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Antimicrobial Agents and Chemotherapy

Talles Prosperi de Paula, Patrícia Campi Santos, Raquel Duque do Nascimento Arifa, Angélica T Vieira, Ludmila de Matos Baltazar, Thiago Vinícius Ávila, Caio Tavares Fagundes, Zélia Menezes Garcia, Renata Lacerda Lima, Mauro Martins Teixeira, Danielle G Souza
The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and down-modulation of the production of pro-inflammatory mediators in the initial phase of infection in C57BL/6 mice with K...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Elizabeth L Berkow, Natalie S Nunnally, Alex Bandea, Randall Kuykendall, Karlyn Beer, Shawn R Lockhart
Emergence of azole resistant Aspergillus fumigatus has become a clinical problem in many parts of the world. Several amino acid mutations in the azole target protein, Cyp51Ap, contribute to this resistance, with the most concerning being the environmentally-derived TR34 /L98H and TR46 /Y121F/T289A mutations. Here, we performed passive surveillance to assess a sample of the A. fumigatus population in the US for the presence of these mutations. We found 1.4% of those isolates to exhibit elevated MIC via broth microdilution and five of those isolates harbored the TR34 /L98H mutation...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Melanie T Cushion, Alan Ashbaugh, Keeley Hendrix, Michael J Linke, Nikeya Tisdale, Steven G Sayson, Aleksey Porollo
The echinocandins are a class of anti-fungal agents that target β-1,3-D-glucan (BG) biosynthesis. In the ascigerous Pneumocystis species, treatment with these drugs deplete the asci life cycle stage which contain BG, but large numbers of forms which do not express BG remain in the infected lungs. In the present study, the gene expression profiles of Pneumocystis murina were compared between infected untreated mice and those treated with anidulafungin for 2 weeks to understand the metabolism of the persisting forms...
February 20, 2018: Antimicrobial Agents and Chemotherapy
M V Sheraton, K H Yam, C H Tan, H S Oh, E Mancini, L Yang, S A Rice, P M A Sloot
Segregation of bacteria based on their metabolic activity in biofilms plays an important role in the development of antibiotic drug resistance. Mushroom-shaped biofilm structures, which are reported for many bacteria, exhibit topographically varying levels of multiple drug resistance from the cap of the mushroom to its stalk. Understanding the dynamics behind the formation of such structures can aid in design of drug delivery systems, antibiotics, or physical systems for removal of biofilms. We explore the development of metabolically heterogenous Pseudomonas aeruginosa biofilms using numerical models and laboratory knock-out experiments on wild-type and chemotaxis deficient mutants...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Miné de Kock, Joel Tarning, Lesley Workman, Elizabeth N Allen, Mamadou M Tekete, Abdoulaye A Djimde, David J Bell, Steve A Ward, Karen I Barnes, Paolo Denti
Sulfadoxine/pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children between 3 to 59 months in the sub-Sahel regions of Africa. Sub-optimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 paediatric and 386 adult patients were analysed using nonlinear mixed effects modelling to evaluate the current dosing regimen and, if needed, propose an optimised dosing regimen in children under five years old...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Chao Chen, Susana Gardete, Robert Sander Jansen, Annanya Shetty, Thomas Dick, Kyu Y Rhee, Véronique Dartois
Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb's efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil's synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Helgi Padari, Tuuli Metsvaht, Eva Germovsek, Charlotte I Barker, Karin Kipper, Koit Herodes, Joseph F Standing, Kersti Oselin, Tõnis Tasa, Hiie Soeorg, Irja Lutsar
Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg/q12h. At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, 12 h after injection...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Agibothu Kupparam Hemanth Kumar, Alok Kumar, Thiruvengadam Kannan, Rakesh Bhatia, Dipti Agarwal, Santosh Kumar, Rajeshwar Dayal, Sheo Pratap Singh, Geetha Ramachandran
We studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH) and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR TB) being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR TB at the Sarojini Naidu Medical College, Agra, India who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Laura Fernández-García, Felipe Fernandez-Cuenca, Lucía Blasco, Rafael López-Rojas, Anton Ambroa, María Lopez, Álvaro Pascual, Germán Bou, María Tomás
Unknown are the mechanisms of tolerance and persistence associated to several compounds in A.baumannii clinical isolates. Using transcriptomic and microbiological studies, we found a link between bacterial tolerance mechanisms to clorhexidine as well as the development of persistence in presence of imipenem in A.baumannii strain belonging to ST-2 clinical clone (OXA-24 ß-lactamase and AbkAB TA system by plasmid). Interestingly, A.baumannii ATCC17978 strain (AbkAB TA system by plasmid) showed persistence in presence of imipenem and chlorhexidine...
February 20, 2018: Antimicrobial Agents and Chemotherapy
N J Ajami, J L Cope, M C Wong, J F Petrosino, L Chesnel
Clostridium difficile infection (CDI), a common cause of hospital-acquired infections, typically occurs after disruption of the normal gut microbiome by broad-spectrum antibiotics. Fidaxomicin is a narrow-spectrum antibiotic that demonstrates reduced impact on the normal gut microbiota and is approved for the treatment of CDI. To further explore the benefits of this property, we used a murine model to examine the effects of fidaxomicin versus vancomycin on gut microbiota and susceptibility to C. difficile colonization while tracking microbiota recovery over time...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Bin Huang, Yuting He, Xingyan Ma, Renxin Cai, Jianming Zeng, Yang Lu, Weizheng Zhang, Kai Lan, Sunmei E, Yi-Wei Tang, Barry N Kreiswirth, Cha Chen, Liang Chen
Next generation sequencing of six mcr-1- harboring Escherichia coli and Klebsiella pneumoniae isolates collected from a tertiary care hospital in China revealed significant sequence variations in the regions flanking the mcr-1 gene. While sequence variations significantly affect the expression and promoter activity of mcr-1 , the mcr-1 gene expressions do not correlate with the in vitro colistin resistance levels, which warrants further in-depth investigations.
February 20, 2018: Antimicrobial Agents and Chemotherapy
Nicole S Delino, Manabu Aoki, Hironori Hayashi, Shin-Ichiro Hattori, Simon B Chang, Yuki Takamatsu, Cuthbert D Martyr, Debananda Das, Arun K Ghosh, Hiroaki Mitsuya
We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C5 position of P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2' -cyclopropyl (Cp)(or isopropyl)-aminobenzothiazole (Abt). Their 50% effective concentrations (EC50 s) were 2.5-30 nM against wild-type HIV-1NL4-3 , 0.3-6.7 nM against HIV-2EHO , and 0.9-90 nM against laboratory-selected-PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR )...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Alison A Jack, Saira Khan, Lydia C Powell, Manon F Pritchard, Konrad Beck, Hina Sadh, Lucy Sutton, Alessandra Cavaliere, Hannah Florance, Philip D Rye, David W Thomas, Katja E Hill
Pseudomonas aeruginosa plays a major role in many chronic infections. Its ability to readily form biofilms contributes to its success as an opportunistic pathogen and its resistance/tolerance to antimicrobial/antibiotic therapy. A low molecular weight alginate oligomer (OligoG CF-5/20), derived from marine algae, has previously been shown to impair motility in P. aeruginosa biofilms and disrupt pseudomonal biofilm assembly. As these bacterial phenotypes are regulated by quorum sensing (QS), we hypothesized that OligoG CF-5/20 may induce alterations in QS signalling in P...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Emily G Armitage, Amjed Q I Alqaisi, Joanna Godzien, Imanol Peña, Alison J Mbekeani, Vanesa Alsonso-Herranz, Ángeles López-Gonzálvez, Julio Martín, Raquel Gabarro, Paul W Denny, Michael P Barrett, Coral Barbas
With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral Leishmania sis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments for Leishmania sis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new, more successful treatments for Leishmania sis...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Chang-Wei Lei, Yan-Peng Chen, Ling-Han Kong, Jin-Xin Zeng, Yong-Xiang Wang, An-Yun Zhang, Hong-Ning Wang
A novel 61,578 bp genomic island named Proteus genomic island 2 (PGI2) was characterized in P. mirabilis of swine origin in China. The 23.85-kb backbone of PGI2 is related to that of Salmonella genomic island 1 and Acinetobacter genomic island 1. The MDR region of PGI2 is a complex class 1 integron containing fourteen different resistance genes. PGI2 was conjugally mobilized in trans to Escherichia coli in the presence of a conjugative IncC helper plasmid.
February 20, 2018: Antimicrobial Agents and Chemotherapy
Melina Ruggiero, Delphine Girlich, Laura Dabos, Pablo Power, Thierry Naas, Gabriel Gutkind
The bla PER-2 harboring plasmid pCf587 (191,541 bp) belongs to lineage IncA/C1 and is closely related to pRA1. It contains a large resistance island including the bla PER-2 gene between two copies of IS Kox2 -like elements, the toxin-antitoxin module pemK-pemI, several other resistance genes inserted within a Tn 2 transposon, a Tn 21 -like structure, and a class 1 integron. pCf587 belongs into ST 13, a new pMLST.
February 20, 2018: Antimicrobial Agents and Chemotherapy
Kimberly F Breglio, Rifat S Rahman, Juliana M Sá, David J Roberts, Thomas E Wellems
Some Kelch mutations of Plasmodium falciparum K13 protein confer increased survival to dihydroartemisinin (DHA)-treated ring-stage parasites. Here, we ask if K13 mutations affect a dormancy phenotype allowing parasites to survive DHA exposure then sorbitol selection. Although recrudescence from dormancy differed between two distinct parasites lines, it was similar for isogenic lines carrying single-site substitutions in K13. Therefore, K13 mutations do not alter the DHA-sorbitol combined dormancy phenotype; traits from other loci likely determine this phenotype...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Daniel Wibberg, Ileana P Salto, Felix G Eikmeyer, Irena Maus, Anika Winkler, Patrice Nordmann, Alfred Pühler, Laurent Poirel, Andreas Schlüter
Multidrug-resistant (MDR) Acinetobacter baumannii strains appeared as serious emerging nosocomial pathogens in clinical environments and especially in intensive care units (ICUs). A. baumannii strain K50 recovered from a hospitalized patient in Kuwait exhibited resistance to carbapenems, and additionally to ciprofloxacin, chloramphenicol, sulfonamides, amikacin and gentamicin. Genome sequencing revealed that the strain possesses two plasmids, pK50a (79.6 kb) and pK50b (9.5 kb) and a 3.75 Mb chromosome. A. baumannii K50 exhibits an Average Nucleotide Identity (ANI) value of 99...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Rajbharan Yadav, Kate E Rogers, Phillip J Bergen, Jürgen B Bulitta, Carl M J Kirkpatrick, Steven C Wallis, David L Paterson, Roger L Nation, Jeffrey Lipman, Jason A Roberts, Cornelia B Landersdorfer
Augmented renal clearance (ARC) in critically-ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa using the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically-ill patient and static concentration time-kill experiments (SCTK), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, at two inocula (105...
February 20, 2018: Antimicrobial Agents and Chemotherapy
Joseph Meletiadis, Maria Siopi, Athanassios Tsakris, Johan W Mouton, Spyros Pournaras
The lack of a quantifiable marker for echinocandins activity hinders in vitro PK/PD studies for Aspergillus spp. We developed an in vitro PK/PD model simulating anidulafungin pharmacokinetics and assessing its pharmacodynamics against A. fumigatus with a new easily quantifiable, sensitive and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196,V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) MEC and one (AFU79728) with MEC>16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane tube (DM) inoculated with 103 cfu/mL...
February 20, 2018: Antimicrobial Agents and Chemotherapy
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