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Antimicrobial Agents and Chemotherapy

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https://www.readbyqxmd.com/read/28096166/the-role-of-renal-drug-exposure-in-polymyxin-b-induced-nephrotoxicity
#1
Pooja Manchandani, Jian Zhou, Jessica T Babic, Kimberly R Ledesma, Luan D Truong, Vincent H Tam
Despite dose-limiting nephrotoxic potentials, polymyxin B has re-emerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225-250 g) were divided into 3 dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg and 20 mg/kg) subcutaneously once daily...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096165/in-vitro-activity-of-ceftolozane-tazobactam-against-multidrug-resistant-non-fermenting-gram-negative-bacilli-isolated-from-patients-with-cystic-fibrosis
#2
Patrick Grohs, Gary Taieb, Philippe Morand, Iheb Kaibi, Isabelle Podglajen, Marie Lavollay, Jean-Luc Mainardi, Fabrice Compain
Ceftolozane-tazobactam was tested against 58 multidrug-resistant non-fermenting Gram-negative bacilli (35 Pseudomonas aeruginosa, 11 Achromobacter xylosoxydans and 12 Stenotrophomonas maltophilia) isolated from cystic fibrosis patients and compared to ceftolozane alone, ceftazidime, meropenem and piperacillin-tazobactam. Ceftolozane-tazobactam was the most active agent against P. aeruginosa but was inactive against A. xylosoxydans and S. maltophilia In time-kill experiments ceftolozane-tazobactam had complete bactericidal activity against 2/6 (33%) clinical isolates...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096164/pharmacodynamics-of-ceftaroline-plus-ampicillin-against-enterococcus-faecalis-in-an-in-vitro-pharmacokinetic-pharmacodynamic-model-of-simulated-endocardial-vegetations
#3
Brian J Werth, Laura M Shireman
The combination of ampicillin plus ceftaroline has been suggested to be more reliably synergistic against E. faecalis than ampicillin plus ceftriaxone using time-kill methods. The purpose of this study was to determine if this trend persists in a two-compartment-model of simulated endocardial vegetations(SEV) using clinically relevant pharmacokinetic exposures of these antimicrobials. Three clinically-derived E. faecalis strains were included in the study. The MICs of study antimicrobials were determined by broth microdilution...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096163/large-scale-evaluation-of-in-vitro-amphotericin-b-triazole-and-echinocandin-activity-against-coccidioides-species-from-united-states-institutions
#4
George R Thompson, Bridget M Barker, Nathan P Wiederhold
Large-scale testing of Coccidioides isolates has not previously been performed, nor has the frequency of clinical isolates with elevated amphotericin B or triazole MICs been evaluated. Coccidioides isolates (n=581) underwent antifungal susceptibility testing. Elevated MIC values were observed for: fluconazole (MIC ≥16 μg/ml, 37.3% of isolates; ≥32 μg/ml, 7.9%), itraconazole (1.0% ≥2 μg/ml), posaconazole (1.0% ≥1 μg/ml), and voriconazole (1.2% ≥2 μg/ml). However mould-active triazoles exhibited low MICs for the majority of isolates tested...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096162/impact-of-extended-artesunate-duration-on-parasitological-outcome-in-a-cytocidal-murine-malaria-model
#5
Leah A Walker, David J Sullivan
Artemisinin-based combination therapies are a key pillar in global malaria control and are recommended as a first-line Plasmodium falciparum treatment. They rely upon a rapid, 4-log reduction in parasitemia by artemisinin compounds with a short half-life and the killing of remaining parasites by a partner compound with a longer half-life. Current treatment guidelines stipulate giving three 24 hour interval doses or six 12 hour interval doses over a 3-day period. Due to the short half-life of artesunate and artemether, almost all of the resulting cytocidal activity is confined within a single 48 hour asexual P...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096161/perifosine-mechanisms-of-action-in-leishmania-spp
#6
Atteneri López-Arencibia, Carmen Martín-Navarro, Ines Sifaoui, María Reyes-Batlle, Carolina Wagner, Jacob Lorenzo-Morales, Sutherland K Maciver, José E Piñero
The mechanism by which perifosine induced cell death in Leishmania donovani and L. amazonensis is described in this study. The drug reduced Leishmania mitochondrial membrane potential, decreased cellular ATP levels while increasing phosphatidylserine externalization. Perifosine did not increase membrane permeabilization. We also found that the drug inhibited the phosphorylation of Akt in the parasites. These results highlight the potential use of perifosine, as an alternative to miltefosine, against Leishmania...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096160/determinants-of-antibacterial-spectrum-and-resistance-potential-of-the-elongation-factor-g-inhibitor-argyrin-b-in-key-gram-negative-pathogens
#7
Adriana K Jones, Angela L Woods, Kenneth T Takeoka, Xiaoyu Shen, Jun-Rong Wei, Ruth E Caughlan, Charles R Dean
Argyrins are natural products with antibacterial activity against Gram-negative pathogens such as P. aeruginosa, B. multivorans and S. maltophilia We previously showed that argyrin B targets elongation factor G (FusA). Here we show that Argyrin B activity against P. aeruginosa PAO1 (MIC = 8 μg/mL) was not affected by deletion of the MexAB-OprM, MexXY-OprM, MexCD-OprJ or MexEF-OprN efflux pumps. However, argyrin B induced expression of MexXY causing a slight but reproducible antagonism with the MexXY substrate antibiotic ciprofloxacin...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096159/genome-analysis-of-the-carbapenem-and-colistin-resistant-escherichia-coli-isolate-nrz14408-reveal-horizontal-gene-transfer-pathways-towards-pan-resistance-and-enhanced-virulence
#8
Linda Falgenhauer, Hiren Ghosh, Swapnil Doijad, Yancheng Yao, Boyke Bunk, Cathrin Spröer, Martin Kaase, Rolf Hilker, Jörg Overmann, Can Imirzalioglu, Trinad Chakraborty
Colistin is used as a last-resort antibiotic for treating infections caused by multidrug-resistant Enterobacteriaceae, in particular for carbapenem-resistant isolates.….
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096158/vancomycin-area-under-the-curve-estimation-in-obese-adults-the-peak-improves-precision-and-lowers-bias
#9
Manjunath P Pai, Joseph Hong, Lynne Krop
Vancomycin area under the curve (AUC) estimates may be skewed in obese adults due to weight-dependent pharmacokinetic parameters. We demonstrate that peak and trough measurements reduce bias and improve the precision of vancomycin AUC estimates in obese adults (n=75) and validate this in an independent cohort (n=31). The precision and mean %bias of Bayesian vancomycin AUC estimates are comparable between covariate-dependent (R(2)=0.774, 3.55%) and covariate-independent (R(2)=0.804, 3.28%) models when peaks and troughs are measured but not when restricted to trough only measurements (R(2),= 0...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096157/resistance-to-thiacetazone-derivatives-active-against-mycobacterium-abscessus-involves-mutations-in-the-mmpl5-transcriptional-repressor-mab_4384
#10
Iman Halloum, Albertus Viljoen, Varun Khanna, Derek Craig, Christiane Bouchier, Roland Brosch, Geoffrey Coxon, Laurent Kremer
Available chemotherapeutic options are very limited against Mycobacterium abscessus, which imparts a particular challenge in the treatment of cystic fibrosis (CF) patients infected with this rapid-growing mycobacterium. New drugs are urgently needed against this emerging pathogen, but the discovery of active chemotypes has not been performed intensively. Interestingly, however, the repurposing of thiacetazone (TAC), a drug once used to treat tuberculosis, has increased following the deciphering of its mechanism of action and the detection of significantly more potent analogues...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096156/bacterial-derived-cell-penetrating-peptides-deliver-gentamicin-to-kill-intracellular-pathogens
#11
Marta Gomarasca, Thaynan F C Martins, Lilo Greune, Philip R Hardwidge, M Alexander Schmidt, Christian Rüter
Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here we characterized two CPPs, α1H and α2H, derived from the Y. enterocolitica YopM effector protein. These CPPs, as well as Tat(Trans-activator of transcription) from HIV-1 virus, were used to deliver the antibiotic gentamicin to target intracellular bacteria...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096155/inhibition-of-the-%C3%AE-lactamase-blamab-by-avibactam-improves-the-in-vitro-and-in-vivo-efficacy-of-imipenem-against-mycobacterium-abscessus
#12
Anne-Laure Lefebvre, Vincent Le Moigne, Audrey Bernut, Carole Veckerlé, Fabrice Compain, Jean-Louis Herrmann, Laurent Kremer, Michel Arthur, Jean-Luc Mainardi
Mycobacterium abscessus pulmonary infections are treated with a macrolide (clarithromycin or azithromycin), an aminoglycoside (amikacin), and a β-lactam (cefoxitin or imipenem). The triple combination is used without any β-lactamase inhibitor despite production of the broad spectrum β-lactamase BlaMab We determine whether inhibition of BlaMab by avibactam improves the activity of imipenem against M. abscessus. Bactericidal activity of drug combinations was assayed in broth and in human macrophages. The in vivo efficacy of the drugs was tested by monitoring the survival of infected zebrafish embryos...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096154/influence-of-rhlr-and-lasr-on-polymyxin-pharmacodynamics-in-pseudomonas-aeruginosa-implications-for-quorum-sensing-inhibition-with-azithromycin
#13
Zackery P Bulman, Neang S Ly, Justin R Lenhard, Patricia N Holden, Jürgen B Bulitta, Brian T Tsuji
Quorum sensing's impact on polymyxin and azithromycin pharmacodynamics was assessed in Pseudomonas aeruginosa PAO1 and an isogenic rhlR/lasR double knockout. For polymyxin B, greater killing against the rhlR/lasR knockout versus PAO1 was observed at 10(8) CFU/mL(polymyxin B EC50:5.61 versus 12.5mg/L, respectively; p<0.005). Polymyxin B combined with azithromycin (256mg/L) was synergistic against each strain, significantly reducing the respective polymyxin B EC50 compared to monotherapy (p<0.005), and is a promising strategy to combat P...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28096153/plasmidic-qnr-genes-confer-clinical-resistance-to-ciprofloxacin-under-urinary-tract-physiological-conditions
#14
Guillermo Martín-Gutiérrez, José Manuel Rodríguez-Martínez, Álvaro Pascual, Jerónimo Rodríguez-Beltrán, Jesús Blázquez
Escherichia coli variants expressing plasmid-mediated qnr genes are usually susceptible to fluoroquinolones by standard susceptibility testing. Here we show that, under specific urinary tract physiological conditions, susceptible laboratory and clinical strains harboring qnr determinants become fully resistant to ciprofloxacin. Therefore, physiological conditions, mainly urine pH values, should be considered for susceptibility testing of CIP activity against E. coli in UTIs and for selecting appropriate antibiotics for UTI treatment...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069659/mrsa-strains-carrying-the-novel-mecc-gene-full-genome-sequencing-identifies-in-the-genetic-background-several-determinants-that-modulate-the-resistant-phenotype
#15
Catarina Milheiriço, Hermínia de Lencastre, Alexander Tomasz
Most MRSA strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene encoding an extra penicillin-binding protein (PBP2A) that has low affinity to virtually all beta-lactam antibiotics. Recently, a new resistance determinant - the mecC gene - was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069658/scy-078-is-fungicidal-in-time-kill-studies-against-candida-species
#16
Bernard Scorneaux, David Angulo, Katyna Borroto-Esoda, Mahmoud Ghannoum, Michael Peel, Stephen Wring
SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpine antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibility by broth micro-dilution, antifungal carry-over, and time-kill dynamics were determined for 3 reference (ATCC) strains (C. albicans 90028, C. parapsilosis 90018, and C. tropicalis 750), a Quality Control (QC) strain (C krusei 6258), and 4 other strains (C. albicans MYA-2732, 64124, 76485 and C...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069657/obesity-and-heart-failure-predictors-of-failure-in-outpatient-skin-and-soft-tissue-infections
#17
Erin L Conway, John A Sellick, Kari Kurtzhalts, Kari A Mergenhagen
PURPOSE: The purpose of this study was to evaluate risk factors for failure of antibiotic treatment within 30 days for uncomplicated skin infections of outpatients treated in a Veteran's Affairs hospital. METHODS: A retrospective chart review of outpatients between January 2006 to July 2015 with an ICD-9 code of cellulitis or abscess were included in the analysis. The primary outcome was success versus failure of the antibiotic with failure defined as another antibiotic prescribed or hospitalization within 30 days for the original indication...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069656/characterization-of-brpmbl-the-bleomycin-resistance-protein-associated-with-the-carbapenemase-ndm
#18
Laurent Dortet, Delphine Girlich, Anne-Laure Virlouvet, Laurent Poirel, Patrice Nordmann, Bogdan I Iorga, Thierry Naas
The metallo-β-lactamase NDM-1 is one of the most worrysome resistance determinant that is spreading worldwide spread among Gram-negative bacilli. A bleomycin resistance gene, bleMBL, has been associated quite systematically downstream of the blaNDM-1 gene. Here, we characterized the corresponding protein, BRPMBL, conferring resistance to bleomycin, an antitumoral glycopeptide molecule. We have determined whether the expression of the blaNDM-1-bleMBL operon is inducible in presence of carbapenems and/or bleomycin-like molecules using qRT-PCR, minimal inhibitory concentration determination of imipenem and zeocin, and carbapenemase specific activity assays...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069655/mutation-in-an-unannotated-protein-confers-carbapenem-resistance-in-mycobacterium-tuberculosis
#19
Pankaj Kumar, Amit Kaushik, Drew Bell, Varsha Chauhan, Fangfang Xia, Rick L Stevens, Gyanu Lamichhane
β-lactams are the most widely used antibacterials. Among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before Mycobacterium tuberculosis (Mtb) strains resistant to these drugs will emerge. Here, we investigated the genetic basis that confers such resistance. To our surprise, instead of mutations in the known β-lactam targets, a single nucleotide polymorphism in the Rv2421c-Rv2422 intergenic region was common among Mtb mutants selected with meropenem or biapenem...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069654/reduced-chance-of-hearing-loss-associated-with-therapeutic-drug-monitoring-of-aminoglycosides-in-the-treatment-of-multidrug-resistant-tuberculosis
#20
R van Altena, J A Dijkstra, M E van der Meer, J F Borjas Howard, J G W Kosterink, D van Soolingen, T S van der Werf, J W C Alffenaar
Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 - 2012.Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study...
January 9, 2017: Antimicrobial Agents and Chemotherapy
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