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Antimicrobial Agents and Chemotherapy

Kmt Astvad, D Sanglard, E Delarze, R K Hare, M C Arendrup
Candida tropicalis isolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy.Fluconazole efficacy against two weakly (≤25% growth), two moderately (26-50% growth), one resistant heavily (>70% growth) trailing, and one resistant (100% growth) isolates was investigated in vitro and in vivo (a Galleria mellonella survival model and two non-lethal murine models)...
September 17, 2018: Antimicrobial Agents and Chemotherapy
J C Kwong, K Urbancic, J A Trubiano
Beta-lactam therapy for severe staphylococcal infections is associated with superior outcomes when compared to non-beta-lactam therapy. In patients with immediate hypersensitivity to beta-lactams, desensitization has been widely employed to allow beta-lactam therapy, but published protocols for anti-staphylococcal beta-lactams such as flucloxacillin are lacking. Here, we report a case and the desensitization protocol successfully used for a patient with isolated flucloxacillin immediate hypersensitivity, where a penicillin desensitization protocol would likely have resulted in an adverse drug reaction...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Baocun Li, Yang Wang, Fang Shen, Min Wu, Yaming Li, Zhong Fang, Jianyu Ye, Li Wang, Lu Gao, Zhenghong Yuan, Jieliang Chen
Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia, but induce hepatitis B surface antigen (HBsAg) loss in a very few patients and do not much affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Helio S Sader, Robert K Flamm, Cecilia G Carvalhaes, Marina Castanheira
P. aeruginosa isolates ( n = 1,909) were collected from 70 United Sates medical centers and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (MIC50/90 , 2/8 mg/liter) and ceftolozane-tazobactam (MIC50/90 , 0.5/2 mg/liter) were the most active (highest susceptibility rates) compounds after colistin, with national susceptibility rates of 96.9% and 97.5%, respectively. Overall, piperacillin-tazobactam (MIC50/90 , 4/128 mg/liter) and meropenem (MIC50/90 , 0.5/16 mg/liter) were active against 77...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Damon Tan, Htet Lin Htun, Jocelyn Koh, Kala Kanagasabai, Jia-Wei Lim, Pei-Yun Hon, Brenda Ang, Angela Chow
Vancomycin-resistant enterococci (VRE) is an important cause of nosocomial infections in acute care hospitals (ACHs), intermediate- (ITCFs) and long-term care facilities (LTCFs). This study contemporaneously compared the epidemiology and risk factors for VRE colonization in different care settings in a healthcare network. We conducted a serial cross-sectional study in a 1700-bed ACH and its six closely-affiliated ITCFs and LTCFs in June-July, 2014-2016. Rectal swabs or stool were cultured for VRE. Multivariable logistic regression was used to assess for independent risk factors associated with VRE colonization...
September 17, 2018: Antimicrobial Agents and Chemotherapy
S Dian, V Yunivita, A R Ganiem, T Pramaesya, L Chaidir, K Wahyudi, T H Achmad, A Colbers, L Te Brake, R van Crevel, R Ruslami, R Aarnoutse
High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response. In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Srinivasarao Kondaparla, Utsab Debnath, Awakash Soni, Vasantha Rao Dola, Manish Sinha, Kumkum Srivastava, Sunil K Puri, Seturam B Katti
In a focused exploration, we have designed synthesized and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity [for in vitro IC50 = 56.98nM (3D7), 97.76nM (K1); for in vivo (up to at the dose of 12.5 mg/kg); SI = 3510] as a new lead of antimalarial agent. Other compounds 6b , 6d , 7d , 7h , 8c , 8d , 9a and 9c are also showing moderate activity against CQ-sensitive (3D7) strain and superior activity against resistant (K1) strain of P...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Xia-Fei Wei, Chun-Yang Gan, Jing Cui, Ying-Ying Luo, Xue-Fei Cai, Yi Yuan, Jing Shen, Zhi-Ying Li, Wen-Lu Zhang, Quan-Xin Long, Yuan Hu, Juan Chen, Ni Tang, Haitao Guo, Ai-Long Huang, Jie-Li Hu
The capsid of hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, which is the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report herein a cell-based assay in which the formation of core dimers is indicated by the Split Luciferase Complementation (SLC)...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Sonia Lozano, Pablo Gamallo, Carolina González-Cortés, Jesús-Luís Presa Matilla, Rick M Fairhurst, Esperanza Herreros, Chanaki Amaratunga, Janneth Rodrigues
Mutations in the kelch-propeller domain (K13-propeller) of Plasmodium falciparum parasites from Southeast Asia are associated with reduced susceptibility to artemisinin. We exposed in vitro -cultured Stage V gametocytes from Cambodian K13-propeller mutant parasites to dihydroartemisinin and evaluated inhibition of male gamete formation in the in vitro exflagellation inhibition assay (EIA). Gametocytes with R539T and C580Y K13-propeller alleles were less susceptible to dihydroartemisinin and had significantly higher 50% inhibitory concentrations (IC50 s) compared to gametocytes with wild-type alleles...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Caiyun Zhao, Yuan Lv, Minji Wei, Xiangyan Li, Fang Hou, Jin Wang, Xuzhu Ma, Zisheng Kang, Wei Mao, Yan Liu, Yahong Xia, Jihong Tian
Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single ascending dose study to assess safety and tolerability of chinfloxacin. The single dose pharmacokinetic study, food effect study and a multiple dose pharmacokinetics study was conducted in Part B, Part C and Part D, respectively. Part E was a randomized, placebo- and positive-controlled single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/QTc interval...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Zhiwei Zheng, Ruichao Li, Lianwei Ye, Edward Wai-Chi Chan, Sheng Chen
Vibrio alginolyticus is a Gram-negative halophilic and mesophilic bacterium, particularly associated with severe epidemic vibriosis, which causes high mortality for marine animals, including fish, shellfish and shrimp (1).….
September 17, 2018: Antimicrobial Agents and Chemotherapy
Yanqin Li, Xiaohuan Lin, Xuan Yao, Yan Huang, Wenguang Liu, Tao Ma, Binghu Fang
The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli that produces colistin-resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli , including colistin-resistant isolate MZ1501R , HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S Experiments were conducted at a medium inoculum of ∼107 CFU/mL over 48 h...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Cinzia Auriti, Maria Paola Ronchetti, Iliana Bersani, Fabrizio Gennari, Fiammetta Piersigilli
Hepatic fungal abscesses are rare in the neonatal period and often constitute a severe complication of the catheterization of the umbilical vessels. Such life-threatening lesions are observed more frequently in preterm than in other newborn infants and the optimal treatment remains uncertain. We present the case of a preterm neonate, who developed an intrahepatic lesion due to parenteral extravasation, successively contaminated by Candida albicans Despite the maximal pharmacological therapies, the treatment that led to the definitive resolution of the abscess was the placement of a surgical drainage followed by the direct intralesional administration of liposomal amphotericin B (AmBisome), never described in neonates in the literature, which turned out to be a safe and effective approach...
September 17, 2018: Antimicrobial Agents and Chemotherapy
Russell J Benefield, E Susan Slechta, Christopher M Gast, Emily S Spivak, Kimberly E Hanson, Donald P Alexander
We evaluated the effect of rifampin co-administration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in clearance (0.53 vs 0.55 L/hr, P = 1.00), volume of distribution (7.0 vs 7.2 L, P = 0.62), or half-life (9.7 vs 9.6 hrs, P = 0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition.
September 17, 2018: Antimicrobial Agents and Chemotherapy
Mahdi Abastabar, Iman Haghani, Tahereh Shokohi, Mohammad Taghi Hedayati, Seyed Reza Aghili, Ali Jedi, Sulmaz Dadashi, Shafigheh Shabanzadeh, Tahereh Hosseini, Narges Aslani, Jacques F Meis, Hamid Badali
The in vitro activity of tavaborole, a FDA approved antifungal drug, was compared to four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine and fluconazole, the principal choices for the treatment of onychomycosis. Thus it appears that tavaborole is not a candidate for the treatment of onychomycosis due to Candida species, Aspergillus species and dermatophytes.
September 17, 2018: Antimicrobial Agents and Chemotherapy
Nilay Thakkar, Justin A Green, Gavin C K W Koh, Stephan Duparc, David Tenero, Navin Goyal
Tafenoquine is a novel 8-aminoquinoline anti-malarial drug recently approved by US Food and Drug Administration (FDA) for the radical cure of acute P. vivax malaria - first new treatment in almost 60 years. Population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data following oral administration from 6 clinical studies in Phase 1 through Phase 3 with a nonlinear mixed effects modelling approach. The impact of patient demographics, baseline characteristics and extrinsic factors such as formulation were evaluated...
September 10, 2018: Antimicrobial Agents and Chemotherapy
Lois W Martin, Cynthia L Robson, Annabelle M Watts, Andrew R Gray, Claire E Wainwright, Scott C Bell, Kay A Ramsay, Timothy J Kidd, David W Reid, Ben Brockway, Iain L Lamont
The lungs of individuals with cystic fibrosis (CF) become chronically infected with Pseudomonas aeruginosa that is difficult to eradicate by antibiotic treatment. Two key P. aeruginosa antibiotic resistance mechanisms are the AmpC β-lactamase that degrades β-lactam antibiotics and MexXYOprM, a three-protein efflux pump that expels aminoglycoside antibiotics from the bacterial cells. Levels of antibiotic resistance gene expression are likely to be a key factor in antibiotic resistance but have not been determined during infection...
September 10, 2018: Antimicrobial Agents and Chemotherapy
Rui Zhang, Fengbo Wu, Lei Wu, Yaomei Tian, Bailing Zhou, Xueyan Zhang, Rong Huang, Chaoheng Yu, Gu He, Li Yang
Owing to their broad-spectrum antibacterial properties, multi-target effects and low drug resistance, antimicrobial peptides (AMPs) have played critical roles in the clinical therapy of drug-resistant bacterial infections. However, the potential hazard of haemolysis following systemic administration has greatly limited their application. Here, we developed a novel AMP derivative, DP7-C, by modifying a formerly identified highly active AMP with cholesterol to form an amphiphilic conjugate. The prepared DP7-C easily self-assembled into stable nanomicelles in aqueous solution...
September 10, 2018: Antimicrobial Agents and Chemotherapy
R Farrukee, A E Zarebski, J M McCaw, J D Bloom, P C Reading, A C Hurt
Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs) which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to NAI-sensitive wild-type viruses...
September 10, 2018: Antimicrobial Agents and Chemotherapy
Ana Gomes, Ricardo Ferraz, Lauren Ficker, Margaret S Collins, Cristina Prudêncio, Melanie T Cushion, Cátia Teixeira, Paula Gomes
The impact of Pneumocystis pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, auto-immune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both in vitro and in vivo , we now report the potent action of these compounds on Pneumocystis carinii, in vitro Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding...
September 10, 2018: Antimicrobial Agents and Chemotherapy
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