plasmids; Anti-Bacterial Agents; Carbapenems; Bacterial Proteins; beta-Lactamases
PubMed: 38475927
DOI: 10.1186/s40659-024-00485-2 -
Annals of Allergy, Asthma & Immunology... Oct 2023Antibiotic allergies are frequently encountered in clinical practice, and delabeling of these allergies has individual and public health benefits. This review focuses on... (Review)
Review
Antibiotic allergies are frequently encountered in clinical practice, and delabeling of these allergies has individual and public health benefits. This review focuses on the evidence supporting graded challenges without preceding skin testing in adult and pediatric patients to the major groups of antibiotics including penicillins, cephalosporins, sulfamethoxazole, fluoroquinolones, tetracyclines, macrolides, metronidazole, carbapenems, and aztreonam. The cost savings, time savings, and evidence for performing graded challenges outside of an allergy/immunology office are also reviewed for graded challenges to penicillins.
Topics: Adult; Humans; Child; Anti-Bacterial Agents; Penicillins; Aztreonam; Cephalosporins; Drug Hypersensitivity; Hypersensitivity
PubMed: 37031773
DOI: 10.1016/j.anai.2023.03.033 -
Annals of Medicine Dec 2023Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for...
Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in . In the last decade, the management of severe infections due to KPC-producing (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.KEY MESSAGESIn the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwideFollowing the introduction in clinical practice of novel β-lactam/β-lactamase inhibitor combinations and novel β-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolutionTreatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics.
Topics: Humans; Klebsiella pneumoniae; Carbapenems; Monobactams; Anti-Bacterial Agents; Lactams
PubMed: 36856521
DOI: 10.1080/07853890.2022.2152484 -
Microbiology Spectrum Dec 2023To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA),...
To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent (CR-hvKP) strains. Our activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.
Topics: Humans; Aztreonam; Klebsiella pneumoniae; Bacterial Proteins; beta-Lactamases; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Imipenem; Carbapenems; Klebsiella Infections; Microbial Sensitivity Tests
PubMed: 37982631
DOI: 10.1128/spectrum.02806-23 -
The Journal of Antibiotics Mar 2024Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for... (Review)
Review
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
Topics: Humans; Cephalosporin Resistance; Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacterial Infections; Neisseria gonorrhoeae; Monobactams
PubMed: 38114565
DOI: 10.1038/s41429-023-00687-y