Archive for July, 2019

Managing All the Genotypic Knowledge: Approach to a Septic Patient Colonized by Different Enterobacteriales with Unique Carbapenemases

Antimicrob. Agents Chemother. August 2019 V.63 N.8

The recent development of new antimicrobials active against carbapenemase-producing Enterobacteriales (CPE) has brought new hope for the treatment of infections due to these organisms.

However, the evolving epidemiology of bacteria with carbapenemases may complicate management, as providers are faced with treating patients colonized by bacteria producing multiple carbapenemases.

Here, we present the clinical course and treatment of Raoultella planticola bacteremia in a cirrhotic patient known to be colonized with both blaKPC- and blaOXA-48-carrying organisms.

abstract

https://aac.asm.org/content/63/8/e00029-19.abstract?etoc

PDF

https://aac.asm.org/content/aac/63/8/e00029-19.full.pdf

July 27, 2019 at 10:43 am

Building an innovative Chagas disease program for primary care units, in an urban non- endemic city

BMC Public Healthvolume 19, Article number: 904 (2019

Background

On an absolute basis, Argentina is the country with the largest affected population with Chagas Disease (ChD). This constitutes a significant public health issue. As a consequence of Argentina’s migratory patterns, there has been a significant increase of affected population in urban centers. An innovative project for early diagnosis and timely treatment of ChD was designed for Municipal Primary Care Facilities of La Plata City, a non- endemic area, in line with a proposal from the Pan-American Health Organization. The project was a public –private intervention. The objectives of this study were to demonstrate the feasibility of the primary healthcare level for early diagnosis and timely treatment of ChD; to design and implement a tailor made program and to innovate in a public-private association.

Methods

The healthcare barriers for early diagnosis and timely treatment for the population with ChD of La Plata were analyzed. The four dimensions described by Peters et al. (Ann N Y Acad Sci 1136:161–71, 2008) were used. The baseline was measured during a previous pilot project and the same items were evaluated at the end of 2017. The model from Damschroder et al. (Implement Sci 4:50, 2009) was used during the implementation process.

Results

With all the information gathered during this investigation, a “patient-centered” model was designed. During the program, 17,894 people were serologically tested for ChD, 1,394 were positive and 1,035 were treated. Additionally, 3,750 children from 46 public schools were evaluated for risk factors of ChD.

Conclusions

This project showed the feasibility of the primary healthcare level for early diagnosis and timely treatment of ChD. Tailor made programs and public-private associations should be considered for vulnerable populations in emerging economies in order to enhance efforts and obtain better results. This program may be replicated in other countries of Latin America were Chagas is a main public health issue and, with the corresponding adaptations, for other neglected diseases as well.

FULL TEXT

https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7248-5

PDF

https://bmcpublichealth.biomedcentral.com/track/pdf/10.1186/s12889-019-7248-5

July 24, 2019 at 8:15 am

Rates of blood cultures positive for vancomycin-resistant Enterococcus in Ontario: a quasi-experimental study

CMAJ Open

Jennie Johnstone, MD, PhD, Michelle E. Policarpio, MSc, Freda Lam, MPH, Kwaku Adomako, MSc, Chatura Prematunge, MSc, Emily Nadolny, MA, MPH, Ye Li, PhD, Kevin Brown, PhD, Elaine Kerr, ART, BA, Gary Garber, MD

Affiliations: Public Health Ontario (Johnstone, Policarpio, Lam, Adomako, Prematunge, Nadolny, Li, Brown, Garber); St. Joseph’s Health Centre (Johnstone); Department of Medicine (Johnstone, Garber); Dalla Lana School of Public Health (Johnstone, Li, Brown), University of Toronto; Institute for Quality Management in Healthcare (Kerr), Toronto, Ont.; Department of Medicine (Garber), University of Ottawa, Ottawa, Ont.

Background

Some Ontario hospitals have discontinued active screening and isolation programs for vancomycin-resistant Enterococcus (VRE). The aim of this study was to determine whether this practice change is associated with a change in the rate of rise of VRE-positive blood cultures.

Methods

All Ontario hospitals are mandated to report VRE bacteremia. Using this publicly reported data set, we included all validated results between January 2009 and June 2015. Beginning in June 2012, some hospitals discontinued active VRE screening and isolation programs (intervention). We used an interrupted time series Poisson regression to assess the slope change in the incidence rate of VRE-positive blood cultures (primary outcome) after versus before the intervention. Hospitals that continued to screen were the comparison group. Incidence rates were adjusted for hospital type and clustering within hospital site; slope changes are presented as incidence rate ratios (IRRs) with 95% confidence intervals (CIs).

Results

In hospitals that had ceased screening (n = 13), there was an increase in slope after screening and isolation were discontinued compared with before screening and isolation were discontinued (slope change IRR 1.25 [95% CI 1.01-1.54]). In hospitals that continued screening (n = 50), the slope was not significantly different after June 2012 compared with before June 2012 (slope change IRR 0.81 [95% CI 0.56-1.15]).

Interpretation

There was a significant increase in the rate of rise of VRE-positive blood cultures in hospitals that discontinued active VRE screening and isolation programs but not in hospitals that continued to screen and isolate. Hospitals aiming to minimize rising rates should consider maintaining active screening and isolation programs.

FULL TEXT

http://cmajopen.ca/content/5/2/E273.full

PDF

http://cmajopen.ca/content/5/2/E273.full.pdf

July 21, 2019 at 7:55 pm

Emergent Invasive Group A Streptococcus dysgalactiae subsp. equisimilis, US 2015–2018

Emerging Infectious Diseases July 2019

The term group A Streptococcus is considered synonymous for the species Streptococcus pyogenes. We describe an emergent invasive S. dysgalactiae subspecies equisimilis lineage that obtained the group A antigen through a single ancestral recombination event between a group C S. dysgalactiae subsp. equisimilis strain and a group A S. pyogenes strain.

FULL TEXT

https://wwwnc.cdc.gov/eid/article/25/8/18-1758_article?deliveryName=DM4767

PDF (CLIC en DOWNLOAD ARTICLE)

July 21, 2019 at 7:43 pm

Intrapulmonary Pharmacokinetics of Relebactam, a Novel β-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects.

Antimicrob Agents Chemother. February 23, 2018 V.62 N.3

Rizk ML1, Rhee EG2, Jumes PA2, Gotfried MH3, Zhao T2, Mangin E2, Bi S2, Chavez-Eng CM2, Zhang Z2, Butterton JR2.

Abstract

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel β-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem-cilastatin, given intravenously every 6 h for 5 doses, and were randomized to bronchoscopy/bronchoalveolar lavage at 0.5, 1, 1.5, or 3 h after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem. The exposure (area under the concentration-time curve from time zero to infinity) in ELF relative to that in plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture its behavior in plasma, with a partitioning coefficient capturing its behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 55%, based on free drug levels. These results support the clinical evaluation of relebactam with imipenem-cilastatin for the treatment of bacterial pneumonia.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826112/pdf/e01411-17.pdf

July 21, 2019 at 2:45 pm

REVIEW – New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

Clin Microbiol Infect. October 2017 V.23 N.10 P.704-712.

Wright H1, Bonomo RA2, Paterson DL3.

Abstract

BACKGROUND:

Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made.

AIMS:

This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms.

SOURCES:

A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies.

CONTENT:

Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline.

IMPLICATIONS:

The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.

FULL TEXT

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30495-0/fulltext

PDF

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30495-0/pdf

July 21, 2019 at 2:43 pm

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics.

Antimicrob Agents Chemother. June 24, 2019 V.63 N.7  pii: e00496-19.

Ersoy SC1, Abdelhady W1, Li L1, Chambers HF2, Xiong YQ3,4, Bayer AS1,4.

1 Los Angeles Biomedical Research Institute, Torrance, California, USA.

2 Division of Infectious Diseases, Zuckerberg San Francisco General Department of Medicine, San Francisco School of Medicine, University of California, San Francisco, California, USA.

3 Los Angeles Biomedical Research Institute, Torrance, California, USA yxiong@ucla.edu .

4 Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Abstract

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE).

Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens.

In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied.

We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive).

These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam.

Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains.

Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media.

These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.

FULL TEXT

https://aac.asm.org/content/63/7/e00496-19.long

PDF

https://aac.asm.org/content/aac/63/7/e00496-19.full.pdf

July 18, 2019 at 8:59 am

Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype

J Virus Erad April 2019  5:73

Zaunders J et al.

Background

Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3′ long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual.

Methods

PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro.

Results

PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5.

Conclusions

Subject C135’s early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

FULL TEXT

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/pdf/jve-5-73.pdf

July 16, 2019 at 8:46 am

CLINICAL PRACTICE – Measles

New England J of Medicine July 11, 2019

P.M. Strebel and W.A. Orenstein

A 38-year-old man presents to his primary care physician with a 3-day history of fever and cough. He is a father of two children, his wife is pregnant, and he has a history of recent travel outside the United States. The physical examination is notable for a body temperature of 39°C, conjunctivitis, and rhonchi on chest auscultation. The physician suspects bronchitis and prescribes antibiotic agents. Two days later, the patient returns with a red blotchy rash over his face and trunk. The physician becomes concerned about the possibility of measles. How should this case be further evaluated and managed? How might measles have been prevented, and what can be done to prevent the spread of the disease within the patient’s family and community? …..

FULL TEXT

https://www.nejm.org/doi/full/10.1056/NEJMcp1905181?query=TOC

PDF

https://www.nejm.org/doi/pdf/10.1056/NEJMcp1905181?articleTools=true

July 11, 2019 at 3:54 pm

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice.

Nat Commun. July 2, 2019 V.10 N.1 P.2753.

Dash PK1, Kaminski R2, Bella R2, Su H1, Mathews S1, Ahooyi TM2, Chen C2, Mancuso P2, Sariyer R2, Ferrante P2, Donadoni M2, Robinson JA2, Sillman B1, Lin Z1, Hilaire JR1, Banoub M1, Elango M1, Gautam N3, Mosley RL1, Poluektova LY1, McMillan J1, Bade AN1, Gorantla S1, Sariyer IK2, Burdo TH2, Young WB2, Amini S2, Gordon J2, Jacobson JM2, Edagwa B1, Khalili K4, Gendelman HE5.

Author information

1 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

2 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA.

3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

4 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA. kamel.khalili@temple.edu.

5 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA. hegendel@unmc.edu.

Abstract

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice.

HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests.

No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus.

In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606613/pdf/41467_2019_Article_10366.pdf

July 9, 2019 at 6:57 pm

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