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Antimicrobial Agents and Chemotherapy

Alexia Chauzy, Isabelle Lamarche, Christophe Adier, William Couet, Sandrine Marchand
The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle and peritoneal cavity of control rats ( n = 5) and rats with intra-abdominal sepsis ( n = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each media were determined for both molecules in each rat by retrodialysis by drug...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Mispah Mukap, Corin Sprod, Nakapi Tefuarani, Moses Laman, Madhu Page-Sharp, Sam Salman, Brioni R Moore, Kevin T Batty, Timothy M E Davis, Laurens Manning
Background: Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children from Papua New Guinea (PNG) with severe illness, a setting in which healthcare resources are limited and anemia is common. Methods: Using a previously validated liquid chromatography-mass spectroscopy (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5-10 years with acute bacterial meningitis or severe pneumonia...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Robert A Smith, Vincent H Wu, Christopher G Zavala, Dana N Raugi, Selly Ba, Moussa Seydi, Geoffrey S Gottlieb
We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naïve individuals. HIV-2 was sensitive to cabotegravir in both single-cycle and spreading infection assays, with EC50 values in the low to sub-nanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for ART and PrEP in HIV-2-prevalent settings.
July 16, 2018: Antimicrobial Agents and Chemotherapy
James D Blanchard, Valerie Elias, David Cipolla, Igor Gonda, Luiz E Bermudez
Non-tuberculosis mycobacteria (NTM) affects an increasing number of individuals worldwide. The infection is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo Efficacy was examined in macrophages, biofilms and in vivo using intranasal instillation mouse models against Mycobacterium avium and Mycobacterium abscessus Liposomal ciprofloxacin was significantly more active than free ciprofloxacin in macrophages and biofilms against both pathogens...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Stephanie E Barrett, Ryan S Teller, Seth P Forster, Li Li, Megan A Mackey, Daniel Skomski, Zhen Yang, Kerry L Fillgrove, Gregory J Doto, Sandra L Wood, Jose Lebron, Jay A Grobler, Rosa I Sanchez, Zhen Liu, Bing Lu, Tao Niu, Li Sun, Marian E Gindy
Adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of HIV infection. Long-acting drug formulations requiring less frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. Administration of long-acting formulations in a clinical setting enables healthcare providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-deoxyadenosine; EFdA) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for pre-exposure prophylaxis (PrEP)...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Dexi Bi, Jiayi Zheng, Jun-Jie Li, Zi-Ke Sheng, Xingchen Zhu, Hong-Yu Ou, Qianyu Li, Qing Wei
IncFIIK plasmids are associated with the acquisition and dissemination of multiple antimicrobial resistance in Klebsiella pneumoniae and often encountered in clinical isolates of this species. Since the phylogeny and evolution of IncFIIK plasmids remain unclear, herein we performed large-scale in silico typing and comparative analysis of these plasmids in publicly available bacterial/plasmid genomes. IncFIIK plasmids are prevalent in K. pneumoniae , as found in 69% sequenced genomes, covering 66% sequenced STs (sequence types), but sparse in other Enterobacteriaceae...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Thomas Lahlali, Jan Martin Berke, Karen Vergauwen, Adrien Foca, Koen Vandyck, Frederik Pauwels, Fabien Zoulim, David Durantel
The assembly of hepatitis B virus (HBV) core proteins (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty-capsid or aberrant-capsid devoid of pregenomic RNA (pgRNA) and finally block rcDNA neosynthesis and virion progeny. In this study, novel CAMs JNJ-827 and JNJ-890, were found to be potent inhibitors of HBV replication with a respective half maximal effective concentration of 4...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Lisa Nwankwo, Jimstan Periselneris, Jamie Cheong, Keith Thompson, Peter Darby, Neil Leaver, Silke Schelenz, Darius Armstrong-James
There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to healthcare systems.An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice monthly multidisciplinary team meetings and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Md Masud Parvez, Nazia Kaisar, Ho Jung Shin, Yoon Jae Lee, Jae-Gook Shin
Substrate potential of antituberculosis drugs on SLC transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for solute carrier (SLC) family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro The result suggested that, ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Charles A Peloquin, Patrick P J Phillips, Carole D Mitnick, Kathleen Eisenach, Ramonde F Patientia, Leonid Lecca, Eduardo Gotuzzo, Neel R Gandhi, Donna Butler, Andreas H Diacon, Bruno Martel, Juan Santillan, Kathleen Robergeau Hunt, Dante Vargas, Florian von Groote-Bidlingmaier, Carlos Seas, Nancy Dianis, Antonio Moreno-Martinez, Pawandeep Kaur, C Robert Horsburgh
Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Yanan Zhao, Min Hee Lee, Padmaja Paderu, Annie Lee, Cristina Jimenez-Ortigosa, Steven Park, Robert S Mansbach, Karen Joy Shaw, David S Perlin
APX001 is a first-in-class, intravenous and orally available broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 - 2.75 h in mice vs 2 - 2.5 days in humans), making exploration of efficacy in mouse models difficult. With pre-treatment of 1-aminobenzotriazole (ABT), a non-specific cytochrome P450 inhibitor, greatly increased plasma exposure of APX001A was observed in different mice strains of both genders...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Qun Yan, Melissa J Karau, Yash S Raval, Robin Patel
The anti-biofilm activity of oritavancin in combination with rifampin, gentamicin or linezolid was evaluated against ten prosthetic joint infection (PJI) related methicillin-resistant Staphylococcus aureus (MRSA) by time-kill assays. Oritavancin combined with rifampin demonstrated statistically significant bacterial reductions compared to either antimicrobial alone for all ten isolates (P ≤0.001), with synergy being observed for 80% (8/10) of the isolates. Oritavancin and rifampin combination therapy may be an option for treating MRSA PJI...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Cinzia Auriti, Bianca Maria Goffredo, Maria Paola Ronchetti, Fiammetta Piersigilli, Sara Cairoli, Iliana Bersani, Andrea Dotta, Manjunath P Pai
Major gaps exist in our knowledge of antimicrobial pharmacokinetics in critically ill neonates and infants that require validated microsampling and bioanalysis methods to support therapeutic drug monitoring. We compared serially collected intravenous (IV) and heel-stick capillary (HSC) sampled plasma concentrations of micafungin (8 mg/kg) in eight infants born preterm, with systemic candidiasis. The mean (SD) micafungin AUCinf was 316 (65.0) h·mg/L based on HSC concentrations that strongly correlated (R2 = 0...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Anubhav Kanwar, Jennifer L Cadnum, Annette L Jencson, Curtis J Donskey
We examined the impact of systemic antibiotics on the burden of nasal Staphylococcus aureus in hospitalized patients. Of 1482 patients, 237 (16%) had nasal methicillin-susceptible S. aureus (MSSA) and 92 (6%) had nasal methicillin-resistant S. aureus (MRSA) on admission. Treatment regimens including agents with inhibitory activity against MRSA or MSSA significantly reduced the burden of carriage, whereas regimens lacking anti-MRSA activity, including fluoroquinolones, promoted MRSA overgrowth.
July 16, 2018: Antimicrobial Agents and Chemotherapy
Scott A Becka, Elise T Zeiser, Melissa D Barnes, Magdalena A Taracila, Kevin Nguyen, Indresh Singh, Granger G Sutton, John J LiPuma, Derrick E Fouts, Krisztina M Papp-Wallace
Burkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from Cystic Fibrosis. β-Lactam antibiotics are recommended as therapy for infections due to B. multivorans , which possesses two β-lactamase genes, bla penA and bla AmpC PenA is a carbapenemase with a substrate profile similar to the Klebsiella pneumoniae carbapenemase (KPC); in addition, expression of PenA is inducible by β-lactams in B...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Ariane J Sousa-Batista, Douglas Escrivani-Oliveira, Camila Alves Bandeira Falcão, Cintia Iana Monteiro da Silva Philippon, Bartira Rossi-Bergmann
The oral efficacy and safety of a leishmanicidal nitro-chalcone (CH8) were studied in BALB/c mouse infections with Leishmania amazonensis and L. infantum Although ten-fold higher doses of CH8 were needed to produce the same antiparasitic effect as the reference drug miltefosine, the later was nephrotoxic, while CH8 restored disease toxicity markers to normal. This study shows the therapeutic potential of an orally active and hepato/nephroprotective chalcone against both cutaneous and visceral leishmaniasis.
July 16, 2018: Antimicrobial Agents and Chemotherapy
Adrian Richter, Angelika Strauch, Joseph Chao, Mary Ko, Yossef Av-Gay
Mycobacterium abscessus ( Mabs ) is intrinsically resistant to many antimycobacterial antibiotics, which presents serious problems in therapy. Here we describe the development of a novel phenotypic-based microscopic and computerized imaging drug screening approach. A pilot screen of 568 compounds from two libraries identified 17 hits. Eleven of these compounds are described for the first time as active against Mabs The impact of growth media on these compounds' activity was tested revealing that cation-adjusted Mueller Hinton (MHII) broth supports better growth of actively replicating Mabs and improves the associated compounds activity...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Byoung Soo Kwon, Mi-Na Kim, Heungsup Sung, Younsuck Koh, Woo-Sung Kim, Jin-Woo Song, Yeon-Mok Oh, Sang-Do Lee, Sei Won Lee, Jae-Seung Lee, Chae-Man Lim, Chang-Min Choi, Jin-Won Huh, Sang-Bum Hong, Sojung Park, Tae Sun Shim, Yong Pil Chong, Kyung-Wook Jo
Although it is known that in vitro minimal inhibitory concentrations (MICs) of rifampin and ethambutol are poorly correlated with clinical response in Mycobacterium avium complex lung disease (MAC-LD), its evidence is limited. This study investigated the association between treatment outcome and in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Amber Howerton, Cale O Seymour, Senthil K Murugapiran, Zhenlin Liao, Jacqueline R Phan, Alan Estrada, Adam J Wagner, Chrisabelle C Mefferd, Brian P Hedlund, Ernesto Abel-Santos
Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and high incidence of recurrence. We previously reported protection of mice from CDI using the anti-germinant bile salt analog CamSA. Here we describe the effects of CamSA on the hamster model of CDI. CamSA treatment of hamsters showed no toxicity and did not affect the richness or diversity of gut microbiota; however, minor changes in community composition were observed...
July 16, 2018: Antimicrobial Agents and Chemotherapy
Jon P Furuno, Gregory B Tallman, Brie N Noble, Joseph S Bubalo, Graeme N Forrest, James S Lewis, Ana F Bienvenida, Courtney A Holmes, Bo R Weber, Jessina C McGregor
Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared incidence of breakthrough IFI and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1/1/2010 and 6/30/2016. We defined probable or proven breakthrough IFI using the European Organization for Research and Treatment of Cancer (EORTC) criteria...
July 16, 2018: Antimicrobial Agents and Chemotherapy
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