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Antimicrobial Agents and Chemotherapy

Yuki Takamatsu, Manabu Aoki, Haydar Bulut, Debananda Das, Masayuki Amano, Venkata Reddy Sheri, Ladislau C Kovari, Hironori Hayashi, Nicole S Delino, Arun K Ghosh, Hiroaki Mitsuya
Combination antiretroviral therapy has achieved dramatic reductions in the mortality and morbidity in people with HIV-1 infection. Darunavir (DRV) represents a most efficacious and well-tolerated protease inhibitor (PI) with high genetic barrier to the emergence of drug-resistant HIV-1. However, highly DRV-resistant variants have been reported in patients receiving long-term DRV-containing regimens. Here, we report three novel HIV-1 PIs (GRL-057-14, GRL-058-14, and GRL-059-14), all of which contain a P2-amino-substituted- bis -tetrahydrofuranylurethane ( bis -THF) and a P2'-cyclopropyl-amino-benzothiazole (Cp-Abt)...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Belén Borrego, Ana I de Ávila, Esteban Domingo, Alejandro Brun
Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Anthony D Harris, J Kristie Johnson, Lisa Pineles, Lyndsay M O'Hara, Robert A Bonomo, Kerri A Thom
Objective: Acinetobacter baumannii is an important nosocomial pathogen. The objective of this study was to determine the proportion of A. baumannii due to patient-to-patient transmission by analyzing the molecular epidemiology of patients who acquired A. baumannii using peri-anal surveillance cultures in a large 2-year intensive care unit population. Design: Prospective cohort study Methods: Patients who were admitted to the medical and surgical intensive care units (ICUs) at the University of Maryland Medical Center from 2011 to 2013 underwent admission, weekly and discharge peri-anal cultures collected...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Dejun Liu, Weiwen Liu, Ziquan Lv, Junjie Xia, Xing Li, Yuxin Hao, Ying Zhou, Hong Yao, Zhihai Liu, Yang Wang, Jianzhong Shen, Yuebin Ke, Zhangqi Shen
The rapid dissemination of macrolide resistance gene erm (B) will likely compromise the efficacy of macrolides as the treatment of choice for campylobacteriosis. More importantly, erm (B) is always associated with several multidrug resistance genomic islands (MDRGIs), which confer resistance to multiple other antimicrobials. Continuous monitoring of the emergence of erm (B) and analysis of its associated genetic environments is crucial to our understanding of macrolide resistance in Campylobacter In this study, 290 Campylobacter isolates (216 C...
May 13, 2019: Antimicrobial Agents and Chemotherapy
M Andreína Pacheco, Esha R Kadakia, Zainab Chaudhary, Douglas J Perkins, Julia Kelley, Shashidhar Ravishankar, Michael Cranfield, Eldin Talundzic, Venkatachalam Udhayakumar, Ananias A Escalante
Mutations in the Plasmodium falciparum k13 gene ( Pfk13 ) are linked to delayed parasite clearance to artemisinin-based combination therapies (ACTs) in Southeast Asia. To explore the evolutionary rate and constraints acting on this gene, k13 orthologs from species sharing a recent common ancestor with P. falciparum and Plasmodium vivax were analyzed. These comparative studies were followed by genetic polymorphism analyses within P. falciparum using 982 complete Pfk13 sequences from public databases and new data obtained by next-generation sequencing from African and Haitian isolates...
May 13, 2019: Antimicrobial Agents and Chemotherapy
André Birgy, Corinne Levy, Marie-Hélène Nicolas-Chanoine, Aurélie Cointe, Claire A Hobson, Mélanie Magnan, Stéphane Bechet, Philippe Bidet, Robert Cohen, Stéphane Bonacorsi
The recent emergence and diffusion in the community of Escherichia coli isolates belonging to the multidrug-resistant and CTX-M-27-producing ST131 C1-M27 cluster, makes this cluster potentially as epidemic as the worldwide E coli ST131 subclade C2 composed of multidrug resistant isolates producing CTX-M-15. Thirty-five extended-spectrum beta-lactamase (ESBL) producing ST131 isolates were identified in a cohort of 1,885 French children over a 5 year-period. They were sequenced to characterize the ST131 E. coli isolates producing CTX-M-27 recently emerging in France...
May 13, 2019: Antimicrobial Agents and Chemotherapy
C M Thorpe, L A McDermott, M K Tran, J Chang, S G Jenkins, E J C Goldstein, R Patel, B A Forbes, S Johnson, D N Gerding, D R Snydman
Background: In 2011, we initiated a sentinel surveillance network to assess changes in C. difficile antimicrobial susceptibility to fidaxomicin from 6 geographically dispersed medical centers in the US. This report summarizes data from 2013-2016. Methods: C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution. CLSI, EUCAST or FDA breakpoints were used, where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Nicolas Kieffer, Patrice Nordmann, Yves Millemann, Laurent Poirel
Plasmid-mediated colistin resistance of the MCR type is a growing concern in Enterobacteriaceae since it has been described worldwide either in humans and in animals. Here we identified a series of MCR-producing Escherichia coli isolates, corresponding to two different clones (respectively represented by isolates PS1 and PS8b) producing MCR-1 and MCR-5, respectively, from pig fecal samples in France. Plasmid analysis showed that the plasmid carrying the mcr-1 gene (pPS1) possesses an IncHI2 backbone whereas the mcr-5 gene was carried onto a 6,268 bp non-typeable, non self-conjugative plasmid (pPS8b)...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Marva Seifert, Edmund Capparelli, Donald G Catanzaro, Timothy C Rodwell
BACKGROUND: Clinical phenotypic fluoroquinolone susceptibility testing of Mycobacterium tuberculosis (Mtb ) is currently based on Mtb growth at a single critical concentration, which provides limited information for a nuanced clinical response. We propose using specific resistance-conferring Mtb mutations in gyrA together with population pharmacokinetic and pharmacodynamic modeling as a novel tool to better inform fluoroquinolone treatment decisions. METHODS: We sequenced the gyrA resistance determining region of 138 clinical Mtb isolates collected from India, Moldova, Philippines and South Africa, then determined each strain's minimum inhibitory concentration or MIC against ofloxacin, moxifloxacin, levofloxacin, and gatifloxacin...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Giulia Menchinelli, Flora Marzia Liotti, Liliana Giordano, Giulia De Angelis, Maurizio Sanguinetti, Teresa Spanu, Brunella Posteraro
We assessed the antimicrobial-inactivation capability of BACT/ALERT® (FA Plus and FN Plus) or BACTEC™ (Plus Aerobic/F and Plus Anaerobic/F) media for 40 antibiotic/bacterium combinations in simulated adult blood cultures. Besides high recovery rates (93.2% and 88.4%, respectively), we showed that at lowest but clinically relevant antibiotic concentrations, both BACT/ALERT® and BACTEC™ media recovered all the organisms when tested with drugs except for Escherichia coli tested in the presence of meropenem...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Mariana Castanheira, Timothy B Doyle, Rodrigo E Mendes, Helio S Sader
The activity of ceftazidime-avibactam, ceftolozane-tazobactam, and comparators was evaluated for 733 isolates displaying resistance to broad-spectrum cephalosporins and carrying extended-spectrum β-lactamase (ESBL) genes detected by whole genome sequencing analysis. Isolates were collected during 2017 in US hospitals. ESBL-producers were 486 E. coli , 190 K. pneumoniae , 42 E. cloacae and 3 other species. The most common group of ESBL-encoding genes were bla CTX-M-15 -like ( n = 491) and bla CTX-M-15 alone ( n = 168) or plus bla OXA-1 ( n = 260), followed by isolates carrying bla CTX-M-14 -like ( n = 162) that included bla CTX-M-27 and bla CTX-M-14 (104 and 51 isolates) and bla SHV-12 and bla SHV-7 (48 and 22 isolates)...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Luis Ricardo Castellanos, Linda van der Graaf-van Bloois, Pilar Donado-Godoy, Dik J Mevius, Jaap A Wagenaar, Joost Hordijk, Aldert Zomer
The objective of this study was to elucidate the genetic and evolutionary relatedness of bla CMY-2 - and bla SHV-12 -carrying IncI1-Iγ plasmids. Phylogenomic analysis based on core genome alignments and gene presence/absence was performed for different IncI1-Iγ Sequence Types (STs). Most IncI1-Iγ/ST12 and IncI1-Iγ/ST231 plasmids had near-identical core genomes. The data suggests that widespread occurring bla CMY-2 -carrying IncI1-Iγ/ST12 plasmids originate from a common ancestor. In contrast, bla SHV-12 was inserted independently into different IncI1-Iγ/ST231-related plasmids...
May 13, 2019: Antimicrobial Agents and Chemotherapy
Kamilia Abdelraouf, Sean M Stainton, David P Nicolau
Ceftibuten/Clavulanate (CTB/CLA) is a novel β-lactam/β-lactamase combination with potential utility for management of urinary tract infections caused by Extended-spectrum β-lactamase (ESBL)-producing organisms. We examined the pharmacodynamics of the combination against 25 Enterobacteriaceae expressing ß-lactamases (CTX-M, TEM and SHV wild-types and SHV-ESBL) in the murine thigh infection model. MIC values to CTB and CTB/CLA ranged from 1-<32mg/L and 0.125-8mg/L, respectively. Human-simulated regimens of CTB and CLA equivalent to clinical doses of 400 mg PO q8h and 187 mg q8h, respectively, were developed...
May 6, 2019: Antimicrobial Agents and Chemotherapy
M Aruanno, D Bachmann, D Sanglard, F Lamoth
Aspergillus fumigatus is an opportunistic mold responsible of invasive aspergillosis. Triazoles (e.g. voriconazole) represent the first-line treatment, but emerging resistance is of concern. The echinocandin drug caspofungin is used as second line treatment but has limited efficacy. The heat shock protein 90 (Hsp90) orchestrates caspofungin stress response and is the trigger of an adaptive phenomenon called the paradoxical effect (growth recovery at increasing caspofungin concentrations). The aim of this study was to elucidate Hsp90-dependent mechanisms of caspofungin stress response...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Keivan Zandi, Leda Bassit, Franck Amblard, Bryan D Cox, Pouya Hassandarvish, Ehsan Moghaddam, Andrew Yueh, Gisele Olinto Libanio Rodrigues, Ingredy Passos, Vivian V Costa, Sazaly AbuBakar, Longhu Zhou, James Kohler, Mauro M Teixeira, Raymond F Schinazi
Dengue virus (DENV) and Japanese Encephalitis virus (JEV) are two important arthropod-borne viruses from Flaviviridae family. DENV is a global public health problem with significant social and economic impacts especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no US FDA approved antiviral drugs available to treat or prevent DENV and JEV leaving nearly one-third of the worldwide population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Liliana Giordano, Barbara Fiori, Tiziana D'Inzeo, Gabriella Parisi, Flora Marzia Liotti, Giulia Menchinelli, Giulia De Angelis, Flavio De Maio, Francesco Luzzaro, Maurizio Sanguinetti, Brunella Posteraro, Teresa Spanu
We directly tested 484 organisms from clinical ( n = 310) and simulated ( n = 174) positive blood cultures using the NG-Test CARBA 5 assay for carbapenemase-producing Enterobacterales detection. The assay identified all but four of the KPC (170/171), OXA-48-like (22/22), VIM (19/21), and NDM (14/15) producers with no false-positives. Among the clinical K. pneumoniae organisms tested, 122/123 KPC, 1/1 OXA-48-like, and 1/2 VIM producers were detected by the assay. Some VIM and NDM producers yielded scant but still readable bands with the assay...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Maurizio Sanguinetti, Emilia Cantón, Riccardo Torelli, Fabio Tumietto, Ana Espinel-Ingroff, Brunella Posteraro
We determined the in vitro activity of fenticonazole against 318 vaginitis isolates of Candida and bacterial species, and selected 28 isolates for time-kill curve studies. At concentrations equal to 4× MIC, fenticonazole reached the 99.9% killing endpoint by ∼10 h for S. aureus , S. agalactiae , and E. coli ; ∼17 h for both C. albicans and C. parapsilosis ; at concentrations equal to 8× MIC, by ∼19 and ∼20 h for C. glabrata and C. tropicalis , respectively. At concentrations equal to 2× MIC, fenticonazole required ∼20 h to reach the above endpoint against C...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Alba Pérez-Cantero, Loida López-Fernández, Josep Guarro, Javier Capilla
Invasive aspergillosis (IA) is a severe condition mainly caused by Aspergillus fumigatus , although other species of the genus, such as section Nigri members, can also be involved. Voriconazole (VRC) is the recommended treatment for IA; however, the prevalence of azole resistant Aspergillus isolates has alarmingly increased in recent years and the underlying resistance mechanisms in non- fumigatus species remain unclear. We have determined the in vitro susceptibility of 36 strains from section Nigri to VRC, posaconazole (POS) and itraconazole (ITC), and we have explored the role of Cyp51A and Cyp51B, both targets of azoles, in azole resistance...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Maria Karlsson, Richard A Stanton, Uzma Ansari, Gillian McAllister, Monica Y Chan, Erisa Sula, Julian E Grass, Nadezhda Duffy, Melissa L Anacker, Medora L Witwer, J Kamile Rasheed, Christopher A Elkins, Alison Laufer Halpin
We report on a carbapenemase-producing hypervirulent Klebsiella pneumoniae (CP-hvKP) collected from a U.S. patient at an outpatient clinic. The isolate was identified as K. pneumoniae serotype K1, sequence type 23 and included both a hypervirulence (with rmpA , rmpA2 iroBCDN , peg -344 and iucABCD - iutA genes) and a carbapenemase-encoding ( bla KPC-2 ) plasmid. The emergence of CP-hvKP underscores the importance of clinical awareness of this pathotype and the need for continued monitoring of CP-hvKP in the United States...
May 6, 2019: Antimicrobial Agents and Chemotherapy
Lukas Muri, Michael Perny, Jonas Zemp, Denis Grandgirard, Stephen L Leib
Despite available antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective. In vitro , the anti-inflammatory effect of doxycycline and daptomycin were evaluated on primary rat astroglial cells stimulated with S...
May 6, 2019: Antimicrobial Agents and Chemotherapy
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