Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017

Jernigan, John A.; Hatfield, Kelly M; Wolford, Hannah; Nelson, Richard E.; Olubajo, Babatunde; Reddy, Sujan; McCarthy, Natalie L.; Paul, Prabasaj; McDonald, L. Clifford; Kallen, Alex; Fiore, Anthony E.; Craig, Michael; Baggs, James

doi:10.1056/nejmoa1914433

Cited by 412 publications

(312 citation statements)

References 24 publications

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“…Local selection pressure for AMR during COVID-19 will be overlaid on larger, ongoing and highly dynamic regional trends, such as the remarkable growth of PDR A. baumannii and MBL-producing Enterobacteriaceae in Asia and ESBL-producing Enterobacteriaceae in the USA. 14 , 15 …”

Section: Why Might Amr Arise?mentioning

confidence: 99%

PRO: The COVID-19 pandemic will result in increased antimicrobial resistance rates

Clancy

Buehrle

Nguyen

2020

JAC-Antimicrobial Resistance

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We argue that the COVID-19 pandemic will result in increased antimicrobial resistance (AMR). Broad-spectrum antibiotic use is common among hospitalized COVID-19 patients and in excess of reported secondary infection rates, suggesting unnecessary prescribing. Selection pressure is likely to be particularly intense in COVID-19 epicentres and within non-epicentre hospital units dedicated to COVID-19 care. Risk factors that increase the likelihood of hospitalization or poor outcomes among COVID-19 patients, such as advanced age, nursing home residence, debilitation, diabetes and cardiopulmonary or other underlying systemic diseases, also predispose to AMR infections. Worry for AMR emergence is heightened since first-wave COVID-19 epicentres were also AMR epicentres. Disruptive direct and indirect effects of COVID-19 globally on economic systems, governance and public health expenditure and infrastructure may fuel AMR spread. We anticipate that the impact of COVID-19 on AMR will vary between epicentres and non-epicentres, by geographic region, hospital to hospital within regions and within specific hospital units.

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Section: Why Might Amr Arise?mentioning

confidence: 99%

PRO: The COVID-19 pandemic will result in increased antimicrobial resistance rates

Clancy

Buehrle

Nguyen

2020

JAC-Antimicrobial Resistance

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“…Increasing the arsenal of available antibiotics is paramount to addressing the growing resistance crisis ( 1 , 2 ). Encouraging progress has been made in the treatment of Gram-positive pathogens ( 3 ), with two new antibiotic classes, cyclic lipopeptides (daptomycin) and oxazolidinones (linezolid), introduced within the last 20 years.…”

Section: Introductionmentioning

confidence: 99%

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

MacNair

Brown

2020

mBio

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Disruption of the outer membrane (OM) barrier allows for the entry of otherwise inactive antimicrobials into Gram-negative pathogens. Numerous efforts to implement this approach have identified a large number of OM perturbants that sensitize Gram-negative bacteria to many clinically available Gram-positive active antibiotics. However, there is a dearth of investigation into the strengths and limitations of this therapeutic strategy, with an overwhelming focus on characterization of individual potentiator molecules. Herein, we look to explore the utility of exploiting OM perturbation to sensitize Gram-negative pathogens to otherwise inactive antimicrobials. We identify the ability of OM disruption to change the rules of Gram-negative entry, overcome preexisting and spontaneous resistance, and impact biofilm formation. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. We demonstrate that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants. Further, we find that OM perturbation reduces the rate of spontaneous resistance to rifampicin and impairs biofilm formation. Together, these data suggest that OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development. IMPORTANCE The spread of antibiotic resistance is an urgent threat to global health that necessitates new therapeutics. Treatments for Gram-negative pathogens are particularly challenging to identify due to the robust outer membrane permeability barrier in these organisms. Recent discovery efforts have attempted to overcome this hurdle by disrupting the outer membrane using chemical perturbants and have yielded several new peptides and small molecules that allow the entry of otherwise inactive antimicrobials. However, a comprehensive investigation into the strengths and limitations of outer membrane perturbants as antibiotic partners is currently lacking. Herein, we interrogate the interaction between outer membrane perturbation and several common impediments to effective antibiotic use. Interestingly, we discover that outer membrane disruption is able to overcome intrinsic, spontaneous, and acquired antibiotic resistance in Gram-negative bacteria, meriting increased attention toward this approach.

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“…Our study demonstrates the complex molecular epidemiology of ESBL-producing K. pneumoniae , which are of growing concern for healthcare providers worldwide [ 3 ]. We found that each of the consecutive outbreaks in NICUs in three hospitals in a small geographic region was caused by a different dominant clone of bla CTX-M -producing K. pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Outbreaks of Extended-Spectrum Beta-Lactamase-Producing Klebsiella Pneumoniae in Three Neonatal Intensive Care Units Using Whole Genome Sequencing

et al. 2020

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Infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) are on a constant rise and are a noted cause of outbreaks in neonatal intensive care units (NICUs). We used whole genome sequencing (WGS) to investigate the epidemiology of consecutive and overlapping outbreaks caused by ESBL-KP in NICUs in three hospitals in close proximity. Clonality of 43 ESBL-KP isolates from 40 patients was determined by BOX-PCR. Short-read sequencing was performed on representative isolates from each clone. The dominant clones from each NICU were sequenced using long-read sequencing. Bioinformatics methods were used to define multilocus sequence type (MLST), analyze plasmid content, resistomes, and virulence factors. In each NICU, we found a unique dominant clone (ST985, ST37, and ST35), each belonging to a distinct sequence type (ST), as well as satellite clones. A satellite strain in NICU-2 (ST35) was the dominant strain in NICU-3, where it was isolated four weeks later, suggesting transmission. NICU-1- and NICU-2-dominant strains had blaCTX-M-15 carried on a similar transposable element (Tn3-ISEcp1) but at different locations: on a plasmid and on the chromosome, respectively. We concluded that the overlapping ESBL-KP outbreaks were a combination of clonal transmission within NICUs, possible transposable element transmission between NICUs, and repeated importation of ESBL-KP from the community.

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Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017

Cited by 412 publications

References 24 publications

PRO: The COVID-19 pandemic will result in increased antimicrobial resistance rates

PRO: The COVID-19 pandemic will result in increased antimicrobial resistance rates

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

Investigation of Outbreaks of Extended-Spectrum Beta-Lactamase-Producing Klebsiella Pneumoniae in Three Neonatal Intensive Care Units Using Whole Genome Sequencing

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