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Antimicrobial Agents and Chemotherapy

Darel Macdonald, Darren D Thomson, Anna Johns, Adriana Contreras Valenzuela, Jane M Gilsenan, Kathryn M Lord, Paul Bowyer, David W Denning, Nick D Read, Michael J Bromley
Antifungal agents directed against novel therapeutic targets are required for treating invasive, chronic and allergic Aspergillus infections. Competitive fitness profiling technologies have been used in a number of bacterial and yeast systems to identify druggable targets however, development of similar systems in filamentous fungi are complicated by the fact that they undergo cell fusion and heterokaryosis. Here we demonstrate that cell fusion in A. fumigatus under standard culture conditions is not predominately constitutive, as with most ascomycetes, but can be induced by a range of extracellular stressors...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Angela Kavanagh, Soumya Ramu, Yujing Gong, Matthew A Cooper, Mark A T Blaskovich
The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires media supplemented with Ca2+ and the lipoglycopeptides dalbavancin and oritavancin require Tween-80 to be added to the growth media to prevent depletion of free drug via adsorption to the plastic microplate...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Samuel Lipworth, Natasha Hough, Laura Leach, Marcus Morgan, Katie Jeffery, Monique Andersson, Esther Robinson, E Grace Smith, Derrick Crook, Tim Peto, Timothy Walker
Mycobacterium abscessus is emerging as an important pathogen in chronic lung diseases with concern regarding patient to patient transmission. The recent introduction of routine whole genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterise the genetic determinants of resistance. We conducted a systematic review to catalogue all known resistance determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the erm(41) and rrl genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there was paired genotype/phenotype data...
November 5, 2018: Antimicrobial Agents and Chemotherapy
María Ángeles Bordallo-Cardona, Caroline Agnelli, Ana Gómez-Nunez, Carlos Sánchez-Carrillo, Emilio Bouza, Patricia Muñoz, Pilar Escribano, Jesús Guinea
The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n=81), subsequent candidemia episodes (n=9), endocarditis (n=2), and in vitro-generated echinocandin-resistant isolates (n=32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro , and patient prognosis. MSH2 gene was sequenced and isolates were genotyped using six microsatellite markers and MLST based on six housekeeping genes...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Richard A Preston, Grigor Mamikonyan, Stephane DeGraff, James Chiou, Christopher J Kemper, Allan Xu, Mushtaque Mastim, Ravindra Yeole, Rajesh Chavan, Anusuya Patel, H David Friedland, Ashima Bhatia
WCK 5222 is a novel β-lactam-β-lactam enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative PBP2 and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogens. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in forty-eight subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR)...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Awewura Kwara, Hongmei Yang, Sampson Antwi, Anthony Enimil, Fizza S Gillani, Albert Dompreh, Antoinette Ortsin, Theresa Opoku, Dennis Bosomtwe, Anima Sarfo, Lubbe Wiesner, Jennifer Norman, Wael A Alghamdi, Taimour Langaee, Charles A Peloquin, Michael H Court, David J Greenblatt
We compared efavirenz pharmacokinetic (PK) parameters in children with TB/HIV coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children aged 3 to 14 years old with HIV infection with and without TB were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization recommended antituberculosis drugs dosages were used in the co-infected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated LC/MS/MS assays...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Jeff Chamberlain, Katherine Sortino, Phiroze Sethna, Andrew Bae, Randall Lanier, Robert A Bambara, Stephen Dewhurst
Human adenovirus (AdV) can cause fatal disease in immune suppressed individuals, but treatment options are limited - in part because the antiviral cytidine analog, cidofovir (CDV), is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, non-nephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. We have therefore examined the effect of CDVpp on DNA synthesis by a purified AdV5 DNA polymerase (pol)...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Min Ji Choi, Eun Jeong Won, Min Young Joo, Yeon-Joon Park, Soo Hyun Kim, Myung Geun Shin, Jong Hee Shin
A recent surveillance study in Korea revealed that 14% (7/50) of Aspergilus flavus clinical isolates had a voriconazole minimum inhibitory concentration ≥ 4 µg/mL. Of seven non-wild-type (non-WT) isolates, six ear isolates from four hospitals shared the same microsatellite genotype. None of non-WT isolates showed cyp51 mutations associated with azole resistance. However, the mean expression levels of efflux pumps ( MDR2 , atrF , and mfs1 ) and target ( cyp51A) genes exhibited significant differences between non-WT and other isolates...
November 5, 2018: Antimicrobial Agents and Chemotherapy
David C Griffith, Mojgan Sabet, Ziad Tarazi, Olga Lomovskaya, Michael N Dudley
Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Zohar B Weinstein, Muhammad H Zaman
Poor-quality medicines undermine the treatment of infectious diseases such as tuberculosis, which requires months of treatment with rifampicin and other drugs. Rifampicin resistance is a critical concern for tuberculosis treatment. While sub-therapeutic doses of medicine are known to select for antibiotic resistance, the effect of drug degradation products on the evolution of resistance is unknown. Here, we demonstrate that substandard drugs that contain degraded active pharmaceutical ingredients select for gene alterations that confer resistance to standard drugs...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Kellie J Goodlet, Fatima Z Benhalima, Michael D Nailor
<u>Background/Objective</u>: Increasing bacterial resistance and poor patient adherence rates limit the effectiveness of conventional antibiotic therapies for urinary tract infection (UTI). The objective of this study was to investigate whether a single aminoglycoside dose adequately treated UTI.<u>Methods</u>: A systematic search of PubMed/MEDLINE and Google Scholar databases was performed through September 2018 for English-language original research articles assessing the efficacy of one-time parenteral aminoglycoside as UTI monotherapy...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Shaoqi Qu, Cunchun Dai, Fengting Lang, Longfei Hu, Qihe Tang, Haixia Wang, Yanping Zhang, Zhihui Hao
Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment of serious infections caused by multi-resistant Gram-positive bacteria. This study investigated the renal protective activity of rutin in a rat model of VCM-induced kidney injury in male Wistar rats. VCM intraperitoneally at 200 mg/kg twice daily for 7 successive days resulted in significant elevation of blood urea nitrogen and creatinine as well as urinary N-acetyl-β-D-glucosaminidase. Co-administration of VCM with oral rutin at 150 mg/kg significantly reduced these markers of kidney damage...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Ziad Tarazi, Mojgan Sabet, Michael N Dudley, David C Griffith
Minocycline is currently approved in the US for the treatment of infections caused by susceptible isolates of Acinetobacter spp The objective of these studies was to determine the minocycline exposures associated with antibacterial effect against A. baumannii in a rat pneumonia model. Rats received minocycline doses as 30 minute intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii , with MICs ranging between 0.03 - 4 mg/L, were studied. In this model, minocycline produced a bacteriostatic effect with a free 24h AUC/MIC of 10 - 16 and produced 1-log of bacterial killing with a free 24h AUC/MIC of 13 - 24...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Carolina de Miranda Silva, Amirhossein Hajihosseini, Jenny Myrick, Jocelyn Nole, Arnold Louie, Stephan Schmidt, George L Drusano
Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis ( M. tuberculosis ). However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF towards killing of M...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Brian C Monk, Mikhail V Keniya, Manya Sabherwal, Rajni K Wilson, Danyon O Graham, Harith F Hassan, Danni Chen, Joel D A Tyndall
Tetrazole antifungals designed to target fungal lanosterol 14α-demethylase (LDM) appear effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artefacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6×His) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely-used triazole drug posaconazole (PCZ)...
November 5, 2018: Antimicrobial Agents and Chemotherapy
James A Karlowsky, Heather J Adam, Melanie R Baxter, Andrew J Denisuik, Philippe R S Lagacé-Wiens, Andrew J Walkty, Sailaja Puttagunta, Michael W Dunne, George G Zhanel
The in vitro activity of sulopenem was assessed against a 2014-2016 collection of 539 urinary isolates of Escherichia coli from Canadian patients using CLSI-defined broth microdilution methodology. A concentration of sulopenem of 0.03 µg/ml inhibited both 50% (MIC50 ) and 90% (MIC90 ) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by non-susceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant (MDR) phenotypes, extended-spectrum β-lactamases (ESBLs), or AmpC β-lactamases...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Elaine M Barros, Melissa J Martin, Elizabeth M Selleck, François Lebreton, Jorge Luiz M Sampaio, Michael S Gilmore
Lipopeptide daptomycin is a last line cell membrane-targeting antibiotic to treat multidrug-resistant Staphylococcus aureus Alarmingly, daptomycin-resistant S. aureus isolates have emerged. The mechanisms underlying daptomycin resistance are diverse, share similarities with resistance to cationic antimicrobial peptides and other lipopeptides, but remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in ST8 S. aureus HG003. Insertions in conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23)...
November 5, 2018: Antimicrobial Agents and Chemotherapy
Huiwen Zheng, Dongxin Liu, Jie Lu, Yuanyuan Song, Shengfen Wang, Yanlin Zhao, Xin Ni
Treatment efficacy of Mycobacterium abscessus infections depends on bacterial genotype. Here the relationship between genotype, as determined using sequence analysis, and antibiotic resistance phenotype was analyzed. The results demonstrate that Mycobacterium abscessus genotype characteristics, including erm (41) sequevar, and mutations of rrl and rrs , are predictive of clarithromycin and amikacin resistance.
November 5, 2018: Antimicrobial Agents and Chemotherapy
Stathis D Kotsakis, Carl-Fredrik Flach, Mohammad Razavi, D G Joakim Larsson
While carbapenem resistance in Gram-negatives is mainly due to production of efficient carbapenemases, β-lactamases with narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10 type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study two novel OXA-10 variants were identified as the sole carbapenem hydrolyzing enzymes in meropenem resistant Enterobacteria isolated from hospital waste water and found by NGS to express additional β-lactam resistance mechanisms...
November 5, 2018: Antimicrobial Agents and Chemotherapy
George Zhanel, Ian Critchley, Lynn-Yao Lin, Nancy Alvandi
Sarecycline is the first narrow spectrum tetracycline-class antibiotic being developed for acne treatment. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of Cutibacterium acnes In the current study, sarecycline was 16 to 32-fold less active than broad spectrum tetracyclines-such as minocycline and doxycycline-against aerobic Gram-negative bacilli associated with normal human intestinal microbiome...
November 5, 2018: Antimicrobial Agents and Chemotherapy
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