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Jennifer A. Wambach, Lawrence M. Nogee
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 961-962, October 15, 2019.
Rashid, T., Haghighi, F., Hasan, I., Basseres, E., Alam, M. J., Sharma, S. V., Lai, D., DuPont, H. L., Garey, K. W.
Objective: Clostridioides difficile spores can survive in the environment either in mono- or mixed-species biofilms. However, no previous studies have investigated chemical disinfection of C. difficile spores embedded in biofilms. Thus, the purpose of this study was to assess the in vitro effectiveness of hospital disinfectants against C. difficile spores embedded within biofilms.Methods: Five unique C. difficile strains embedded in three different biofilm types grown for 72 or 120 hours were exposed to seven different hospital disinfectants. C. difficile log CFU/mL was calculated after manufacturer determined contact times along with biofilm biomass and microscopy. The primary analysis compared differences between C. difficile vegetative cell and spore counts as well as biomass after exposure to disinfectants.Results: C. difficile vegetative cells and spores were recovered from biofilms regardless the type of biofilm growth or biofilm growth time. No disinfectant was able to completely eliminate C. difficile from the biofilms. Overall, Clorox, OPA, and Virex were most effective at killing C. difficile spores regardless of biofilm age, ribotype, or wash conditions (p= 0.001, each). Clorox and OPA were also effective at killing total vegetative cell growth (P=0.001, each) but Virex was found to be ineffective against vegetative cell growth in biofilms (p=0.77). Clorox and Virex were most effective in reducing biomass followed by Nixall, OPA and Vital oxide.Conclusion. No disinfectant was able to completely eliminate C. difficile embedded within biofilms although differences among disinfectants were noted. Future research will be required to determine methods to eradicate this persister reservoir.
Iregui, A., Khan, Z., Landman, D., Quale, J.
WCK 4234 is a novel diazabicyclooctane with potent inhibitory activity against class A and D carbapenemases and class C enzymes. We examined the in vitro activity of meropenem + WCK 4234 (4 or 8 μg/ml) against Gram-negative pathogens from New York City. Three groups were analyzed: a contemporary collection of isolates, a collection of known carbapenem-resistant isolates, and a collection of isolates with defined resistance mechanisms. From the contemporary collection, 1) all Enterobacteriaceae were susceptible to meropenem + WCK 4234, 2) susceptibility rates for Acinetobacter baumannii to meropenem alone were 56.5%, with WCK 4234 4 μg/ml 82.6%, and with WCK 4234 8 μg/ml 95.7%, and 3) WCK 4234 had modest effect on susceptibility for P. aeruginosa. Against a collection of carbapenem-resistant isolates, WCK 4234 added to meropenem 1) restored meropenem susceptibility against KPC-producing K. pneumoniae, 2) improved susceptibility against A. baumannii, and 3) had a negligible effect for P. aeruginosa. When tested against isolates with defined mechanisms of resistance, K. pneumoniae with blaKPC had higher meropenem + WCK 4234 MICs albeit well below the susceptibility breakpoint; efflux systems or porins did not correlate with susceptibility. For A. baumannii, MICs of meropenem + WCK 4234 did not correlate with efflux systems, outer membrane protein, blaampC or blaoxa-51, however MICs were higher in isolates with ESBLs. For P. aeruginosa, isolates with relatively higher MICs to meropenem + WCK 4234 had increased expression of ampC. WCK 4234 is a potent β-lactamase inhibitor that when combined with meropenem, displays promising activity against multidrug-resistant pathogens.
Devanathan, A. S., Pirone, J. R., Akkina, R., Remling-Mulder, L., Luciw, P., Adamson, L., Garcia, J. V., Kovarova, M., White, N. R., Schauer, A. P., Blake, K., Sykes, C., Burgunder, E. M., Srinivas, N., Rosen, E. P., Kashuba, A. D. M.
For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of 6 ARVs in 3 preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some – but not all - ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.
Michael Quintel, Mattia Busana, Luciano Gattinoni
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 954-956, October 15, 2019.
Eric P. Nolley, Joseph M. Pilewski
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 956-957, October 15, 2019.
Guitor, A. K., Raphenya, A. R., Klunk, J., Kuch, M., Alcock, B., Surette, M. G., McArthur, A. G., Poinar, H. N., Wright, G. D.
The identification and association of the nucleotide sequences encoding antibiotic resistance elements is critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, which are both heavily time-consuming operations. An accurate and sensitive method to identify both rare and common resistance elements in complex metagenomic samples is needed. Referencing the Comprehensive Antibiotic Resistance Database, we designed a set of 37,826 probes to specifically target over 2000 nucleotide sequences associated with antibiotic resistance in clinically relevant bacteria. Testing of this probeset on DNA libraries generated from multi-drug resistant bacteria to selectively capture resistance genes reproducibly produced higher reads on-target at greater length of coverage when compared to shotgun sequencing. We also identified additional resistance gene sequences from human gut microbiome samples that sequencing alone was not able to detect. Our method to capture the resistome enables sensitive gene detection in diverse environments where antibiotic resistance represents less than 0.1% of the metagenome.
CD40, encoded by TNFRSF5, participates in the survival of B cells, process of antigen presentation and generation of CD8+ T cell memory. It also has an important effect on HCV antiviral immune response. This study aims to investigate whether TNFRSF5 gene polymorphisms are associated with HCV infection outcomes among Chinese population.
Three single nucleotide polymorphism (SNPs) (rs1535045, rs1883832, rs4810485) on TNFRSF5 were genotyped by TaqMan assay among Chinese population, including 1513 uninfected subjects, 496 spontaneous viral clearance subjects and 768 persistent HCV-infected subjects. Logistic analysis was used to compare these SNPs among different groups in this cross-sectional study. Functional annotations of the identified SNPs were further evaluated by bioinformatics analysis.
After adjusted by age, gender and routes of infection, the results of logistic analysis indicated that individuals carrying rs1535045 T allele had a higher risk to infect HCV compared with C allele (in recessive model, adjusted OR = 1.368, 95%CI = 1.070-1.749, P = 0.012). Subjects carried rs1535045 TT genotype were more likely to infect HCV than wild CC genotype (adjusted OR = 1.397, 95%CI = 1.078-1.809, P = 0.011). For rs1883832, T allele was significantly associated with an increased risk of HCV infection (in recessive model, adjusted OR = 1.337, 95%CI = 1.069-1.673, P = 0.011). Subjects with TT genotype had more possibility to infect HCV (adjusted OR = 1.351, 95%CI = 1.060-1.702, P = 0.015). In the stratified analysis, rs1535045 and rs1883832 were remained in various subgroups and the heterogeneity test showed no pronounced heterogeneity in any pairwise comparison (all P > 0.05). In addition, the results of the cumulative effects showed a tendency of that the more risk alleles (rs1535045 T and rs1883832 T) subjects carried, the more possibility of HCV infection exhibited (P
Ramendra R, Isnard S, Lin J, et al.
AbstractBackgroundCytomegalovirus (CMV) seropositivity and anti-CMV IgG levels are associated with adverse health outcomes in elderly populations. Among people living with HIV (PLWH) CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation.MethodsA total of 150 PLWH (79 ART-naïve and 71 ART-treated) were compared to 26 HIV-uninfected controls (UC). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, non-specific B cell activation, anti-CMV and anti-EBV IgG levels, and pro-inflammatory cytokines were measured.ResultsCMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and HIV-uninfected participants. In contrast, total non-specific IgG, IgM, IgA, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independently of sociodemographic and behavioural characteristics of the study population.ConclusionCMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV co-infection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH.
Saladini, F., Giannini, A., Boccuto, A., Dragoni, F., Appendino, A., Albanesi, E., Vicenti, I., Zazzi, M.
Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC and CAB demonstrated a comparable activity on a panel of INSTI resistant strains isolated from patients exposed to RAL, EVG and/or DTG, with a significantly reduced susceptibility only with the Q148H/K/R plus one-two additional INSTI mutations pathway.
Carli J. Lehr, Melissa Skeans, Elliott Dasenbrook, Aliza Fink, Gabriela Fernandez, Albert Faro, Maryam Valapour
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 1013-1021, October 15, 2019.
Shen, Z., Gao, Q., Qin, J., Liu, Y., Li, M.
Here, we report a NDM-5-producing ST35 hypervirulent K. pneumoniae strain, isolated from the blood of a male patient. It showed a remarkable resistance to serum killing and neutrophil phagocytosis and a high virulence in a mouse peritonitis infection model. Instead of carrying a pLVPK-like virulence plasmid, chromosomal integration of ICEKp1 (~76 kb) was identified in a specific asparagine-tRNA gene, harboring the iron acquisition system salmochelin (iroBCDN) and yersiniabactin and a variant of rmpA gene.
Nosyk B, , Zang X, et al.
AbstractWe estimated 10-year (2020-2030) trajectories for HIV incidence in six US cities. Estimated incidence will only decrease in two of six cities, with the overall population-weighted incidence decreasing 3.1% [-1.0% - 8.5%] by 2025, and 4.3% [-2.6% - 12.7%] by 2030 across cities. Targeted, context-specific combination implementation strategies will be necessary to meet the newly-established national targets.
Fojo A, Dowdy D.
HIV“Ending the HIV epidemic” planEpidemics/prevention & controldynamic transmission model
Kapoor, M., Moloney, M., Soltow, Q. A., Pillar, C. M., Shaw, K. J.
Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for invasive fungal infections. We determined that the median frequencies of spontaneous mutations conferring reduced susceptibility to MGX in Candida albicans, C. glabrata, and C. parapsilosis ranged from 3 x 10-8 to
Maarten van den Berge, Huib A. M. Kerstjens
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 951-952, October 15, 2019.
Leddy A, Sheira L, Tamraz B, et al.
AbstractBackgroundFood insecurity is a well-established determinant of sub-optimal self-reported antiretroviral therapy (ART) adherence, but few studies have investigated this association using objective adherence measures. Concentration of ART in hair is an objective and validated measure of drug adherence and exposure. We examined the association of food insecurity with levels of ART concentrations in hair among women living with HIV (WLHIV) in the United States (US).MethodsWe analyzed longitudinal data collected semi-annually from 2013- 2015 from the Women’s Interagency HIV Study, a multi-site prospective cohort study of WLHIV and HIV-negative controls. Our sample comprised 1,944 person-visits from 677 WLHIV. Food insecurity was measured using the US Household Food Security Survey Module. ART concentrations in hair were measured using high performance liquid chromatography with mass spectrometry detection for regimens including darunavir, atazanavir, raltegravir or dolutegravir. We conducted multiple three-level linear regressions that accounted for repeated measures and the ART medication(s) taken at each visit, adjusting for sociodemographic and clinical characteristics.ResultsAt baseline, 59% of participants were virally suppressed and 45% reported food insecurity. In the base multivariable model, each 3-point increase in food insecurity was associated with 0.94-fold lower ART concentration in hair (95% CI: 0.89, 0.99). This effect remained unchanged after adjusting for self-reported adherence.ConclusionsFood insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with sub-optimal ART adherence and/or drug absorption. Interventions that aim to improve ART adherence among WLHIV should consider and address the role of food insecurity.
Chow D, Bernas M, Gangcuangco L, et al.
Fischer, K., Nguyen, K., LiWang, P. J.
Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here we unify previous work on the importance of other glycans to Grft potency against HIV-1, and Grft's role in mediating conformational change of gp120, by mutating nearly every glycosylation site in gp120. In addition to significant loss of Grft activity by removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by mutation that results in the glycan at N448 shifting to N446, indicating that glycan importance may be related to their effect on glycosylation density. Grft's ability to alter the structure of gp120, exposing the CD4 binding site, only correlated with the presence of glycosylation at N295 in B clade strains, but not C clade strains. We further demonstrate that Grft can rescue the activity of bNAbs PGT121 and PGT126 in the event of loss or shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates Grft could be an important combinational therapeutic.
Caverly, L. J., Spilker, T., Kalikin, L. M., Stillwell, T., Young, C., Huang, D. B., LiPuma, J. J.
We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam-β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter; including multi-drug-resistant and extensively-drug-resistant strains. None of the newer β-lactam-β-lactamase combination drugs showed increased activity compared to older agents against Stenotrophomonas maltophilia or Pandoraea spp.
Donnellan, S., Aljayyoussi, G., Moyo, E., Ardrey, A., Martinez-Rodriguez, C., Ward, S. A., Biagini, G. A.
Clinical studies of new anti-tubercular drugs are costly and time consuming. Owing to the extensive TB treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of pre-clinical models in predicting the activity of fluoroquinolones underlines the importance of developing new and more robust predictive tools that will optimise the design of future trials. Here, we have used high-content imaging screening and pharmacodynamic intracellular modelling (PDi) to identify and prioritise fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modelling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilisation) rates when compared against 8-independent clinical trials. Additionally, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict relapse rate. These data further support that PDi-based modelling offers a much-needed decision making tool for the TB drug development pipeline.
John R. Balmes
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 958-959, October 15, 2019.
Brody H. Foy, Marcia Soares, Rafel Bordas, Matthew Richardson, Alex Bell, Amisha Singapuri, Beverley Hargadon, Christopher Brightling, Kelly Burrowes, David Kay, John Owers-Bradley, Salman Siddiqui
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 982-991, October 15, 2019.
Matthieu Schmidt, Tài Pham, Antonio Arcadipane, Cara Agerstrand, Shinichiro Ohshimo, Vincent Pellegrino, Alain Vuylsteke, Christophe Guervilly, Shay McGuinness, Sophie Pierard, Jeff Breeding, Claire Stewart, Simon Sin Wai Ching, Janice M. Camuso, R. Scott Stephens, Bobby King, Daniel Herr, Marcus J. Schultz, Mathilde Neuville, Elie Zogheib, Jean-Paul Mira, Hadrien Rozé, Marc Pierrot, Anthony Tobin, Carol Hodgson, Sylvie Chevret, Daniel Brodie, Alain Combes
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 1002-1012, October 15, 2019.
Hussein, M., Han, M.-L., Zhu, Y., Zhou, Q., Lin, Y.-W., Hancock, R. E. W., Hoyer, D., Creek, D. J., Li, J., Velkov, T.
In the present study, we employed untargeted metabolomics to investigate the synergistic killing mechanism of polymyxin B in combination with an aminoglycoside, amikacin against a polymyxin-susceptible isolate P. aeruginosa FADDI-PA111 (MICs = 2 mg/L for both polymyxin B and amikacin) and a polymyxin-resistant Liverpool Epidemic Strain LESB58 (the corresponding MIC for both polymyxin B and amikacin is 16 mg/L ). The metabolites were extracted at 15 min, 1 and 4 h following treatment with polymyxin B alone (2 mg/L for FADDI-PA111; 4 mg/L for LESB58), amikacin alone (2 mg/L) and in combination; and analyzed using LC-MS. At 15 min and 1 h, polymyxin B alone induced significant perturbations in glycerophospholipid and fatty acid metabolism pathways in FADDI-PA111, and to a lesser extent in LESB58. Amikacin alone at 1 and 4 h induced significant perturbations in peptide and amino acid metabolism, which is in line with the mode of action of aminoglycosides. Pathway analysis of FADDI-PA111 revealed that the synergistic effect of the combination was largely due to the inhibition of cell envelope biogenesis which was initially driven by polymyxin B via suppression of key metabolites involved in lipopolysaccharide, peptidoglycan and membrane lipids (15 min and 1 h) and later by amikacin (4 h). Overall, these novel findings demonstrate that the disruption of the cell envelope biogenesis, central carbohydrate metabolism, decreased levels of amino sugars and a downregulated nucleotide pool are the metabolic pathways associated with the synergistic killing of polymyxin-amikacin combination against P. aeruginosa. This mechanistic study might help optimizing synergistic polymyxin B combinations in the clinical setting.
Wang, L., Liu, D., Lv, Y., Cui, L., Li, Y., Li, T., Song, H., Hao, Y., Shen, J., Wang, Y., Walsh, T. R.
A novel, plasmid-mediated, high-level tigecycline resistance tet(X) gene variant, tet(X5), was detected in a clinical Acinetobacter baumannii isolate from China in 2017. Tet(X5) shows 84.5% and 90.5% amino acid identity to Tet(X3) and Tet(X4), respectively, with similar binding sites and a comparable affinity for tetracyclines. The tet(X5)-containing plasmid could only be transferred to A. baumannii via electro-transformation. This report follows the recent study describing the identification of tet(X3) and tet(X4).
Mroue, N., Arya, A., Brown Gandt, A., Russell, C., Han, A., Gavrish, E., LaFleur, M.
It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate the ClpP protease, killing high-density, non-dividing cultures of bacteria, tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug resistant Gram-positive pathogens in MIC assays with no pre-existing resistance detected. Killing of stationary phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant Enterococcus faecalis (VRE). None of the approved antibiotics linezolid, ampicillin, or oxacillin had bactericidal activity when tested alone under these conditions. ADEP4 initially caused killing, but regrowth of the culture was apparent within 96 hours due to resistance. Combinations of ADEP4 with linezolid or oxacillin caused substantially improved killing of MRSA and MSSA cultures respectively, and no regrowth due to resistance was observed. The combination of ADEP4 and ampicillin eradicated cultures of VRE to the limit of detection within 52 hours. These data suggest that combining ClpP activators with traditional antibiotics may be a good strategy to treat complicated Gram-positive infections.
Simon Finch, Amelia Shoemark, Alison J. Dicker, Holly R. Keir, Alexandria Smith, Samantha Ong, Brandon Tan, Jean-Yu Choi, Thomas C. Fardon, Diane Cassidy, Jeffrey T. J. Huang, James D. Chalmers
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 992-1001, October 15, 2019.
Lin K, Lee Y, Huang S, et al.
Burnham J, Geng E, Venkatram C, et al.
AbstractDissemination and implementation science seeks generalizable knowledge about closing the gap between clinical discovery and actual use in routine practice and public health. The field of infectious diseases enjoys an abundance of highly efficacious interventions (e.g., antimicrobial agents, HIV treatment) which are not adequately used in routine care, thereby missing critical opportunities to improve population health. In this article, we summarize salient features of dissemination and implementation science, reviewing definitions and methodologies for infectious diseases clinicians and researchers. We give examples of the limited use of dissemination and implementation science in infectious diseases thus far, suggest opportunities for application, and provide resources for interested readers to use and apply to their own research and practice.
Nyuykonge, B., Croughs, P. D., Fahal, A. H., Verbon, A., van de Sande, W. W. J.
The use of the Sensititre™ YeastOne™ YO10 Alamar Blue assay for the in vitro susceptibility testing of Madurella mycetomatis was evaluated in M. mycetomatis isolates with and without pyomelanin secretion. Pyomelanin secretion did not influence visual endpoint reading, however, it caused a shift in peak absorbance from 570 nm to 620 nm when read spectrophotometrically. Therefore, when choosing the method for end-point reading the presence of pyomelanin should be considered.
Sandhu, B. K., Edwards, A. N., Anderson, S. E., Woods, E. C., McBride, S. M.
Clostridioides difficile causes severe antibiotic-associated diarrhea and colitis. C. difficile is an anaerobic, Gram-positive spore former that is highly resistant to β-lactams, the most commonly prescribed antibiotics. The resistance of C. difficile to β-lactam antibiotics allows the pathogen to replicate and cause disease in antibiotic-treated patients. However, the mechanisms of β-lactam resistance in C. difficile are not fully understood. Our data reinforce prior evidence that C. difficile produces a β-lactamase, which is a common β-lactam resistance mechanism found in other bacterial species. Herein we characterize the C. difficile bla operon that encodes a lipoprotein of unknown function and a β-lactamase that was greatly induced in response to several classes of β-lactam antibiotics. An in-frame deletion of the operon abolished β-lactamase activity in C. difficile strain 630erm and resulted in decreased resistance to the β-lactam ampicillin. We found that the activity of this β-lactamase, BlaCDD, is dependent upon the redox state of the enzyme. In addition, we observed that transport of BlaCDD out of the cytosol and to the cell surface is facilitated by an N-terminal signal sequence. Our data demonstrate that a co-transcribed lipoprotein, BlaX, aids in BlaCDD activity. Further, we identified a conserved BlaRI regulatory system and demonstrated via insertional disruption that BlaRI controls transcription of the blaXCDD genes in response to β-lactams. These results provide support for the function of a β-lactamase in C. difficile antibiotic resistance, and reveal the unique roles of a co-regulated lipoprotein and reducing environment in C. difficile β-lactamase activity.
Sunad Rangarajan, Victor J. Thannickal
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 959-960, October 15, 2019.
Koibuchi T, Yotsuyanagi H.
Brian L. Graham, Irene Steenbruggen, Martin R. Miller, Igor Z. Barjaktarevic, Brendan G. Cooper, Graham L. Hall, Teal S. Hallstrand, David A. Kaminsky, Kevin McCarthy, Meredith C. McCormack, Cristine E. Oropez, Margaret Rosenfeld, Sanja Stanojevic, Maureen P. Swanney, Bruce R. Thompson
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page e70-e88, October 15, 2019.
Sanjay H. Chotirmall
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 952-954, October 15, 2019.
van Wijk, F., Waterval, J., van Aerde, K., Henriet, S. S. V., Meijer, F. J. A., Borra, L. C., Aarnoutse, R. E., van Ingen, J.
Mycobacterium abscessus is an extensively drug-resistant opportunistic pathogen that can cause chronic otomastoiditis. There are no evidence-based treatment regimens for this severe infection. We treated four children with M. abscessus otomastoiditis with a structured regimen of topical imipenem and tigecycline, intravenous imipenem and tigecycline and oral clofazimine and azithromycin and adjunctive surgery. This structured approach led to cure, with one year of follow-up after treatment. Adverse events were frequent, mostly caused by tigecycline.
Kuipers, S., Ruth, M. M., Mientjes, M., de Sevaux, R. G. L., van Ingen, J.
We report a case of a 58-year old renal transplant patient who developed recurrent urinary tract infection with an ESBL-positive Klebsiella pneumoniae strain in the first month post-transplant. Even though carbapenems tested susceptible and despite repeated meropenem treatment, his infection recurred. The infection eventually evolved into epididymitis that was successfully treated with meropenem and bacteriophages. This case demonstrates the difficulty of treating relapsing ESBL-positive Gram-negative infections in renal transplant patients.
Ceballos, S., Kim, C., Qian, Y., Mobashery, S., Chang, M., Torres, C.
The in vitro activities of five quinazolinone antibacterials, compounds Q1-Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (both in μg/ml) were as follows: Q1 (0.5/2), Q2 (1/4), Q3 (2/4), Q4 (0.06/0.25) and Q5 (0.125/0.5). Several strains with high MIC values for some of these compounds (from 8 to >32 μg/ml) exhibited amino-acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.
Shin S, Satyanarayana V, Ekstrand M, et al.
AbstractBackgroundMalnutrition is a common clinical concern among children in low-income communities affected by HIV. We examined the effect of a community-based nutritional intervention on anthropometric and clinical outcomes of children of women living with HIV in rural India.MethodsWe assigned women living with HIV and their child (oldest 3-8 years) to one of the four programs: 1) community-based HIV care program; 2) Program 1 + nutritional education; 3) Program 1 + food supplement; and 4) all elements of Programs 1-3. Study data were collected at baseline, months 6, 12, and 18. We applied mixed-effects modeling with restricted maximum likelihood estimation to examine changes in weight (all children) and CD4+ T cell counts (HIV-infected children only).ResultsOverall, 600 mother-child pairs were enrolled (150 per group) with 100% retention at follow-up visits. Approximately 20% of children were living with HIV. Children in Program 4 had higher weight gain compared to Programs 1, 2 and 3 at all time points (adjusted p < 0.001). We found higher increase in CD4+ T cells across all time points among participants in Programs 3 and 4 compared to Program 1 (adjusted p < 0.001). Factorial analysis suggested a synergistic effect of combining nutritional education and food supplements for weight gain, but not for increase in CD4+ T cells.ConclusionsA combination of nutrition education and food supplements provided to women living with HIV significantly increased weight and CD4+ T cells and such interventions can be integrated into HIV care programs in low-income settings.
In recent years, some rare fungi have been increasingly recognized as new human pathogens. Here we reported the first fatal case of human severe pneumonia complicated by multiple organ dysfunction caused by Acrophialophora levis infection. However, its pathogenic mechanism and risk factors are unknown. Acrophialophora genus has only reported in six cases of human infection worldwide, but it has not been reported previously in China.
A 71-year-old male patient with severe pneumonia complicated with multiple organ dysfunction caused by A. levis infection. The fungal identification was based on micromorphology and sequence analysis of the internal transcriptional spacer (ITS) of ribosomal RNA genes recovered from lower respiratory tract secretions. The microbial characteristics, sensitivity to antifungal drugs of this isolated A. levis were studied. Anti-infective regimen, liposomal amphotericin B combined with tegacycline, was used to prevent infection. The next day, the fever decreased, body temperature fluctuated between 36.5 and 37.8 degree, cough and sputum decreased, and sputum volume decreased, with oxygen uptake for 5 L/min, blood oxygen saturation over 95%. After 17 days of treatment, CT reexamination showed that the lesions in the right lung and left upper lung were absorbed and pleural effusion was reduced. The next 8 days, the patient asked to return to the local hospital for treatment. The local hospital stopped using liposomal amphotericin B because of the absence of liposomal amphotericin B, and died of respiratory failure 2 days later.
This study is the first to report the occurrence, risk factors, molecular determinants, microbial characteristics and susceptibility to antifungal agents of A. levis infection in China. In addition, six published cases of human infection with Acrophialophora were reviewed.
Hallie C. Prescott, Theodore J. Iwashyna, Bronagh Blackwood, Thierry Calandra, Linda L. Chlan, Karen Choong, Bronwen Connolly, Paul Dark, Luigi Ferrucci, Simon Finfer, Timothy D. Girard, Carol Hodgson, Ramona O. Hopkins, Catherine L. Hough, James C. Jackson, Flavia R. Machado, John C. Marshall, Cheryl Misak, Dale M. Needham, Pinaki Panigrahi, Konrad Reinhart, Sachin Yende, Ross Zafonte, Kathryn M. Rowan, Derek C. Angus
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 8, Page 972-981, October 15, 2019.
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