In vitro and in vivo evaluation of an adamantyl-based phenyl sulfonyl acetamide against cutaneous leishmaniasis models of L. amazonensis.
Abstract Phenotypic assay against L. amazonensis in vitro and in vivo led to identification of an adamantyl-based phenyl sulfonyl acetamide (1) as a promising antileishmanial agent. Compound 1 inhibited the growth of intracellular forms of L. amazonensis (IC50 4 μM), exhibited low toxicity to host cells, with selectivity index>125. However, in cutaneous leishmaniasis mouse model, 1 did not reduce lesions and parasite load when administered as monotherapy or given simultaneously with suboptimal dose of miltefosine. PMID: 32928731 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Santos CC, Zhang H, Batista MM, de Oliveira GM, Demarque KC, da Silva-Gomes NL, Moreira OC, Ogungbe IV, Soeiro MNC Tags: Antimicrob Agents Chemother Source Type: research

Mutations identified in the HCV polymerase of ribavirin treated chronic hepatitis C patients cause resistance and affect viral replication fidelity.
In conclusion, prolonged exposure of HCV to ribavirin in chronic hepatitis C patients induces NS5B resistance mutations leading to increased polymerase fidelity, which could be one mechanism for ribavirin resistance. PMID: 32928732 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Mejer N, Fahnøe U, Galli A, Ramirez S, Weiland O, Benfield T, Bukh J Tags: Antimicrob Agents Chemother Source Type: research

Activity of aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against multidrug resistant Stenotrophomonas maltophilia.
The objectives of this study were to evaluate and compare the in vitro activity and understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia. A panel of 47 clinical S. maltophilia strains non-susceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution and 6 isolates were then evaluated in time-kill analyses. Three isolates with varying aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase polymerase chain reac...
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Biagi M, Lamm D, Meyer K, Vialichka A, Jurkovic M, Patel S, Mendes RE, Bulman ZP, Wenzler E Tags: Antimicrob Agents Chemother Source Type: research

In Vivo Pharmacodynamic Target Assessment of Antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in a Neutropenic Murine Pneumonia Model.
Abstract We determined in vivo efficacy and target PK/PD exposures of antofloxacin against S. pneumoniae and S. aureus in the murine pneumonia model. The mean plasma fAUC/MIC targets associated with stasis, 1-log10 and 2-log10 kill effects were 8.93, 19.2 and 48.1 for S. pneumoniae; whereas they were 30.5, 55.4 and 115.8 for S. aureus The fAUC/MIC targets in murine lung epithelial lining fluids (ELF) for the same endpoints were nearly 2-fold higher than those in plasma. PMID: 32928734 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Zhou YF, Liu P, Dai SH, Sun J, Liu YH, Liao XP Tags: Antimicrob Agents Chemother Source Type: research

Gallic and Ellagic acids: Promising adjuvants to conventional amphotericin B for the treatment of cutaneous leishmaniasis.
In this study we demonstrated the potential association effect of conventional amphotericin B (Amph B) and Gallic acid (GA) or Ellagic acid (EA) in topical formulation for treatment of cutaneous leishmaniasis in BALB/c mice. Preliminary stability tests and in vitro drug release studies with Amph B, GA, Amph B + GA, EA and Amph B + EA in the composition and in vivo treatment of BALB/c mice infected by Leishmania major were performed. After 40 days of infection, the animals were divided into 6 groups, treated 2x/day, for 21 days with the gel of Amph B, GA, Amph B + GA, EA and Amph B + EA and the negative control group was tr...
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: de Moraes Alves MM, Arcanjo DDR, Figueiredo KA, Oliveira JSSM, Viana FJC, Coelho ES, Lopes GLN, Gonçalves JCR, Carvalho ALM, Rizzo MDS, Chaves MH, de Mendonça IL, Carvalho FAA Tags: Antimicrob Agents Chemother Source Type: research

Application of histone deacetylase inhibitors MPK472 and KSK64 as a potential treatment option for Acanthamoeba keratitis.
In this study, the effects of HDACi such as MPK472 and KSK64 on A. castellanii trophozoites and cysts were observed. MPK472 and KSK64 showed at least 60% amoebicidal activity against Acanthamoeba trophozoite at a concentration of 10 μM upon 8 h. Neither of the two HDACi affected mature cysts, but significant amoebicidal activities (36.4% and 33.9%) were observed against encysting Acanthamoeba following treatment with 5 and 10 μM HDACi for 24 h. Light microscopy and transmission electron microscopy results confirmed that the encystation of Acanthamoeba was inhibited by the two HDACi. In addition to this, low cytopathi...
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Lee HA, Park SM, Chu KB, Quan FS, Kurz T, Pflieger M, Moon EK Tags: Antimicrob Agents Chemother Source Type: research

The effect of exposure to chlorhexidine residues at "during use" concentrations on antimicrobial susceptibility profile, efflux, conjugative plasmid transfer and metabolism of Escherichia coli.
In conclusion, E. coli phenotype responses to CHX exposure are concentration dependent, with realistic residual CHX concentrations resulting in stable clinical cross-resistance to antibiotics. PMID: 32928737 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Wesgate R, Fanning S, Hu Y, Maillard JY Tags: Antimicrob Agents Chemother Source Type: research

Small molecule inhibitors of Chikungunya virus: mechanisms of action and antiviral drug resistance.
Abstract Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide. CHIKV infection leads to a febrile illness known as Chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment. In this review, we highlight the different strategies used for developing CHIKV small-molecule inhibitors, ranging from high-throughput cell-based screening, in silico sc...
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Kovacikova K, van Hemert MJ Tags: Antimicrob Agents Chemother Source Type: research

In Vitro Activity of WCK 5222 (Cefepime-Zidebactam) against Worldwide Collected Gram-Negative Bacilli Not Susceptible to Carbapenems.
Abstract WCK 5222 (cefepime-zidebactam, 2g + 1g, q8h) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined in vitro susceptibility of 1,385 clinical isolates of carbapenem not susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also carbapenem not susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) during 2014-2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using CLSI broth microdiluti...
Source: Antimicrobial Agents and Chemotherapy - September 14, 2020 Category: Microbiology Authors: Karlowsky JA, Hackel MA, Bouchillon SK, Sahm DF Tags: Antimicrob Agents Chemother Source Type: research

Novel antibiotics may be non-inferior, but are they becoming less effective? A systematic review.
Abstract Novel antibiotics approved by non-inferiority trials may become less effective over time in two scenarios: the treatment effect in studies on novel antibiotics may be consistently worse than studies on older antibiotics; or when a decreasingly effective control arm is used in a series of non-inferiority trials. Our systematic review of 175 non-inferiority antibiotic trials found these scenarios to be rare. PMID: 32900680 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Bai AD, Komorowski AS, Lo CKL, Tandon P, Li X, Mokashi V, Cvetkovic A, Findlater A, Liang L, Loeb M, Mertz D, McMaster Infectious Diseases Fellow Research Group Tags: Antimicrob Agents Chemother Source Type: research

Characterization of a novel hybrid plasmid coharboring bla KPC-2 and qnrVC4 in a clinical Citrobacter freundii strain.
Abstract The prevalence of carbapenemase-producing Enterobacterales has become a significant threat to public health.…. PMID: 32900681 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Zhu Y, Liu L, Schwarz S, Liu W, Wang C, Yang Q, Luan T, Wang L, Liu S, Zhang W Tags: Antimicrob Agents Chemother Source Type: research

Building optimal 3-drug combination chemotherapy regimens.
Conclusions: A model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations that can then be trialed. PMID: 32900682 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Drusano GL, Neely MN, Kim S, Yamada WM, Schmidt S, Duncanson B, Nole J, Mtchedlidze N, Peloquin CA, Louie A Tags: Antimicrob Agents Chemother Source Type: research

Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents When Tested against a Large Collection of Contemporary Stenotrophomonas maltophilia Isolates from Medical Centers Worldwide.
Abstract Aztreonam-avibactam was tested against 1,839 Stenotrophomonas maltophilia collected worldwide and demonstrated potent activity against isolates from all geographic regions and infection types (overall MIC50/90, 4/4 mg/L; 97.8% inhibited at ≤8 mg/L). Trimethoprim-sulfamethoxazole (TMP-SMX; MIC50/90, ≤0.5/1 mg/L; 95.4% susceptible) and minocycline (MIC50/90, 0.5/2 mg/L; 99.5% susceptible) also were very active. Aztreonam-avibactam inhibited 84.7% of TMP-SMX-nonsusceptible isolates at ≤8 mg/L. Aztreonam-avibactam may represent a valuable option to treat S. maltophilia infections, addressing a major ...
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Sader HS, Duncan LR, Arends SJR, Carvalhaes CG, Castanheira M Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of Two Commercial Broth Microdilution Methods Using Different Interpretive Criteria for the Detection of Molecular Mechanisms of Acquired Azole and Echinocandin Resistance in Four Common Candida Species.
Abstract The abilities of the new Vitek 2 AST-YS08 (YS08) and Sensititre YeastOne (SYO) systems to detect resistances of Candida isolates to azoles and echinocandins were evaluated. In total, 292 isolates including 28 Candida albicans (6 Erg11 and 2 Fks mutants), 57 Candida parapsilosis (26 Erg11 mutants), 24 Candida tropicalis (10 Erg11 and 1 Fks mutants), and 183 Candida glabrata (39 Pdr1 and 13 Fks mutants) isolates were tested. Categorical agreements (CAs) between Clinical and Laboratory Standards Institute (CLSI) and YS08 fluconazole MICs using clinical breakpoints were 92.4% (C. albicans), 96.5% (C. parapsil...
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Lim HJ, Shin JH, Kim MN, Yong D, Byun SA, Choi MJ, Lee SY, Won EJ, Kee SJ, Kim SH, Shin MG Tags: Antimicrob Agents Chemother Source Type: research

Activities of Cefiderocol with Simulated Human Plasma Concentrations against Carbapenem-resistant Gram-negative Bacilli in an In Vitro Chemostat Model.
Abstract Activity of cefiderocol under simulated human plasma concentrations at the recommended dosing regimen of 2 g every 8 h with a 3-h infusion were evaluated using an in vitro chemostat model. Against a total of 6 meropenem-resistant Gram-negative strains with cefiderocol MIC of 0.5 to 4 μg/ml including metallo-β-lactamase producers and carbapenem-resistant Acinetobacter baumannii, cefiderocol treatment showed bactericidal effect within 8 h, and sustained efficacy with no marked bacterial regrowth over 24 h. PMID: 32900685 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Matsumoto S, Kanazawa S, Sato T, Yamano Y Tags: Antimicrob Agents Chemother Source Type: research

Multicentric analysis of the species distribution and antifungal susceptibility of cryptic isolates from Aspergillus section Fumigati.
Abstract Antifungal susceptibility of Aspergillus cryptic species is poorly known. We assessed 51 isolates belonging to 7 Fumigati cryptic species, by EUCAST reference method and concentration gradient strips (CGS). Species-specific patterns were observed, with high minimum inhibitory concentrations (MICs) for azole drugs, except for A. hiratsukae and A. tsurutae, and high MICs for amphotericin B for A. lentulus and A. udagawae Essential and categorical agreements between EUCAST and CGS were between 53.3 and 93.3%. PMID: 32900686 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - September 8, 2020 Category: Microbiology Authors: Imbert S, Normand AC, Cassaing S, Gabriel F, Kristensen L, Bonnal C, Lachaud L, Costa D, Guitard J, Hasseine L, Palous M, Piarroux M, Hendrickx M, Piarroux R, Fekkar A Tags: Antimicrob Agents Chemother Source Type: research

Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: A First Approach for the Study of Pharmacologic Sanctuaries.
This study aimed to characterize in vitro dolutegravir (DTG) and bictegravir (BIC) binding. They had a preferential binding to human serum albumin (HSA) with two classes of albumin sites. Human alpha-1-acid glycoprotein (HAAG) binding of DTG and BIC showed an atypical nonlinear binding. The low affinity site on HSA, the main plasma binding protein, suggest that the high protein binding rate should not impair passive diffusion. PMID: 32868324 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Gelé T, Gouget H, Furlan V, Becker PH, Taburet AM, Lambotte O, Barrail-Tran A Tags: Antimicrob Agents Chemother Source Type: research

Antimicrobial resistance of Neisseria gonorrhoeae isolates from high risk men in Johannesburg, South Africa.
Conclusions. We demonstrate high prevalence of antimicrobial-resistance in Neisseria gonorrhoeae strains obtained from high-risk men in South Africa. Introduction of diagnostics and scale-up of surveillance are warranted to prevent emergence of multidrug-resistant infections. PMID: 32868325 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Maduna LD, Kock MM, van der Veer BMJW, Radebe O, McIntyre J, van Alphen LB, Peters RPH Tags: Antimicrob Agents Chemother Source Type: research

Population Pharmacokinetic and Pharmacodynamic Analysis to Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1.
Abstract Doravirine is a non-nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus (HIV)-1 infection. A population pharmacokinetic (PK) model for treatment-naïve participants in doravirine clinical studies was updated with data from switch participants in the DRIVE-SHIFT trial, and used to estimate individual post-hoc PK parameter values and evaluate the efficacy exposure-response relationship. The results support the 100 mg dose for people living with HIV switching to a doravirine-based regimen (NCT02397096). PMID: 32868326 [PubMed - as supplied by publisher] (Source: ...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Vaddady P, Kandala B, Yee KL Tags: Antimicrob Agents Chemother Source Type: research

Removal of remdesivir's metabolite GS-441524 by hemodialysis in a double lung transplant recipient with COVID-19.
in G Abstract Remdesivir has reported efficacy against SARS-CoV-2 in vitro and in vivo. Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In ICU settings, in which multiple organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and SEBCD. Additional studies may prove informative, particularly in the evaluations of therapeutic options for COVID-19. PMID: 32868327 [PubMed - as sup...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Lê MP, Le Hingrat Q, Jaquet P, Wicky PH, Bunel V, Massias L, Visseaux B, Messika J, Descamps D, Mal H, Timsit JF, Peytavin G Tags: Antimicrob Agents Chemother Source Type: research

In vivo evolution of CTX-M-215, a novel narrow-spectrum β-lactamase in an Escherichia coli clinical isolate conferring resistance to mecillinam.
In vivo evolution of CTX-M-215, a novel narrow-spectrum β-lactamase in an Escherichia coli clinical isolate conferring resistance to mecillinam. Antimicrob Agents Chemother. 2020 Aug 31;: Authors: Yin M, Hu G, Shen Z, Fang C, Zhang X, Li D, Doi Y, Zhang Y, Wang M, Guo Q Abstract Here we report a novel narrow-spectrum β-lactamase CTX-M-215 identified in an Escherichia coli clinical isolate in China and conferring high-level resistance to mecillinam but not to cefotaxime. CTX-M-215 differed from CTX-M-125, a CTX-M-ESBL by an N132D substitution, which decreased the hydrolytic activities towards...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Yin M, Hu G, Shen Z, Fang C, Zhang X, Li D, Doi Y, Zhang Y, Wang M, Guo Q Tags: Antimicrob Agents Chemother Source Type: research

Preclinical Profile and Characterization of the HBV Core Protein Inhibitor ABI-H0731.
Abstract ABI-H0731, a first-generation Hepatitis B Virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a Phase 1b clinical trial and is currently being further evaluated in Phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2 derived cell lines: HepAD38 and HepG2-NTCP and Primary Human Hepatocyte (PHH)), ABI-H0731 exhibited selective inhibition of HBV DNA replication (EC50 from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed cccDNA formation in two de novo infection mod...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Huang Q, Cai D, Yan R, Li L, Zong Y, Guo L, Mercier A, Zhou Y, Tang A, Henne K, Colonno R Tags: Antimicrob Agents Chemother Source Type: research

Cefiderocol Resistance in Acinetobacter baumannii: Roles of β-lactamases, Siderophore Receptors, and Penicillin Binding Protein 3.
We examined the resistance mechanisms in twelve Acinetobacter baumannii strains with cefiderocol MICs ranging from ≤ 0.03->32 μg/ml. Cefiderocol resistance could not be explained by β-lactamase activity. Cefiderocol resistance was associated with reduced expression of the siderophore receptor gene pirA Mutations involving PBP3 may have contributed to resistance in one strain. Additional studies are needed to assess the role of other siderophore receptors. PMID: 32868330 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Malik S, Kaminski M, Landman D, Quale J Tags: Antimicrob Agents Chemother Source Type: research

R93P Substitution in the PmrB HAMP Domain Contributes to Colistin Heteroresistance in Escherichia coli Isolates from Swine.
In conclusion, point mutations in PmrB and/or PhoQ were primarily associated with CHR. The R93P substitution resulted in the establishment of stable resistant subpopulations in E. coli showing CHR. PMID: 32868331 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Kuang Q, He D, Sun H, Hu H, Li F, Li W, Hu G, Wu H, Yuan L Tags: Antimicrob Agents Chemother Source Type: research

Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models Against Gram-Negative Pathogens.
Abstract MRX-8 is a novel polymyxin analogue in development for the treatment of infections caused by Gram-negative pathogens including those resistant to other antibiotic classes. In the current study, we examined the pharmacodynamic activity of MRX-8 against a variety of common Gram-negative pathogens in the neutropenic mouse thigh and lung models. Additionally, we examined polymyxin B (PMB) as a comparator. Plasma pharmacokinetics of MRX-8 and PMB were linear over a broad dosing range of 0.156-10 mg/kg and had similar AUC0-∞ exposures of MRX-8 0.22-12.64 mg*h/L and PMB 0.12-13.22 mg*h/L. Dose-fractionatio...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Lepak AJ, Wang W, Andes DR Tags: Antimicrob Agents Chemother Source Type: research

Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-na ïve Patients.
Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-naïve Patients. Antimicrob Agents Chemother. 2020 Aug 31;: Authors: Reichmuth ML, Hömke R, Zürcher K, Sander P, Avihingsanon A, Collantes J, Loiseau C, Borrell S, Reinhard M, Wilkinson RJ, Yotebieng M, Fenner L, Böttger EC, Gagneux S, Egger M, Keller PM, International epidemiology Databases to Evaluate AIDS (IeDEA) Abstract Mutations in the genes of the F420 signaling pathway, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, of Mycobacterium tuberculosis (Mtb) complex can lead to delamani...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Reichmuth ML, Hömke R, Zürcher K, Sander P, Avihingsanon A, Collantes J, Loiseau C, Borrell S, Reinhard M, Wilkinson RJ, Yotebieng M, Fenner L, Böttger EC, Gagneux S, Egger M, Keller PM, International epidemiology Databases to Evaluate AIDS (IeDEA) Tags: Antimicrob Agents Chemother Source Type: research

In Vitro Activity of the Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 in Combination with Meropenem against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii.
Abstract QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase producing gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1-16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (CRAB) collected worldwide that were highly resistant to carbapenems (MIC50/MIC90 for meropenem 64/>64 μg/ml). Addition of QPX7728 resulted in a marked c...
Source: Antimicrobial Agents and Chemotherapy - August 31, 2020 Category: Microbiology Authors: Nelson K, Rubio-Aparicio D, Tsivkovski R, Sun D, Totrov M, Dudley M, Lomovskaya O Tags: Antimicrob Agents Chemother Source Type: research

Applicability of outpatient quality indicators for appropriate antibiotic use in a primary health care area: a point prevalence survey.
CONCLUSIONS: The QIs evaluated were applicable to clinical practice and proved useful for identifying areas with room for improvement in our setting and for guiding the design of future interventions with specific objectives. PMID: 32839215 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: March-López P, Madridejos R, Tomas R, Boix L, Arcenillas P, Gómez L, Padilla E, Xercavins M, Martinez L, Massats Ú, Badia C, Sánchez Lledó JM, Domingo Casino A, Nicolás J, Calbo E Tags: Antimicrob Agents Chemother Source Type: research

Targeting CARD9 With Small Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-glucans.
Targeting CARD9 With Small Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-glucans. Antimicrob Agents Chemother. 2020 Aug 24;: Authors: Kottom TJ, Carmona EM, Limper AH Abstract Pneumocystis jirovecii, the opportunistic fungi that causes Pneumocystis Pneumonia (PCP) in humans, is a significant contributor to morbidity and mortality in immunocompromised patients. Given the profound deleterious inflammatory effects of the major β-glucan cell wall carbohydrate constituents of Pneumocystis through Dectin-1 engagement and downstream Caspa...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Kottom TJ, Carmona EM, Limper AH Tags: Antimicrob Agents Chemother Source Type: research

Adjuvant β-lactam therapy combined with vancomycin or daptomycin for methicillin-resistant Staphylococcus aureus bacteraemia: a systematic review and meta-analysis.
The objective of this study is to perform a systematic review and meta-analysis of the current evidence on adjuvant β-lactam (BL) therapy combined with vancomycin (VAN) or daptomycin (DAP) for MRSAB. PubMed, Embase and Cochrane Library were systematically searched for publications reporting clinical outcomes of BLs+VAN or BLs+DAP for adult patients with MRSAB through April 5, 2020. Meta-analysis techniques were applied using random-effects modelling. Three randomized controlled trials and 12 retrospective cohort studies were identified, totalling 2594 patients. Combination treatment significantly reduced the risk of c...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Wang C, Ye C, Liao L, Wang Z, Hu Y, Deng C, Liu L Tags: Antimicrob Agents Chemother Source Type: research

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline.
Abstract Omadacycline is a once-daily oral or intravenous (IV) aminomethylcycline antibiotic approved in the United States for treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received IV omadacycline 100 mg (mild) or 50 mg (moderate and severe), and oral omadacycline 300 mg (mild) or 150 mg (moderate); oral omadacycline was not evaluated in those with severe hepatic impairment. ...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Kovacs SJ, Ting L, Praestgaard J, Sunkara G, Sun H, Stein DS, Tanaka SK, Villano S Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of in vitro activity of manogepix against multidrug-resistant and pan-resistant Candida auris from the New York Outbreak.
Abstract An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are pan-resistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is currently in Phase 2 clinical development for the treatment o...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Zhu Y, Kilburn S, Kapoor M, Chaturvedi S, Shaw KJ, Chaturvedi V Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of the combination of azithromycin and naphthoquine in animal malaria models.
In this study, we assessed the combination of azithromycin and naphthoquine in animal malaria models. A dose-dependent interaction was observed in Peters' 4-day suppressive test on P. berghei K173 infected mice. Moreover, at inhibition levels 90% or above, synergistic effects were found for combinations at various ratios. At an optimal dose ratio of 1:1, the combination acted synergistically even after 4 weeks since first dose and provided a more effective and sustained prophylaxis than naphthoquine alone in blood stage P. berghei K173 and P. cynomolgi bastianelli L challenge models. The ability of the combination to delay...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Bei ZC, Li GF, Zhao JH, Zhang M, Ji XG, Wang JY Tags: Antimicrob Agents Chemother Source Type: research

A five-in-one first-in-human study to assess safety, tolerability, and pharmacokinetics of RO7049389, an inhibitor of hepatitis B virus capsid assembly, after single and multiple ascending doses in healthy participants.
The objectives of this first-in-human study are to assess the safety, tolerability, pharmacokinetics (PK), food effect, inhibitory effect on CYP3A, and effect on QT of RO7049389 in healthy participants. Five components, single ascending doses (SAD) cohorts, multiple ascending doses (MAD) cohorts, food effect assessment, drug-drug interaction assessment, and concentration-QT analysis were integrated in one study (five-in-one). Participants randomly received a single dose of 150-2500 mg RO7049389 or placebo in SAD cohorts (n = 41), or multiple doses of 200-800 mg RO7049389 or placebo in MAD cohorts (n = 42). A single doses o...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Feng S, Gane E, Schwabe C, Zhu M, Triyatni M, Zhou J, Bo Q, Jin Y Tags: Antimicrob Agents Chemother Source Type: research

Prevalence of Plasmodium falciparum Kelch 13 (PfK13) and ubiquitin-specific protease 1 (pfubp1) gene polymorphisms in returning travellers from Africa reported in Eastern China.
This study showed limited variation in PfK13 among returning travellers from African countries and suggested other potential molecular markers, such as pfubp1, for use in surveillance of African isolates in ACT susceptibility studies. Further clinical trials research is under way to investigate these PfK13 and pfubp1 mutations, as well as other candidate molecular markers, and their roles in delaying parasite clearance. PMID: 32839222 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Yan H, Kong X, Zhang T, Xiao H, Feng X, Tu H, Feng J Tags: Antimicrob Agents Chemother Source Type: research

Fluoroquinolone versus beta-lactam oral step-down therapy for uncomplicated streptococcal bloodstream infections.
The objective of this study was to compare clinical outcomes for patients who received an oral FQ versus an oral beta-lactam (BL) as step-down therapy for uncomplicated streptococcal BSIs.This multi-center, retrospective cohort study analyzed adult patients who completed therapy with an oral FQ or BL with at least one blood culture positive for a Streptococcus species from January 1, 2014 to June 30, 2019. The primary outcome was clinical success, defined as lack of all-cause mortality, recurrent BSI with the same organism, and infection-related readmission at 90 days. A multivariable logistic regression model for predicto...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Arensman K, Shields M, Beganovic M, Miller JL, LaChance E, Anderson M, Dela-Pena J Tags: Antimicrob Agents Chemother Source Type: research

In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, In Combination with Beta-Lactams Against Carbapenem-Resistant K. pneumoniae.
The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant K. pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤ 2 mg/L in the presence of 8 mg/L QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or...
Source: Antimicrobial Agents and Chemotherapy - August 24, 2020 Category: Microbiology Authors: Sabet M, Tarazi Z, Griffith DC Tags: Antimicrob Agents Chemother Source Type: research

Erratum for Amblard et al., "Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice".
Erratum for Amblard et al., "Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses In Vitro and in Humanized Mice". Antimicrob Agents Chemother. 2020 Aug 20;64(9): Authors: Amblard F, Boucle S, Bassit L, Cox B, Sari O, Tao S, Chen Z, Ozturk T, Verma K, Russell O, Rat V, de Rocquigny H, Fiquet O, Boussand M, Di Santo J, Strick-Marchand H, Schinazi RF PMID: 32819965 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 20, 2020 Category: Microbiology Authors: Amblard F, Boucle S, Bassit L, Cox B, Sari O, Tao S, Chen Z, Ozturk T, Verma K, Russell O, Rat V, de Rocquigny H, Fiquet O, Boussand M, Di Santo J, Strick-Marchand H, Schinazi RF Tags: Antimicrob Agents Chemother Source Type: research

Erratum for Wang et al., "Cocarriage of Distinct bla KPC-2 and bla OXA-48 Plasmids in a Single Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Isolate".
Erratum for Wang et al., "Cocarriage of Distinct bla KPC-2 and bla OXA-48 Plasmids in a Single Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Isolate". Antimicrob Agents Chemother. 2020 Aug 20;64(9): Authors: Wang YC, Tang HL, Liao YC, Chiou CS, Chen YT, Chiang MK, Lu MC, Lai YC PMID: 32819966 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 20, 2020 Category: Microbiology Authors: Wang YC, Tang HL, Liao YC, Chiou CS, Chen YT, Chiang MK, Lu MC, Lai YC Tags: Antimicrob Agents Chemother Source Type: research

Antibiotic consumption and stewardship at a hospital outside of an early Coronavirus disease 2019 epicentre.
Abstract There are scant data on impact of coronavirus disease (COVID)-19 on hospital antibiotic consumption, and no data from outside epicentres. At our non-epicentre hospital, antibiotic days of therapy (DOT) and bed days of care (BDOC) were reduced by 151.5/month and 285/month, respectively, for March-June 2020, compared to 2018-19 (P=0.001 and P
Source: Antimicrobial Agents and Chemotherapy - August 19, 2020 Category: Microbiology Authors: Buehrle DJ, Decker BK, Wagener MM, Adalja A, Singh N, McEllistrem MC, Nguyen MH, Clancy CJ Tags: Antimicrob Agents Chemother Source Type: research

Identification of a Novel Plasmid-Borne Gentamicin Resistance Gene in Non-typhoidal Salmonella Isolated From Retail Turkey.
Abstract The spread of antibiotic resistant bacteria presents a global health challenge. Efficient surveillance of bacteria harboring antibiotic resistance genes (ARG) is a critical aspect to controlling this spread. Increased access to microbial genomic data from many diverse populations informs this surveillance, but only if functional ARG are identifiable within the dataset. Current, homology-based approaches are effective at identifying the majority of ARG within given clinical and non-clinical datasets for several pathogens, yet there are still some ARG whose identities remain elusive. By coupling phenotypic ...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Kim HL, Rodriguez RD, Morris SK, Zhao S, Donato JJ Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Abstract Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, Phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open label study which evaluated 1) the pharmacoki...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Bach T, Galbiati S, Kennedy JK, Deye G, Nomicos EYH, Codd EE, Garcia HH, Horton J, Gilman RH, Gonzalez AE, Winokur P, An G Tags: Antimicrob Agents Chemother Source Type: research

Longitudinal surveillance and combination antimicrobial susceptibility testing of multidrug-resistant achromobacter spp. from cystic fibrosis patients.
Conclusions: This study enriches the understanding of MDR Achromobacter spp. epidemiology, confirms prevalence and chronic colonization of A. xylosoxidans in CF lungs. It presents in vitro data to support the efficacy of new combinations for use in the treatment of chronic Achromobacter infections. PMID: 32816722 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Okoliegbe IN, Hijazi K, Cooper K, Ironside C, Gould IM Tags: Antimicrob Agents Chemother Source Type: research

Suboptimal dosing of fluconazole in critically ill patients - time to rethink dosing.
Conclusions: Fluconazole clearance is highly variable in ICU patients and strongly dependent on renal function and CRRT. Trough concentrations correlated well with AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend a dose of 400mg for patients with poor to moderate renal function, 600mg for patients with adequate renal function and 800mg for patients treated with CRRT. PMID: 32816723 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Muilwijk EW, de Lange DW, Schouten JA, Wasmann RE, Ter Heine R, Burger DM, Colbers A, Haas PJ, Verweij PE, Pickkers P, Brüggemann RJ Tags: Antimicrob Agents Chemother Source Type: research

Population pharmacokinetics of caspofungin among extracorporeal membrane oxygenation (ECMO) patients during the postoperative period of lung transplantation(LTx).
Conclusion:ECMO did not have a significant impact on the PK of caspofungin in patients after LTx. Some factors were identified as statistically significant covariates related to the PK of caspofungin ; however, their impact on clinical practice of caspofungin needs to be investigated further in more studies. PMID: 32816724 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Wang Q, Zhang Z, Liu D, Chen W, Cui G, Li P, Zhang X, Li M, Zhan Q, Wang C Tags: Antimicrob Agents Chemother Source Type: research

Identification of small molecule inhibitors targeting Porphyromonas gingivalis interspecies adherence and determination of their in vitro and in vivo efficacy.
Abstract P. gingivalis is one of the primary causative agents of periodontal disease and initially colonizes the oral cavity by adhering to commensal streptococci. Adherence requires the interaction of a minor fimbrial protein (Mfa1) of P. gingivalis with streptococcal antigen I/II (AgI/II). Our previous work identified an AgI/II peptide that potently inhibited adherence and significantly reduced P. gingivalis virulence in vivo, suggesting that this interaction represents a potential target for drug discovery. To develop targeted small molecule inhibitors of this protein-protein interaction, we performed a virtual...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Roky M, Tan J, Sztukowska MN, Trent JO, Demuth DR Tags: Antimicrob Agents Chemother Source Type: research

Antifungal susceptibility profiles and drug resistant mechanisms of clinical Lomentospora prolificans isolates.
We examined six different in vitro drug combinations and found that the combination of voriconazole and terbinafine achieved the most synergistic effort against L. prolificans We then annotated L. prolificans whole genome and located its Cyp51 and Fks1 genes. We completely sequenced the two genes to determine if any mutation would be related to azole and echinocandin resistance in L. prolificans We found no amino acid changes in Cyp51 protein and no tandem repeats in 5' upstream region of the Cyp51 gene. However, we identified three intrinsic amino acid residues (G138S, M220I, T289A) in Cyp51 protein that were linked to az...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Wu Y, Grossman N, Totten M, Memon W, Fitzgerald A, Ying C, Zhang SX Tags: Antimicrob Agents Chemother Source Type: research

Emergence of carbapenem-resistant Providencia rettgeri and Providencia stuartti producing IMP-type metallo- β-lactamase in Japan.
Emergence of carbapenem-resistant Providencia rettgeri and Providencia stuartti producing IMP-type metallo-β-lactamase in Japan. Antimicrob Agents Chemother. 2020 Aug 17;: Authors: Iwata S, Tada T, Hishinuma T, Mari T, Satoshi O, Arai-Kuwahara K, Ogawa M, Shimojima M, Kirikae T Abstract Four Providencia rettgeri isolates and a Providencia stuartii isolate were obtained from urine samples of five patients in 2018 in Japan. All the isolates were resistant to imipenem and meropenem. Of them, three were highly resistant to both carbapenems with the minimum inhibitory concentrations (MICs) of 512 μ...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Iwata S, Tada T, Hishinuma T, Mari T, Satoshi O, Arai-Kuwahara K, Ogawa M, Shimojima M, Kirikae T Tags: Antimicrob Agents Chemother Source Type: research

Assessing the safety, tolerability, pharmacokinetics and biodistribution of novel oral formulations of amphotericin B following single and multiple dose administration to Beagle dogs.
Abstract The purpose of this study was to assess the safety, tolerability, pharmacokinetics and biodistribution of novel oral amphotericin B (AmpB) formulations following single and multiple oral dose administration to healthy beagle dogs. The liquid formulation of AmpB was administered to three male dogs and the capsule formulations of AmpB were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on Day 1, 2 and 3 (up to 72 hours post-dosing). Dogs receiving the capsule formulations further received a single oral dose of 100 mg once daily for three more days and...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Wasan KM, Wasan EK, Hnik P Tags: Antimicrob Agents Chemother Source Type: research

Vancomycin Heteroresistance and Clinical Outcomes in Coagulase-Negative Staphylococcal Bloodstream Infections.
Abstract Coagulase-negative staphylococci (CoNS) are a common etiology of serious and recurrent infections in immunocompromised patients. Although most isolates appear susceptible to vancomycin, a single strain might have a subpopulation of resistant bacteria. This phenomenon is termed heteroresistance and may adversely affect the response to treatment. A retrospective cohort study was performed of pediatric patients with leukemia treated at St. Jude Children's Research Hospital who developed CoNS central line-associated bloodstream infection (CLABSI). Available isolates were sequenced and tested for vancomycin he...
Source: Antimicrobial Agents and Chemotherapy - August 17, 2020 Category: Microbiology Authors: Dao TH, Alsallaq R, Parsons J, Ferrolino J, Hayden RT, Rubnitz JE, Rafiqullah IM, Robinson DA, Margolis EB, Rosch JW, Wolf J Tags: Antimicrob Agents Chemother Source Type: research