Publications by authors named "Cesar A Arias"

209 Publications

Emergence of Clinical Clostridioides difficile Isolates With Decreased Susceptibility to Vancomycin.

Clin Infect Dis 2022 Jan;74(1):120-126

University of Texas Health Science Center, School of Public Health, Department of Epidemiology, Human Genetics, and Environmental Sciences, Center for Infectious Diseases, Houston, Texas,USA.

Background: Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population.

Methods: Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, and in vivo testing in a CDI mouse model.

Results: Of the Houston stool samples, 114/438 (26%) had vancomycin nonsusceptible C. difficile isolates and 128/438 (29%) were metronidazole nonsusceptible. Similarly, 66 out of 98 (67%) and 83/98 (85%) of the Nairobi patients harbored vancomycin and metronidazole nonsusceptible isolates, respectively. Vancomycin treatment of a CDI mouse model infected with a vancomycin nonsusceptible isolate failed to eradicate the infection. Whole-genome sequencing analyses did not identify vanA genes, suggesting a different mechanism of resistance.

Conclusions: C. difficile strains exhibiting reduced susceptibility to vancomycin are currently circulating in patient populations. The spread of strains resistance to vancomycin, a first-line antibiotic for CDI, poses a serious therapeutic challenge. Routine susceptibility testing may be necessary.
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http://dx.doi.org/10.1093/cid/ciaa912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752249PMC
January 2022

Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed.

Antimicrob Agents Chemother 2022 Jan 10:AAC0199121. Epub 2022 Jan 10.

Antimicrobial Resistance Division, WHO, Geneva, Switzerland.

There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes 'traditional' and 'non-traditional' antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.
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http://dx.doi.org/10.1128/AAC.01991-21DOI Listing
January 2022

Impact of Bicarbonate-β-Lactam Exposures on Methicillin-Resistant (MRSA) Gene Expression in Bicarbonate-β-Lactam-Responsive vs. Non-Responsive Strains.

Genes (Basel) 2021 10 20;12(11). Epub 2021 Oct 20.

The Lundquist Institute, Torrance, CA 90502, USA.

Methicillin-resistant (MRSA) infections represent a difficult clinical treatment issue. Recently, a novel phenotype was discovered amongst selected MRSA which exhibited enhanced β-lactam susceptibility in vitro in the presence of NaHCO (termed 'NaHCO-responsiveness'). This increased β-lactam susceptibility phenotype has been verified in both ex vivo and in vivo models. Mechanistic studies to-date have implicated NaHCO-mediated repression of genes involved in the production, as well as maturation, of the alternative penicillin-binding protein (PBP) 2a, a necessary component of MRSA β-lactam resistance. Herein, we utilized RNA-sequencing (RNA-seq) to identify genes that were differentially expressed in NaHCO-responsive (MRSA 11/11) vs. non-responsive (COL) strains, in the presence vs. absence of NaHCO-β-lactam co-exposures. These investigations revealed that NaHCO selectively repressed the expression of a cadre of genes in strain 11/11 known to be a part of the -- regulon, as well as a number of genes involved in the anchoring of cell wall proteins in MRSA. Moreover, several genes related to autolysis, cell division, and cell wall biosynthesis/remodeling, were also selectively impacted by NaHCO-OXA exposure in the NaHCO-responsive strain MRSA 11/11. These outcomes provide an important framework for further studies to mechanistically verify the functional relevance of these genetic perturbations to the NaHCO-responsiveness phenotype in MRSA.
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http://dx.doi.org/10.3390/genes12111650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619011PMC
October 2021

Real-World Performance of Susceptibility Testing for Ceftolozane/Tazobactam against Non-Carbapenemase-Producing Carbapenem-Resistant Pseudomonas aeruginosa.

Antimicrob Agents Chemother 2022 Jan 15;66(1):e0165721. Epub 2021 Nov 15.

Genomics & Resistant Microbes (GeRM), Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollogrid.412187.9, Santiago, Chile.

Ceftolozane/tazbactam (C/T) is a potent anti-pseudomonal agent that has clinical utility against infections caused by non-carbapenemase, producing-carbapenem-resistant Pseudomonas aeruginosa (non-CP-CR-PA). Accurate, precise, and reliable antimicrobial susceptibility testing (AST) is crucial to guide clinical decisions. However, studies assessing the performance of different AST methods against non-CP-CR-PA (the main clinical niche for C/T), are lacking. Here, we evaluated performance of gradient strips (Etest and MIC test strip [MTS], and disk diffusion [DD]) using CLSI breakpoints. Additionally, we assessed the performance of DD using EUCAST breakpoints. For all susceptibility tests, we used a collection of 97 non-CP-CR-PA clinical isolates recovered from 11 Chilean hospitals. Both gradient strips and DD had acceptable performance when using CLSI breakpoints, yielding a categorical agreement (CA) of >90% and 92%, respectively. In contrast, DD using EUCAST breakpoints performed suboptimally (CA 81%). MTS yielded a higher essential agreement (EA, >90%) than Etest (84%). Importantly, the performance of all methods varied significantly when the isolates were stratified by their degree of susceptibility to other anti-pseudomonal β-lactams. All methods had 100% CA when testing isolates that were pan-susceptible to all β-lactams (Pan-β-S). However, the CA markedly decreased when testing isolates resistant to all β-lactams (Pan-β-R). Indeed, the CA was 81% for Etest (six errors), 78% for MTS (seven errors), and 78% and 56% for DD when using CLSI (seven errors) or EUCAST breakpoints (14 errors), respectively. Our results suggest that all manual AST methods have strikingly decreased performance in the context of Pan-β-R P. aeruginosa with potentially major clinical implications.
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http://dx.doi.org/10.1128/AAC.01657-21DOI Listing
January 2022

Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.

Lancet Infect Dis 2021 Nov 9. Epub 2021 Nov 9.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.

Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete.

Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96).

Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions.

Funding: The National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(21)00399-6DOI Listing
November 2021

Evaluation of Bacteriophage Cocktails Alone and in Combination with Daptomycin against Daptomycin-Nonsusceptible Enterococcus faecium.

Antimicrob Agents Chemother 2022 Jan 1;66(1):e0162321. Epub 2021 Nov 1.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.

Enterococcus faecium is a significant multidrug-resistant pathogen. Bacteriophage cocktails are being proposed to complement antibiotic therapy. After a screen of 8 E. faecium strains against 4 phages, 2 phages (113 and 9184) with the broadest host ranges were chosen for further experiments. Transmission electron microscopy, whole-genome sequencing, comparative genome analyses, and time-kill analyses were performed. Daptomycin (DAP) plus the phage cocktail (113 [myophage] and 9184 [siphopage]) showed bactericidal activity in most regimens, while DAP addition prevented phage 9184 resistance against daptomycin-nonsusceptible E. faecium.
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http://dx.doi.org/10.1128/AAC.01623-21DOI Listing
January 2022

Real World Long-term Assessment of The Efficacy of Tocilizumab in Patients with COVID-19: Results From A Large De-identified Multicenter Electronic Health Record Dataset in the United States.

Int J Infect Dis 2021 Dec 29;113:148-154. Epub 2021 Sep 29.

School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, United States. Electronic address:

Background: Studies have shown conflicting results on the efficacy of tocilizumab (TCZ) for patients with COVID-19, with many confounders of clinical status and limited duration of the observation. Here, we evaluate the real-world long-term efficacy of TCZ in COVID-19 patients.

Methods: We conducted a retrospective study of hospitalized adult patients with COVID-19 using a large US-based multicenter COVID-19 database (Cerner Real-World Data; updated in September, 2020). The TCZ group was defined as patients who received at least one dose of the drug. Matching weight (MW) and a propensity score weighting method were used to balance confounding factors.

Results: A total of 20,399 patients were identified. 1,510 and 18,899 were in the TCZ and control groups, respectively. After MW adjustment, no statistically significant differences in all-cause mortality were found for the TCZ vs. control group (Hazard Ratio [HR]:0.76, p=0.06). Survival curves suggested a better trend in short-term observation, driven from a subgroup of patients requiring oxygen masks, BIPAP or CPAP.

Conclusion: We observed a temporal (early) benefit of TCZ, especially in patients on non-invasive high-flow supplemental oxygen. However, the benefit effects faded with longer observation. The long-term benefits and risks of TCZ should be carefully evaluated with follow-up studies.
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http://dx.doi.org/10.1016/j.ijid.2021.09.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479513PMC
December 2021

Evaluation of Susceptibility Testing Methods for Aztreonam and Ceftazidime-Avibactam Combination Therapy on Extensively Drug-Resistant Gram-Negative Organisms.

Antimicrob Agents Chemother 2021 10 23;65(11):e0084621. Epub 2021 Aug 23.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Centergrid.240145.6, Houston, Texas, USA.

Carbapenem-resistant (CRE) and Pseudomonas aeruginosa (CR-PA) producing metallo-β-lactamases (MBLs) cause severe nosocomial infections with no defined treatment. The combination of aztreonam (ATM) with ceftazidime-avibactam (CZA) is a potential therapeutic option, but there is no approved, feasible testing method for use in clinical laboratories to assess the activity of two antimicrobials in combination. Here, we evaluate the performance of four ATM-CZA combination testing methods, as follows: broth disk elution (DE), disk stacking (DS), strip stacking (SS), and strip crossing (SX). We used 10 clinical, representative and 6 P. aeruginosa isolates harboring MBL, Guiana extended-spectrum beta-lactamase (GES), or non-MBL enzymes. Four of these isolates were from clinical cases treated by ATM-CZA. All CRE producing NDM and CR-PA producing GES that were resistant to ATM and CZA alone were susceptible to the ATM-CZA combination. P. aeruginosa generating NDM or VIM remained resistant to ATM-CZA, likely due to non-β-lactamase mechanisms, and all other isolates were susceptible to ATM or CZA alone. The most accurate, precise, and reproducible methods of low complexity were disc elution and both strip methods (SX and SS) using MIC test strips (MTS) , all with 100% sensitivity and specificity, followed by Etest with SX (95.83% sensitivity, 100% specificity) and SS (87.5% sensitivity, 100% specificity). DS had the lowest performance. DE is particularly valuable in low-resource settings that routinely use disks. MTS yielded higher categorical agreements by SX (94%) and SS (84%), relative to Etest by SX (90%) and SS (82%). P. aeruginosa results yielded the majority of the errors. These methods may allow laboratories to inform clinical decision making like combination therapy for severe infections caused by extensively drug-resistant
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http://dx.doi.org/10.1128/AAC.00846-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522751PMC
October 2021

Invasive Infections during a COVID-19 Case Surge.

Antimicrob Agents Chemother 2021 09 2;65(10):e0114621. Epub 2021 Aug 2.

University of Miamigrid.26790.3agrid.418456.agrid.26790.3a Health System, Miami, Florida, USA.

Clinical cases of C. auris noted during a COVID-19 surge led to an epidemiological, clinical, and genomic investigation. Evaluation identified a close genetic relationship but inconclusive epidemiologic link between all cases. Prolonged hospitalization due to critical illness from COVID-19 and use of antimicrobials may have contributed to clinical infections.
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http://dx.doi.org/10.1128/AAC.01146-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448104PMC
September 2021

Selective digestive decontamination with oral colistin plus gentamicin for persistent bacteraemia caused by non-carbapenemase-producing carbapenem-resistant in a neutropenic patient.

JAC Antimicrob Resist 2021 Jun 21;3(2):dlab079. Epub 2021 Jun 21.

Genomics and Resistance Microbes (GeRM) Lab, Facultad de Medicina CAS-UDD, Instituto de Ciencias e Innovación en Medicina (ICIM), Santiago, Chile.

Background: Carbapenem-resistant (CR) have become an increasing public health problem worldwide. While most CR around the world harbour a carbapenemase enzyme, the clinical relevance of non-carbapenemase-producing CR (non-CP-CR) is increasingly recognized. Selective digestive decontamination (SDD) has been proven successful as a decolonization strategy for patients colonized with Gram-negatives in the ICU. However, it is not regularly used to treat invasive infections.

Objectives: To report the use of SDD as a useful strategy for managing recalcitrant CR bloodstream infections.

Patients And Methods: We present a neutropenic patient with a recalcitrant bloodstream infection with non-CP-CR treated with SDD. Besides, genomic analyses of five isolates of non-CP-CR was performed.

Results: After 11 days of SDD treatment with oral colistin and gentamicin, bacteraemia was successfully eradicated. Genomic analysis indicates a fully carbapenem-resistant phenotype evolved and suggests that the mechanism of carbapenem resistance in our strains relates to gene amplification of narrow-spectrum β-lactamases.

Conclusions: Our report highlights that SDD might be a useful strategy to manage CR bloodstream infections, when intestinal translocation is the likely source of the bacteraemia. In addition, the development of a resistant phenotype during therapy is worrisome as therapies directed against these organisms are likely to favour the amplification process.
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http://dx.doi.org/10.1093/jacamr/dlab079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215431PMC
June 2021

Genomic analysis of carbapenem-resistant Pseudomonas aeruginosa ST143 clone showing susceptibility to broad-spectrum cephalosporins.

J Glob Antimicrob Resist 2021 09 24;26:177-179. Epub 2021 Jun 24.

Universidade Federal de São Paulo (UNIFESP), Laboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine-Escola Paulista de Medicina (EPM), São Paulo - SP, Brazil.

Objectives: Using whole-genome sequencing (WGS), we aimed to characterise a Pseudomonas aeruginosa ST143 clinical strain (Pb9) that presented resistance to meropenem and imipenem and susceptibility to piperacillin/tazobactam and broad-spectrum cephalosporins.

Methods: The antimicrobial susceptibility profile was confirmed by broth microdilution. WGS was performed using an Illumina MiSeq platform to identify possible genetic determinants of β-lactam resistance. Transcription levels of chromosomally encoded efflux systems and oprD were evaluated by RT-qPCR.

Results: WGS analysis showed that no acquired carbapenemase-encoding gene was found in isolate Pb9, although mutations in the chromosomally encoded β-lactamase genes bla, bla and bla were observed. In addition, we detected a premature stop codon in the major porin-encoding gene oprD coupled with hyperexpression of MexAB-OprM and MexEF-OprN.

Conclusion: Our results suggest that the β-lactam resistance phenotype presented by strain Pb9 might be related to an association of OprD loss with hyperexpression of the efflux pump systems MexAB-OprM and MexEF-OprN. However, the contribution of OXA-488, PDC-5 and PIB-1 to this phenotype remains unclear and warrants further investigation.
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http://dx.doi.org/10.1016/j.jgar.2021.05.019DOI Listing
September 2021

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing.

Clin Infect Dis 2021 Jun 23. Epub 2021 Jun 23.

Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Background: Immunoassays designed to detect SARS-CoV-2 protein antigens are now commercially available. The most widely used tests are rapid lateral flow assays that generate results in approximately 15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 antigen (Ag) assays have also been developed. The overall accuracy of SARS-CoV-2 Ag tests, however, is not well defined. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best practice guidance related to SARS-CoV-2 Ag testing. This guideline is the third in a series of rapid, frequently updated COVID-19 diagnostic guidelines developed by IDSA.

Objective: IDSA's goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and non-medical settings.

Methods: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations.

Results: The panel agreed on five diagnostic recommendations. These recommendations address antigen testing in symptomatic and asymptomatic individuals as well as assess single versus repeat testing strategies.

Conclusions: Data on the clinical performance of U.S. Food and Drug Administration SARS-CoV-2 Ag tests with Emergency Use Authorization is mostly limited to single, one-time testing versus standard nucleic acid amplification testing (NAAT) as the reference standard. Rapid Ag tests have high specificity and low to modest sensitivity compared to reference NAAT methods. Antigen test sensitivity is heavily dependent on viral load, with differences observed between symptomatic compared to asymptomatic individuals and the time of testing post onset of symptoms. Based on these observations, rapid RT-PCR or laboratory-based NAAT remain the diagnostic methods of choice for diagnosing SARS-CoV-2 infection. However, when molecular testing is not readily available or is logistically infeasible, Ag testing can help identify some individuals with SARS-CoV-2 infection. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.
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http://dx.doi.org/10.1093/cid/ciab557DOI Listing
June 2021

Efficacy of Omadacycline against Multidrug-Resistant Enterococcus faecium Strains in a Mouse Peritonitis Model.

Antimicrob Agents Chemother 2021 08 17;65(9):e0070921. Epub 2021 Aug 17.

Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Omadacycline (OMC) showed better potency than daptomycin (DAP) or vancomycin (VAN) against Van, Amp, DAP-nonsusceptible, linezolid-resistant, (B) Enterococcus faecium strains. In a mouse peritonitis model, OMC also showed significantly better animal survival during the study and at its end than DAP or VAN with these E. faecium strains. However, OMC, DAP, and VAN showed comparable and efficacies against a non-vancomycin-resistant, tetracycline-resistant, DAP-susceptible E. faecium strain.
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http://dx.doi.org/10.1128/AAC.00709-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370196PMC
August 2021

Techniques in bacterial strain typing: past, present, and future.

Curr Opin Infect Dis 2021 08;34(4):339-345

University of Texas Health Science Center at Houston - School of Public Health.

Purpose Of Review: The advancement of molecular techniques such as whole-genome sequencing (WGS) has revolutionized the field of bacterial strain typing, with important implications for epidemiological surveillance and outbreak investigations. This review summarizes state-of-the-art techniques in strain typing and examines barriers faced by clinical and public health laboratories in implementing these new methodologies.

Recent Findings: WGS-based methodologies are on track to become the new 'gold standards' in bacterial strain typing, replacing traditional methods like pulsed-field gel electrophoresis and multilocus sequence typing. These new techniques have an improved ability to identify genetic relationships among organisms of interest. Further, advances in long-read sequencing approaches will likely provide a highly discriminatory tool to perform pangenome analyses and characterize relevant accessory genome elements, including mobile genetic elements carrying antibiotic resistance determinants in real time. Barriers to widespread integration of these approaches include a lack of standardized workflows and technical training.

Summary: Genomic bacterial strain typing has facilitated a paradigm shift in clinical and molecular epidemiology. The increased resolution that these new techniques provide, along with epidemiological data, will facilitate the rapid identification of transmission routes with high confidence, leading to timely and effective deployment of infection control and public health interventions in outbreak settings.
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http://dx.doi.org/10.1097/QCO.0000000000000743DOI Listing
August 2021

Evaluation of the Vitek 2, Phoenix, and MicroScan for Antimicrobial Susceptibility Testing of Stenotrophomonas maltophilia.

J Clin Microbiol 2021 08 18;59(9):e0065421. Epub 2021 Aug 18.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Stenotrophomonas maltophilia causes high-mortality infections in immunocompromised hosts with limited therapeutic options. Many U.S. laboratories rely on commercial automated antimicrobial susceptibility tests (cASTs) and use CLSI breakpoints (BPs) for S. maltophilia. However, contemporary data on these systems are lacking. We assessed performance of Vitek 2, MicroScan WalkAway, and Phoenix relative to that of reference broth microdilution for trimethoprim-sulfamethoxazole (SXT), levofloxacin (LEV), minocycline (MIN), and ceftazidime (CAZ) with 109 S. maltophilia bloodstream isolates. Using CLSI breakpoints, categorical agreement (CA) was below 90% on all systems and drugs, with the exception of SXT by MicroScan (98.1%) and Phoenix (98.1%) and MIN by MicroScan (100%) and Phoenix (99.1%). For SXT, Vitek 2 yielded a 77.1% CA. LEV and CAZ CA ranged from 67% to 85%. Very major errors (VME) were >3% for SXT (MicroScan, Phoenix), LEV (MicroScan), and CAZ (all systems). Major errors (ME) were >3% for SXT (Vitek 2), LEV (Phoenix), and CAZ (MicroScan, Phoenix). Minor errors were >10% for CAZ and LEV on all systems. Data were analyzed with EUCAST pharmacokinetic/pharmacodynamic CAZ, LEV, ciprofloxacin (CIP), and tigecycline (TGC) breakpoints when possible. CA was <90% for all. VME were >3% for CAZ (all systems), LEV (MicroScan), and TGC (Vitek 2), and ME were >3% for LEV (MicroScan), CAZ (all systems), ciprofloxacin (Vitek 2 and MicroScan), and TGC (Vitek 2, Phoenix). Minor errors (MI) were >10% for all agents and systems, by EUCAST breakpoints with an intermediate category (LEV, CAZ, CIP). Laboratories should use caution with cASTs for S. maltophilia, as a high rate of errors may be observed.
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http://dx.doi.org/10.1128/JCM.00654-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373028PMC
August 2021

Evaluation of the Performance of Manual Antimicrobial Susceptibility Testing Methods and Disk Breakpoints for .

Antimicrob Agents Chemother 2021 Feb 8. Epub 2021 Feb 8.

Dept of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN

are an emerging cause of serious infections with high associated mortality in immunocompromised patients. Treatment of infections is complicated by intrinsic resistance to many antimicrobials, including carbapenems, aminoglycosides, and some cephalosporins. Despite this, >90% of isolates are susceptible to trimethoprim-sulfamethoxazole (SXT), which is front-line therapy for this organism. Side-effects of SXT include bone marrow suppression, which precludes its use for many neutropenic patients. In this population, levofloxacin (LEV), minocycline (MIN), ceftazidime (CAZ), ciprofloxacin (CIP) and tigecycline (TIG) are used as alternative therapies - all of which require testing to inform susceptibilities. The reference standard method for testing is broth microdilution (BMD), but very few clinical laboratories perform reference BMD. Furthermore, interpretive criteria are not available for CIP or TIG for , although generic pharmacokinetic/pharmacodynamic (PK/PD) MIC breakpoints are available for these drugs. We assessed performance of disk and gradient diffusion tests relative to BMD for 109 contemporary isolates of Categorical agreement for SXT, LEV and MIN disk diffusion was 93%, 89%, and 95%, respectively. Categorical agreement for SXT, LEV, MIN and CAZ gradient strips was 98%, 85%, 93%, 71%, respectively by Etest (bioMerieux), and 98%, 83%, 99%, and 73%, by MTS (Liofilchem). CIP and TGC, two clinically valuable alternatives to SXT, did not demonstrate promising disk to MIC correlates using CLSI M100 or PK/PD breakpoints. Manual commercial tests perform well for , with the exception of tests for LEV and CAZ, where high error rates were observed.
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http://dx.doi.org/10.1128/AAC.02631-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092892PMC
February 2021

A Test for the Rapid Detection of the Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus.

J Clin Microbiol 2021 03 19;59(4). Epub 2021 Mar 19.

Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia

The cefazolin inoculum effect (CzIE) has been associated with therapeutic failures and mortality in invasive methicillin-susceptible (MSSA) infections. A diagnostic test to detect the CzIE is not currently available. We developed a rapid (∼3 h) CzIE colorimetric test to detect staphylococcal-β-lactamase (BlaZ) activity in supernatants after ampicillin induction. The test was validated using 689 bloodstream MSSA isolates recovered from Latin America and the United States. The cefazolin MIC determination at a high inoculum (10 CFU/ml) was used as a reference standard (cutoff ≥16 μg/ml). All isolates underwent genome sequencing. A total of 257 (37.3%) of MSSA isolates exhibited the CzIE by the reference standard method. The overall sensitivity and specificity of the colorimetric test was 82.5% and 88.9%, respectively. Sensitivity in MSSA isolates harboring type A BlaZ (the most efficient enzyme against cefazolin) was 92.7% with a specificity of 87.8%. The performance of the test was lower against type B and C enzymes (sensitivities of 53.3% and 72.3%, respectively). When the reference value was set to ≥32 μg/ml, the sensitivity for isolates carrying type A enzymes was 98.2%. Specificity was 100% for MSSA lacking The overall negative predictive value ranged from 81.4% to 95.6% in Latin American countries using published prevalence rates of the CzIE. MSSA isolates from the United States were genetically diverse, with no distinguishing genomic differences from Latin American MSSA, distributed among 18 sequence types. A novel test can readily identify most MSSA isolates exhibiting the CzIE, particularly those carrying type A BlaZ. In contrast to the MIC determination using high inoculum, the rapid test is inexpensive, feasible, and easy to perform. After minor validation steps, it could be incorporated into the routine clinical laboratory workflow.
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http://dx.doi.org/10.1128/JCM.01938-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092731PMC
March 2021

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing.

Clin Infect Dis 2021 Jan 22. Epub 2021 Jan 22.

Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Background: Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19). Direct detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids in respiratory tract specimens informs patient, healthcare institution and public health level decision-making. The numbers of available SARS-CoV-2 nucleic acid detection tests are rapidly increasing, as is the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) recognized a significant need for frequently updated systematic reviews of the literature to inform evidence-based best practice guidance.

Objective: The IDSA's goal was to develop an evidence-based diagnostic guideline to assist clinicians, clinical laboratorians, patients and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss the nuance of test result interpretation in a variety of practice settings and highlight important unmet research needs in the COVID-19 diagnostic testing space.

Methods: IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations.

Results: The panel agreed on 17 diagnostic recommendations.

Conclusions: Universal access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention and the public response to the COVID-19 pandemic. Information on the clinical performance of available tests is rapidly emerging, but the quality of evidence of the current literature is considered moderate to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is recommended for asymptomatic individuals with known or suspected contact with a COVID-19 case. Testing asymptomatic individuals without known exposure is suggested when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions, dictate eligibility for surgery, or inform solid organ or hematopoietic stem cell transplantation timing. Ultimately, prioritization of testing will depend on institutional-specific resources and the needs of different patient populations.
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http://dx.doi.org/10.1093/cid/ciab048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929045PMC
January 2021

Daptomycin Resistance in Enterococcus faecium Can Be Delayed by Disruption of the LiaFSR Stress Response Pathway.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Department of BioSciences, Rice University, Houston, Texas, USA

LiaFSR signaling plays a major role in mediating daptomycin (DAP) resistance in enterococci, and the lack of a functional LiaFSR pathway leads to DAP hypersusceptibility. Using experimental evolution, we evaluated how with a response regulator gene deletion evolved DAP resistance. We found that knocking out LiaFSR signaling significantly delayed the onset of resistance, but resistance could emerge eventually through various alternate mechanisms that were influenced by the environment.
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http://dx.doi.org/10.1128/AAC.01317-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097453PMC
March 2021

Emergence and Transmission of Daptomycin and Vancomycin-Resistant Enterococci Between Patients and Hospital Rooms.

Clin Infect Dis 2021 Dec;73(12):2306-2313

Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Vancomycin-resistant enterococci (VRE) are a major cause of morbidity and mortality in immunocompromised patients. Tracking the dissemination of VRE strains is crucial to understand the dynamics of emergence and spread of VRE in the hospital setting.

Methods: Whole genome sequencing (WGS) and phylogenetic analyses were performed to identify dominant VRE strains and potential transmission networks between 35 patients with VRE-positive rectal swabs and their rooms (main rooms and bathrooms) on the leukemia (LKM) and the hematopoietic cell transplant (HCT) floors. Sequence types (STs), drug resistance genes, and patients' outcomes were also determined.

Results: A total of 89 VRE strains grouped into 10 different STs, of which newly described STs were isolated from both floors (ST736, ST494, ST772, and ST1516). We observed highly genetically related strains transmitted between rooms, floors, and time periods in an average period of 39 days (ranging from 3 to 90 days). Of 5 VRE bacteremia events, 3 strains were lacking the pili operon fms14-17-13 (ST203) and the remaining 2 were resistant to daptomycin (DAP; ST736, ST664). Of 10 patients harboring DAP-resistant strains, only 2 were exposed to DAP within 4 months before strain recovery.

Conclusions: Our comparisons of VRE strains derived from the environment and immunocompromised patients confirmed horizontal transfer of highly related genetic lineages of multidrug-resistant (particularly to DAP) VRE strains between HCT and LKM patients and their room environment. Implementing WGS can be useful in distinguishing VRE reservoirs where interventions can be targeted to prevent and control the spread of highly resistant organisms.
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http://dx.doi.org/10.1093/cid/ciab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677550PMC
December 2021

Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic.

Clin Infect Dis 2021 Dec;73(11):e4472-e4474

Center for Antimicrobial Resistance and Microbial Genomics, UTHealth McGovern School of Medicine, Houston, Texas, USA.

We report the emergence of non-susceptibility to cefiderocol from a subpopulation of Pseudomonas aeruginosa recovered from a patient without history of cefiderocol exposure. Whole genome sequencing identified mutations in major iron transport pathways previously associated with cefiderocol uptake. Susceptibility testing should be performed before therapy with siderophore cephalosporins.
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http://dx.doi.org/10.1093/cid/ciaa1909DOI Listing
December 2021

Scientific evidence for the control of antimicrobial resistance.

Rev Panam Salud Publica 2020 17;44:e128. Epub 2020 Dec 17.

Pan American Association of Infectious Diseases Santo Domingo Dominican Republic Pan American Association of Infectious Diseases, Santo Domingo, Dominican Republic.

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http://dx.doi.org/10.26633/RPSP.2020.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746004PMC
December 2020

IS26-mediated amplification of blaOXA-1 and blaCTX-M-15 with concurrent outer membrane porin disruption associated with de novo carbapenem resistance in a recurrent bacteraemia cohort.

J Antimicrob Chemother 2021 01;76(2):385-395

Center for Antimicrobial Resistance and Microbial Genomics, Division of Infectious Diseases, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.

Background: Approximately half of clinical carbapenem-resistant Enterobacterales (CRE) isolates lack carbapenem-hydrolysing enzymes and develop carbapenem resistance through alternative mechanisms.

Objectives: To elucidate development of carbapenem resistance mechanisms from clonal, recurrent ESBL-positive Enterobacterales (ESBL-E) bacteraemia isolates in a vulnerable patient population.

Methods: This study investigated a cohort of ESBL-E bacteraemia cases in Houston, TX, USA. Oxford Nanopore Technologies long-read and Illumina short-read sequencing data were used for comparative genomic analysis. Serial passaging experiments were performed on a set of clinical ST131 Escherichia coli isolates to recapitulate in vivo observations. Quantitative PCR (qPCR) and qRT-PCR were used to determine copy number and transcript levels of β-lactamase genes, respectively.

Results: Non-carbapenemase-producing CRE (non-CP-CRE) clinical isolates emerged from an ESBL-E background through a concurrence of primarily IS26-mediated amplifications of blaOXA-1 and blaCTX-M-1 group genes coupled with porin inactivation. The discrete, modular translocatable units (TUs) that carried and amplified β-lactamase genes mobilized intracellularly from a chromosomal, IS26-bound transposon and inserted within porin genes, thereby increasing β-lactamase gene copy number and inactivating porins concurrently. The carbapenem resistance phenotype and TU-mediated β-lactamase gene amplification were recapitulated by passaging a clinical ESBL-E isolate in the presence of ertapenem. Clinical non-CP-CRE isolates had stable carbapenem resistance phenotypes in the absence of ertapenem exposure.

Conclusions: These data demonstrate IS26-mediated mechanisms underlying β-lactamase gene amplification with concurrent outer membrane porin disruption driving emergence of clinical non-CP-CRE. Furthermore, these amplifications were stable in the absence of antimicrobial pressure. Long-read sequencing can be utilized to identify unique mobile genetic element mechanisms that drive antimicrobial resistance.
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http://dx.doi.org/10.1093/jac/dkaa447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816169PMC
January 2021

Resistance in Vancomycin-Resistant Enterococci.

Infect Dis Clin North Am 2020 12;34(4):751-771

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin St. MSB 2.112, Houston, TX 77030, USA; Center for Antimicrobial Resistance and Microbial Genomics (CARMiG); Department of Microbiology and Molecular Genetics, 6431 Fannin St. MSB 2.112, Houston, TX 77030, USA; University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA; Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia. Electronic address:

Serious infections owing to vancomycin-resistant enterococci have historically proven to be difficult clinical cases, requiring combination therapy and management of treatment-related toxicity. Despite the introduction of new antibiotics with activity against vancomycin-resistant enterococci to the therapeutic armamentarium, significant challenges remain. An understanding of the factors driving the emergence of resistance in vancomycin-resistant enterococci, the dynamics of gastrointestinal colonization and microbiota-mediated colonization resistance, and the mechanisms of resistance to the currently available therapeutics will permit clinicians to be better prepared to tackle these challenging hospital-associated pathogens.
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http://dx.doi.org/10.1016/j.idc.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640809PMC
December 2020

Dynamics of Dissemination from Non-CG258 to Other via IncN Plasmids in an Area of High Endemicity.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Department of Microbiology and Parasitology, Bacteria and Cancer Group, Universidad de Antioquia, Medellín, Colombia.

Carbapenem-resistant (CRE) pose a significant threat to global public health. The most important mechanism for carbapenem resistance is the production of carbapenemases. carbapenemase (KPC) represents one of the main carbapenemases worldwide. Complex mechanisms of dissemination have been reported in Colombia, a country with a high endemicity of carbapenem resistance. Here, we characterized the dynamics of dissemination of gene among CRE infecting and colonizing patients in three hospitals localized in a highly endemic area of Colombia (2013 and 2015). We identified the genomic characteristics of KPC-producing recovered from patients infected/colonized and reconstructed the dynamics of dissemination of using both short and long read sequencing. We found that spread of among in the participating hospitals was due to intra- and interspecies horizontal gene transfer (HGT) mediated by promiscuous plasmids associated with transposable elements that was originated from a multispecies outbreak of KPC-producing in a neonatal intensive care unit. The plasmids were detected in isolates recovered in other units within the same hospital and nearby hospitals. The gene "epidemic" was driven by IncN-pST15-type plasmids carrying a novel Tnb structure and non-Tn elements (NTE) in spp., , spp., and spp. Of note, was found to coexist with in species of the complex. Our findings suggest that the main mechanism for dissemination of is HGT mediated by highly transferable plasmids among species of in infected/colonized patients, presenting a major challenge for public health interventions in developing countries such as Colombia.
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http://dx.doi.org/10.1128/AAC.01743-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674068PMC
November 2020

Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19:Serologic Testing.

Clin Infect Dis 2020 Sep 12. Epub 2020 Sep 12.

Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Background: The availability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologic testing has rapidly increased. Current assays use a variety of technologies, measure different classes of immunoglobulin or immunoglobulin combinations and detect antibodies directed against different portions of the virus. The overall accuracy of these tests, however, has not been well-defined. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the coronavirus disease 2019 (COVID-19) serology literature and construct best practice guidance related to SARS-CoV-2 serologic testing. This guideline is the fourth in a series of rapid, frequently updated COVID-19 guidelines developed by IDSA.

Objective: IDSA's goal was to develop evidence-based recommendations that assist clinicians, clinical laboratories, patients and policymakers in decisions related to the optimal use of SARS-CoV-2 serologic tests in a variety of settings. We also highlight important unmet research needs pertaining to the use of anti-SARS-CoV-2 antibody tests for diagnosis, public health surveillance, vaccine development and the selection of convalescent plasma donors.

Methods: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 serologic tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations.

Results: The panel agreed on eight diagnostic recommendations.

Conclusions: Information on the clinical performance and utility of SARS-CoV-2 serologic tests are rapidly emerging. Based on available evidence, detection of anti-SARS-CoV-2 antibodies may be useful for confirming the presence of current or past infection in selected situations. The panel identified three potential indications for serologic testing including: 1) evaluation of patients with a high clinical suspicion for COVID-19 when molecular diagnostic testing is negative and at least two weeks have passed since symptom onset; 2) assessment of multisystem inflammatory syndrome in children; and 3) for conducting serosurveillance studies. The certainty of available evidence supporting the use of serology for either diagnosis or epidemiology was, however, graded as very low to moderate.
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http://dx.doi.org/10.1093/cid/ciaa1343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543294PMC
September 2020

Strain-Specific Adaptations of to Serial In Vitro Passage in Daptomycin (DAP): Genotypic and Phenotypic Characteristics.

Antibiotics (Basel) 2020 Aug 15;9(8). Epub 2020 Aug 15.

Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Viridans group streptococci (VGS), especially the subgroup, are pivotal pathogens in a variety of invasive endovascular infections, including "toxic shock" in neutropenic cancer patients and infective endocarditis (IE). Previously, we showed that the serial in vitro passage of strains in sublethal daptomycin (DAP) resulted in rapid, high-level and stable DAP-resistance (DAP-R), which is accompanied by distinct changes in several genotypic and phenotypic signatures: (1) the disappearance of two key membrane phospholipids, phosphatidylglycerol (PG) and cardiolipin (CL); (2) increased membrane fluidity; (3) increased positive surface charge; (4) single nucleotide polymorphisms (SNPs) in two loci involved in CL biosynthesis (); and (5) DAP hyperaccumulation. The current study examined these same metrics following in vitro serial DAP passages of a separate well-characterized bloodstream isolate (SF100). Although some metrics seen in prior DAP post-passage strains were recapitulated with SF100 (e.g., SNPs, enhanced membrane fluidity), we observed the following major differences (comparing the parental versus post-passage variant): (1) no change in PG content; (2) reduced, but not absent, CL, with enhancement in phosphatidic acid (PA) content; (3) an unusual pattern of CL localization; (4) significantly decreased positive surface charge; (5) no difference in DAP accumulation; and (6) no SNPs. Thus, strains are not "pre-programmed" phenotypically and/or genotypically to adapt in an identical manner during the evolution of the DAP-R.
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http://dx.doi.org/10.3390/antibiotics9080520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460094PMC
August 2020

Measles or Not Measles? That Is the Question!

Open Forum Infect Dis 2020 Aug 22;7(8):ofaa311. Epub 2020 Jul 22.

Department of Internal Medicine, Division of Infectious Diseases, The University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA.

We present a diagnostically challenging case of a patient who presented with fever and rash during a measles outbreak. The diagnosis was complicated by the interpretation of the results of serological tests, which resulted in implementation of major preventive measures in the hospital. The patient was later confirmed to have murine typhus.
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http://dx.doi.org/10.1093/ofid/ofaa311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423290PMC
August 2020
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