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Antimicrobial Agents and Chemotherapy

Amit Kaushik, Nicole C Ammerman, Jin Lee, Olumide Martins, Barry N Kreiswirth, Gyanu Lamichhane, Nicole M Parrish, Eric L Nuermberger
Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to MABC's intrinsic resistance to most antibiotics, including β-lactams. MABC organisms express a broad-spectrum β-lactamase that is resistant to traditional β-lactam-based β-lactamase inhibitors but inhibited by a newer non-β-lactam-based β-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC to some β-lactams is increased in the presence of avibactam...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Anastasia Geladari, Maria Simitsopoulou, Charalampos Antachopoulos, Emmanuel Roilides
Carbapenem-resistant Klebsiella pneumoniae (CR- Kp ) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampicin (RIF), meropenem (MEM), gentamicin (GEN) and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN or TGC against CR- Kp mature biofilms. Twenty CR- Kp blood isolates were derived from equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Nicholas Turner, Andrew Strand, Dilraj S Grewal, Gary Cox, Sana Arif, Arthur W Baker, Eileen K Maziarz, Jennifer H Saullo, Cameron R Wolfe
Treatment options for drug-resistant CMV are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically-confirmed resistance to letermovir while on therapy...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Andrew C Marshall, Sarah E Kidd, Stephanie J Lamont-Friedrich, Georgia Arentz, Peter Hoffmann, Bryan R Coad, John B Bruning
Aspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen (2-phenyl-1,2-benzoselenazol-3(2H)-one) is an inhibitor of A. fumigatus TrxR ( Ki = 0.22 μM) and inhibits growth of Aspergillus spp. with in vitro MIC values of 16-64 μg/mL...
January 14, 2019: Antimicrobial Agents and Chemotherapy
María Pérez-Varela, Jordi Corral, Jesús Aranda, Jordi Barbé
While the relationship between Acinetobacter baumannii efflux pumps and antimicrobial resistance is well-documented, less is known about the involvement of these proteins in the pathogenicity of this nosocomial pathogen. In previous work, we identified the AbaQ MFS efflux pump and demonstrated its participation in the motility and virulence of A. baumannii In the present study, we examined the role in these processes of A. baumannii transporters belonging to different superfamilies of efflux pumps. Genes encoding known or putative permeases belonging to efflux pump superfamilies other than MFS were selected and the corresponding knockouts constructed...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Nabila Ismail, Remco P H Peters, Nazir A Ismail, Shaheed V Omar
Six in-vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harbouring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants, however atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Sheng Zeng, Karine Soetaert, Faustine Ravon, Marie Vandeput, Dirk Bald, Jean-Michel Kauffmann, Vanessa Mathys, Ruddy Wattiez, Véronique Fontaine
Accumulating evidence suggests that bactericidal activity of some antibiotics may not be directly initiated by target inhibition. The activity of isoniazid (INH), a key first-line bactericidal anti-tuberculosis drug currently known to inhibit mycolic acid synthesis, becomes extremely poor under stress conditions, such as hypoxia and starvation. This suggests that the target inhibition may not fully explain the bactericidal activity of the drug. Here, we report that INH rapidly increased M. bovis BCG cellular ATP levels and enhanced oxygen consumption...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Fabio Arena, Luca Marchetti, Lucia Henrici De Angelis, Enivarco Maglioni, Martina Contorni, Maria Iris Cassetta, Andrea Novelli, Gian Maria Rossolini
Ceftolozane-tazobactam (C/T) pharmacokinetics during extracorporeal membrane oxygenation (ECMO) has not been previously studied. In this work we report on the C/T plasmatic levels in a lung transplant (LTX) recipient during ECMO, treated with C/T (i.v., 2 g ceftolozane and 1 g tazobactam, every 8 hours]) for a Pseudomonas aeruginosa pulmonary infection.
January 14, 2019: Antimicrobial Agents and Chemotherapy
Marissa A Valentine-King, Katherine Cisneros, Margaret O James, Robert W Huigens, Mary B Brown
Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium , have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics such as beta-lactams, vancomycin, sulfonamides and trimethoprim of no value. To address this shortage, we screened nitroxoline, triclosan, and a library of 20 novel, halogenated phenazine, quinoline, and NH125 analogues against Ureaplasma spp...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Adam D Tomich, Erik H Klontz, Daniel Deredge, John P Barnard, Christi L McElheny, Megan L Eshbach, Ora A Weisz, Patrick Wintrode, Yohei Doi, Eric J Sundberg, Nicolas Sluis-Cremer
The spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active against Escherichia coli , including multidrug-resistant strains...
January 14, 2019: Antimicrobial Agents and Chemotherapy
G Ström Hallenberg, S Börjesson, S Sokerya, T Sothyra, U Magnusson
Colistin is today considered a last-line antimicrobial for the treatment of infections in humans caused by multidrug-resistant Enterobacteriaceae [1]. The dissemination of colistin resistance has received increased attention since a mobilized gene conferring resistance to colistin, mcr-1 , was described in Enterobacteriaceae from humans and food-producing animals in China in 2015 [2], and additional gene homologs have since been identified [3-15].
January 14, 2019: Antimicrobial Agents and Chemotherapy
Nitesh Kumar Khandelwal, Mohd Wasi, Remya Nair, Meghna Gupta, Mohit Kumar, Alok K Mondal, Naseem A Gaur, Rajendra Prasad
Target alteration and over production, drug efflux by overexpression of plasma membrane localized multidrug transporters comprise the conventional mechanisms of azole antifungal resistance. Here, we identify a novel and conserved mechanism of azole resistance not only in the budding yeast, Saccharomyces cerevisiae but also in the pathogenic yeast, Candida albicans We observe that the vacuolar membrane localized, MRP subfamily ABC transporter, of S. cerevisiae , Ybt1, can import azoles into the vacuole. Interestingly, the Ybt1 homologue in C...
January 14, 2019: Antimicrobial Agents and Chemotherapy
M J Melchers, J Teague, P Warn, J Hansen, F Bernardini, A Wach, D Obrecht, G E Dale, J W Mouton
Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein targeting antibiotics. It specifically interacts with LptD and inhibits LPS transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding, the pharmacokinetics of murepavadin in plasma and ELF (pulmonary) in infected animals as well as determining the exposure response relationship. Treatment of CD-1® neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24h, and the number of CFU per lung was determined...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Hang Yang, Yujing Gong, Huaidong Zhang, Irina Etobayeva, Paulina Miernikiewicz, Dehua Luo, Xiaohong Li, Xiaoxu Zhang, Krystyna Dabrowska, Daniel C Nelson, Jin He, Hongping Wei
Streptococcus pneumoniae is one of the leading pathogens that cause a variety of mucosal and invasive infections. With the increased emergence of multidrug-resistant S. pneumoniae , new antimicrobials with mechanisms of action different from conventional antibiotics are urgently needed. In this study, we identified a putative lysin (gp20) encoded by the Streptococcus phage SPSL1 using the LytA autolysin as a template. Molecular dissection of gp20 revealed a binding domain (GPB) containing choline-binding repeats (CBRs) that are high specificity for S...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Si-Chan Li, Qi Ye, Hua Xu, Long Zhang, Yang Wang
Background: Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize dosing strategy in order to improve therapeutic efficacy. Methods: We performed a prospective pharmacokinetic study of pediatric patients aged 0-12 years...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Maria Sionidou, Katerina Manika, Georgia Pitsiou, Paschalina Kontou, Kalliopi Chatzika, Paul Zarogoulidis, Ioannis Kioumis
This study aims to evaluate moxifloxacin's (MXF's) pharmacokinetic profile in serum and sputum/bronchial secretions of 22 patients, with acute exacerbation of COPD (AECOPD), hospitalized in ward and ICU. The data showed that ICU patients had lower concentration in secretions (p=0.01).Thought, no other statistically significant differences were observed in pharmacokinetic parameters and penetration in secretions between less and critically ill. MXF showed a favorable pharmacokinetic profile and the pharmacodynamic targets for common pathogens for AECOPD were achieved...
January 14, 2019: Antimicrobial Agents and Chemotherapy
W J Weiss, M E Pulse, P Nguyen, E J Growcott
LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with K. pneumoniae producing either KPC-2 or NDM-1; pre-treatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in the kidney, urine and bladder. The successful treatment of murine infection models established with carbapenem resistant K. pneumoniae further supports the clinical development of LYS228...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Luděk Eyer, Martina Fojtíková, Radim Nencka, Ivo Rudolf, Zdeněk Hubálek, Daniel Ruzek
West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2' -C- methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C 2'-methylated nucleosides, 7-deaza-2' -C- methyladenosine, significantly protected WNV-infected mice from disease progression and mortality...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Cindy J Bednasz, Charles S Venuto, Qing Ma, Eric S Daar, Paul E Sax, Margaret Fischl, Ann C Collier, Kimberly Y Smith, Camlin Tierney, Edward P Acosta, Donald E Mager, Gene D Morse
Introduction AIDS Clinical Trial Group A5202 ( identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine, or abacavir/lamivudine in treatment-naïve adults living with HIV-1, evaluating efficacy, safety and tolerability. We report an analysis on the contribution of participant characteristics to the disposition of tenofovir plasma concentrations...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Kristie L Connolly, Ann E Eakin, Carolina Gomez, Blaire L Osborn, Magnus Unemo, Ann E Jerse
There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESCS strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, f TMIC ) of 24 h and 37 h, respectively...
January 14, 2019: Antimicrobial Agents and Chemotherapy
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