The antifungal drug isavuconazole is both amebicidal and cysticidal against Acanthamoeba castellanii.
Abstract Current treatments for Acanthamoeba keratitis rely on a combination of chlorhexidine gluconate, propamidine isethionate, and polyhexamethylene biguanide. These disinfectants are nonspecific and inherently toxic, which limits their effectiveness. Furthermore, in 10% of cases, recurrent infection ensues due to the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient, safe, target-specific drugs which are capable of preventing recurrent Acanthamoeba infection is a critical unmet need for averting blindness. Since both trophozoites and cysts contain specific set...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Shing B, Singh S, Podust LM, McKerrow JH, Debnath A Tags: Antimicrob Agents Chemother Source Type: research

A Comparison of Treatment Outcomes Between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem/Cilastatin/Relebactam Versus Colistin Plus Imipenem/Cilastatin in Patients With Imipenem-Nonsusceptible Bacterial Infections.
Conclusions: Outcomes in SmMITT were generally consistent with those in mMITT, suggesting that outcomes may be applicable to real-world use of IMI/REL for treating imipenem-nonsusceptible gram-negative pathogens. PMID: 32094127 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Kaye KS, Boucher HW, Brown ML, Aggrey A, Khan I, Joeng HK, Tipping RW, Du J, Young K, Butterton JR, Paschke A Tags: Antimicrob Agents Chemother Source Type: research

Meropenem/Vaborbactam versus Ceftazidime/Avibactam for Treatment of Carbapenem-Resistant Enterobacteriaceae Infections.
Abstract Background. The comparative efficacy of ceftazidime/avibactam and meropenem/vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections remains unknown.Methods. This was a multicenter, retrospective cohort study of adults with CRE infections who received ceftazidime/avibactam or meropenem/vaborbactam for ≥72 hours from February 2015 to October 2018. Patients with a localized urinary tract infection and repeat study drug exposures after the first episode were excluded. The primary endpoint was clinical success compared between treatment groups. Secondary endpoints included 30- ...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Ackley R, Roshdy D, Meredith J, Minor S, Anderson WE, Capraro GA, Polk C Tags: Antimicrob Agents Chemother Source Type: research

The predominant distribution of OXA-48-like carbapenemase in fecal colonization.
Abstract Carbapenem-resistant Enterobacteriaceae (CRE) has become a public health threat worldwide.…. PMID: 32094129 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Yuan WL, Xu JL, Guo L, Deng QF, Deng DY Tags: Antimicrob Agents Chemother Source Type: research

In Vitro and Intracellular Activities of Omadacycline Against Legionella pneumophila.
This study investigated the activity of omadacycline against Legionella pneumophila strains isolated between 1995 and 2014 from nosocomial or community-acquired respiratory infections. Omadacycline exhibited extracellular activity similar to comparator antibiotics; intracellular penetrance was found by day 3 of omadacycline exposure. These results support the utility of omadacycline as an effective antibiotic for the treatment of CABP caused by L. pneumophila. PMID: 32094130 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Dubois J, Dubois M, Martel JF Tags: Antimicrob Agents Chemother Source Type: research

Thiostrepton reactivates latent HIV-1 through p-TEFb and NF- κB pathway mediated by heat shock response.
Thiostrepton reactivates latent HIV-1 through p-TEFb and NF-κB pathway mediated by heat shock response. Antimicrob Agents Chemother. 2020 Feb 24;: Authors: Peng W, Hong Z, Chen X, Gao H, Dai Z, Zhao J, Liu W, Li D, Deng K Abstract Antiretroviral therapy (ART) suppresses HIV-1 replication, but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. "Shock and Kill" strategy targets these latently-infected cells and boosts immune recognition and clearance, which conti...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Peng W, Hong Z, Chen X, Gao H, Dai Z, Zhao J, Liu W, Li D, Deng K Tags: Antimicrob Agents Chemother Source Type: research

Lactoferrin is broadly active against yeasts and highly synergistic with amphotericin B.
Abstract Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertake a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mould species, and assess interactions with six widely used antifungal drugs. LF was broadly and consistently active across all yeast species (MIC 8-64 μg/ml), with the extent...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Fernandes KE, Weeks K, Carter DA Tags: Antimicrob Agents Chemother Source Type: research

INVESTIGATING THE EFFECTS OF OSMOLYTES AND ENVIRONMENTAL pH ON BACTERIAL PERSISTERS.
Abstract Bacterial persisters are phenotypic variants that temporarily demonstrate an extraordinary tolerance toward antibiotics. Persisters have been linked to the recalcitrance of biofilm related infections; hence, a complete understanding of their physiology can lead to improvement of therapeutic strategies for such infections. Mechanisms pertaining to persister formation are thought to be associated with stress response pathways triggered by intra- or extra-cellular stress factors. Unfortunately, studies demonstrating the effects of osmolyte- and/or pH- induced stresses on bacterial persistence are largely mis...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Karki P, Mohiuddin SG, Kavousi P, Orman MA Tags: Antimicrob Agents Chemother Source Type: research

Novel endochin-like quinolones exhibit potent in vitro activity against Plasmodium knowlesi but do not synergise with proguanil.
Abstract Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc 1 complex, a target critical to the survival of both liver and blood stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimised to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and P vivax, their activity against the zoonotic P knowlesi is unknown. We screened several of these novel endochin-like quinolones (EL...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: van Schalkwyk DA, Riscoe MK, Pou S, Winter RW, Nilsen A, Duffey M, Moon RW, Sutherland CJ Tags: Antimicrob Agents Chemother Source Type: research

Antimicrobial Activity of Ceftolozane-Tazobactam and Comparators When Tested against Clinical Isolates of Haemophilus influenzae from the United States and Europe.
Abstract Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by β-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC50/90 values were 0.12/0.25 mg/L and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/L; the highest MIC value was only 2 mg/L. Our results support using ceftolozane-tazobactam to treat H. influenzae infections. PMID: 32094135 [PubMed - as supplied by p...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Sader HS, Carvalhaes CG, Duncan LR, Shortridge D Tags: Antimicrob Agents Chemother Source Type: research

Impact of Daptomycin Dose Exposure Alone or in Combination with β- lactams or Rifampin against Vancomycin-Resistant Enterococci (VRE) in an In vitro Biofilm Model.
Impact of Daptomycin Dose Exposure Alone or in Combination with β- lactams or Rifampin against Vancomycin-Resistant Enterococci (VRE) in an In vitro Biofilm Model. Antimicrob Agents Chemother. 2020 Feb 24;: Authors: Jahanbakhsh S, Singh NB, Yim J, Kebriaei R, Smith JR, Lev K, Tran TT, Rose WE, Arias CA, Rybak MJ Abstract Enterococcus faecium (Efm) strains are commonly resistant to vancomycin and β-lactams. In addition, Efm often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of DAP dosing regimens (8, 10, 12 and...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Jahanbakhsh S, Singh NB, Yim J, Kebriaei R, Smith JR, Lev K, Tran TT, Rose WE, Arias CA, Rybak MJ Tags: Antimicrob Agents Chemother Source Type: research

Activity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals (2016-2017): Effect of Different Breakpoint Criteria on in the Susceptibility Rates among Aminoglycosides.
Abstract Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016-2017) and only 6 isolates carried 16S rRNA methyltransferases encoding resistance to virtually all aminoglycosides. Plazomicin (89.2-95.9% susceptible) displayed greater activity compared to amikacin (72.5-78.6%), gentamicin (30.4-45.9%) and tobramycin (7.8-22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied t...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Castanheira M, Sader HS, Mendes RE, Jones RN Tags: Antimicrob Agents Chemother Source Type: research

Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379.
Abstract Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanism of action (MOA) and antiviral properties of JNJ-6379 in vitro Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced formation of morphologically intact viral capsids devoid of genomic material ('primary' MOA). JNJ-6379 accelerated the rate and extent of HBV c...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Berke JM, Dehertogh P, Vergauwen K, Mostmans W, Vandyck K, Raboisson P, Pauwels F Tags: Antimicrob Agents Chemother Source Type: research

Genomic epidemiology of complex, multi-species, plasmid-borne bla KPC carbapenemase in Enterobacterales in the UK, 2009-2014.
Group Abstract Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla KPC family) is one of the commonest transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla KPC has historically been associated with distinct K. pneumoniae lineages (clonal group 258 [lsqb]CG258[rsqb]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the UK, bla KPC has represented a large-scale, persistent, management challenge for some hospitals, particularly in North-West England. The dissemination of bla ...
Source: Antimicrobial Agents and Chemotherapy - February 24, 2020 Category: Microbiology Authors: Stoesser N, Phan HTT, Seale AC, Aiken Z, Thomas S, Smith M, Wyllie D, George R, Sebra R, Mathers AJ, Vaughan A, Peto TEA, Ellington MJ, Hopkins KL, Crook DW, Orlek A, Welfare W, Cawthorne J, Lenney C, Dodgson A, Woodford N, Walker AS, TRACE Investigators' Tags: Antimicrob Agents Chemother Source Type: research

In vitro activity of KBP-7072, a novel third-generation tetracycline, against 531 recent geographically diverse and molecularly characterized Acinetobacter baumannii species complex isolates.
In this study, we evaluated the in vitro activity of KBP-7072 and comparator agents by CLSI M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/L) was comparable in activity to ...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Huband MD, Mendes RE, Pfaller MA, Lindley JM, Strand GJ, Benn VJ, Zhang J, Li L, Zhang M, Tan X, Liu Q, Flamm RK Tags: Antimicrob Agents Chemother Source Type: research

In vitro screening of the open source MMV Malaria and Pathogen Boxes to discover novel compounds with activity against Balamuthia mandrillaris.
le DE Abstract Balamuthia mandrillaris, is an under reported pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement usually is fatal. This is due to lack of drugs that are efficacious and that can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open source MMV Malaria and MMV Pathogen boxes (800 compounds total). From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibi...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Rice CA, Lares-Jiménez LF, Lares-Villa F, Kyle DE Tags: Antimicrob Agents Chemother Source Type: research

A novel inhaled dry-powder formulation of ribavirin allows for efficient lung delivery in healthy participants and those with COPD in a Phase 1 study.
Abstract Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent for treatment of respiratory infections in COPD. Using the Particle Replication In Non-wetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (Ribavirin-PRINT-CFI and Ribavirin-PRINT-IP) were developed for efficient delivery ...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Dumont E, Oliver A, Ioannou C, Billiard J, Dennison J, Van Den Berg F, Yang S, Chandrasekaran V, Young G, Lahiry A, Starbuck D, Harrell A, Georgiou A, Hopchet N, Gillies A, Baker S Tags: Antimicrob Agents Chemother Source Type: research

Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe: Report from the SENTRY Antimicrobial Surveillance Program, 2016-2018.
In this report, omadacycline and comparators were tested against 49,000 non-duplicate bacterial isolates collected prospectively during 2016-2018 from medical centers in Europe (24,500 isolates; 40 medical centers [19 countries]) and the United States (24,500 isolates; 33 medical centers [23 states and all 9 United States Census Divisions]). Omadacycline was tested by broth microdilution following Clinical and Laboratory Standards Institute M07 (2018) methods.Omadacycline (MIC50/90, 0.12/0.25 mg/L) inhibited 98.6% of Staphylococcus aureus isolates at ≤0.5 mg/L including 96.3% of methicillin-resistant S. aureus and 99.8%...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Pfaller MA, Huband MD, Shortridge D, Flamm RK Tags: Antimicrob Agents Chemother Source Type: research

Synergistic activity of Clofazimine and Clarithromycin in an aerosol mouse model of Mycobacterium avium infection.
jak C Abstract Infections with nontuberculous mycobacteria (NTM) have a poor prognosis in patients with underlying respiratory diseases. Clofazimine (CFZ) showed both experimental and clinical promising results against clinically relevant NTM. However there is no data on CFZ in combination with the current recommended treatment therefore we aimed to study its in vivo activity in an aerosol mouse model of M. aviumIn an aerosol infection BALB/c mouse model using M. avium strain Chester we treated 58 mice with four combinations of rifampicin (RIF) 10mg/kg, CFZ 25mg/kg, clarithromycin (CLR) and ethambutol (EMB) 100mg/...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Lanoix JP, Joseph C, Peltier F, Castelain S, Andréjak C Tags: Antimicrob Agents Chemother Source Type: research

Role of the Arginine 214 in the substrate specificity of OXA-48.
Abstract Increasing number of variants of the carbapenem-hydrolyzing class D β-lactamase OXA-48 are identified in Enterobacterales worldwide. Among them, OXA-181 and OXA-232 are of particular interest, as they differ from each other by a single amino-acid (AA) substitution at position 214 (R in OXA-181, and S in OXA-232), that results in reduced carbapenem-hydrolyzing activity for OXA-232. To investigate the role of the AA214, the X-ray structure of OXA-232 was determined and the AA214 of OXA-48 and of OXA-232 was replaced by G, L, D, E, S, R, and K using site-directed mutagenesis. These mutants were phenotyp...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Oueslati S, Retailleau P, Marchini L, Berthault C, Dortet L, Bonnin RA, Iorga BI, Naas T Tags: Antimicrob Agents Chemother Source Type: research

Novel Insights Into The Classification of Staphylococcal β-Lactamases In Relation To The Cefazolin Inoculum Effect.
Novel Insights Into The Classification of Staphylococcal β-Lactamases In Relation To The Cefazolin Inoculum Effect. Antimicrob Agents Chemother. 2020 Feb 18;: Authors: Carvajal LP, Rincon S, Echeverri AM, Porras J, Rios R, Ordoñez KM, Seas C, Gomez-Villegas SI, Diaz L, Arias CA, Reyes J Abstract Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin-inoculum effect (CzIE), a phenomenon mediated by staphylococcal β-lactamases. Four variants of staphylococcal β-lactamases have been...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Carvajal LP, Rincon S, Echeverri AM, Porras J, Rios R, Ordoñez KM, Seas C, Gomez-Villegas SI, Diaz L, Arias CA, Reyes J Tags: Antimicrob Agents Chemother Source Type: research

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Rat Model.
Abstract We investigated dose fractionated polymyxin B (PB) on acute kidney injury (AKI). PB 12 mg/kg/day (once, twice, and thrice daily) was administered in rats over 72 hours. Thrice-daily group demonstrated the highest KIM-1 increase (p=0.018) vs. controls (p=0.99) and histopathological damage (p=0.013). A three-compartment model best described the data (bias 0.129 mg/L, imprecision 0.729 mg2/L2, R2 0.652,). AUC24h were similar (p=0.87). Thrice-daily dosing scheme resulted in the most PB-associated AKI in a rat model. PMID: 32071049 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Liu J, Pais GM, Avedissian SN, Gilchrist A, Lee A, Rhodes NJ, Hauser AR, Scheetz MH Tags: Antimicrob Agents Chemother Source Type: research

Drug-drug Interactions between Lumefantrine and Commonly-used Antiretroviral Treatment: An Individual Participant Data Population Pharmacokinetic Meta-Analysis.
Abstract Treating malaria in HIV co-infected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly-used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from ten studies, with 6,100 lumefantrine concentrations from 793 non-pregnant adult participants (41% HIV-malaria co-infected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine expo...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Francis J, Barnes KI, Workman L, Kredo T, Vestergaard LS, Hoglund RM, Byakika-Kibwika P, Lamorde M, Walimbwa SI, Chijioke-Nwauche I, Sutherland CJ, Merry C, Scarsi KK, Nyagonde N, Lemnge MM, Khoo SH, Bygbjerg IC, Parikh S, Aweeka FT, Tarning J, Denti P Tags: Antimicrob Agents Chemother Source Type: research

In Vitro Activity of Ceftazidime-Avibactam Against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial.
This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial (ClinicalTrials.gov identifier NCT01808092). Gram-positive pathogens were included if co-isolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen isolated at baseline, and 149 (18.2%) ...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Stone GG, Bradford PA, Tawadrous M, Taylor D, Cadatal MJ, Chen Z, Chow JW Tags: Antimicrob Agents Chemother Source Type: research

Early bactericidal activity trial of nitazoxanide for pulmonary tuberculosis.
This study was conducted in treatment-naïve adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti.ObjectiveTo assess the safety, bactericidal activity and pharmacokinetics of nitazoxanide (NTZ).DesignThis was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received NTZ 1 gram orally twice daily for 14 days. A control group of ten participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity in an automated liquid culture system.ResultsThe most common adverse events seen in the NTZ group we...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Walsh KF, McAulay K, Lee MH, Vilbrun SC, Mathurin L, Francois DJ, Zimmerman M, Kaya F, Zhang N, Saito K, Ocheretina O, Savic R, Dartois V, Johnson WD, Pape JW, Nathan C, Fitzgerald DW Tags: Antimicrob Agents Chemother Source Type: research

Activity of Cefiderocol and Comparators against Isolates from Cancer Patients.
Abstract Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤ 4 mg/L. It had potent activity against ESBL positive Enterobacteriaceae, carbapenem resistant Enterobacteriaceae, and non-fermenting Gram-negative bacilli including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp. Amikacin, ceftazidime/avibactam and meropenem had appreciable activity against non-CRE Enterobacteriaceae No comparators were active against MDR P. aeruginosa. Only trimethoprim/sulfamethoxazole had appreciable activity against S. maltophilia Overall, cefiderocol was associated with...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Rolston KVI, Gerges B, Shelburne S, Aitken SL, Raad I, Prince RA Tags: Antimicrob Agents Chemother Source Type: research

Hydrogen peroxide-mediated oxygen enrichment eradicates Helicobacter pylori in vitro and in vivo.
Abstract Helicobacter pylori (H. pylori) is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori Inspired by microaerophilic characteristics of H. pylori, we aim at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo During oral administration and after drugs withdrawal, H. pylori counts were both evaluated b...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Di J, Zhang J, Cao L, Huang TT, Zhang JX, Mi YN, Xiao X, Yan PP, Wu ML, Yao T, Liu DZ, Liu J, Cao YX Tags: Antimicrob Agents Chemother Source Type: research

Abacavir exposure in children co-treated for tuberculosis with rifampicin and super-boosted lopinavir-ritonavir.
Abstract In children requiring co-formulated lopinavir/ritonavir-4:1 and rifampicin. adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Rabie H, Tikiso T, Lee J, Fairlie L, Strehlau R, Bobat R, Liberty A, McIlleron H, Andrieux-Meyer I, Cotton M, Lallemant M, Denti P Tags: Antimicrob Agents Chemother Source Type: research

Genomic characterization of Neisseria gonorrhoeae Strains from 2016 United States Sentinel Surveillance Displaying Reduced Susceptibility to Azithromycin.
Abstract In 2016, the proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to azithromycin rose to 3.6%. A phylogenetic analysis of 334 N. gonorrhoeae isolates collected in 2016 revealed a single, geographically diverse lineage of isolates with MICs of 2-16 μg/mL that carried a mosaic-like mtr locus, whereas the majority of isolates with MICs ≥ 16 μg/mL appeared sporadically and carried 23S rRNA mutations. Continued molecular surveillance of N. gonorrheae will identify new resistance mechanisms. PMID: 32071056 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Schmerer MW, Abrams AJ, Seby S, Thomas JC, Cartee J, Lucking S, Vidyaprakash E, Pham CD, Sharpe S, Pettus K, St Cyr SB, Torrone EA, Kersh EN, Antimicrobial-Resistant Neisseria gonorrhoeae Working Group, Gernert KM Tags: Antimicrob Agents Chemother Source Type: research

Multiple copies of bla NDM-5 located on conjugative mega-plasmids from porcine Escherichia coli ST218 isolates.
Abstract The emergence and dissemination of carbapenem-resistant Enterobacteriaceae (CRE) is a serious threat to public health (1).…. PMID: 32071057 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Yao H, Li A, Yu R, Schwarz S, Dong H, Du XD Tags: Antimicrob Agents Chemother Source Type: research

Assessment of drug resistance during phase 2b clinical trials of presatovir in adults naturally infected with respiratory syncytial virus.
Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes. PMID: 32071058 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Porter DP, Guo Y, Perry J, Gossage DL, Watkins TR, Chien JW, Jordan R Tags: Antimicrob Agents Chemother Source Type: research

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum late-stage development and egress.
We report a systematic, cellular phenotype-based antimalarial screening of the MMV Pathogen Box collection, which facilitated the identification of specific blockers of late stage intraerythrocytic development of Plasmodium falciparum First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (EC 50 ≤ 10μM) which also includes 62 additional molecules over previously known antimalarial candidates from Pathogen Box. We identified 90 molecules with EC 50 ≤ 1μM, none of them had significant effect on ring-trophozoite transition while 9 molecules inhibited trophozoite-schiz...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Patra AT, Hingmire TB, Belekar M, Xiong A, Subramanian G, Bozdech Z, Preiser P, Shanmugam D, Chandramohanadas R Tags: Antimicrob Agents Chemother Source Type: research

Hypermutator Pseudomonas aeruginosa exploits multiple genetic pathways to develop multidrug resistance during long-term infections in the airways of cystic fibrosis patients.
ia AM Abstract Pseudomonas aeruginosa exploits intrinsic and acquired resistance mechanisms to resist almost every antibiotic used in chemotherapy. Antimicrobial resistance in P. aeruginosa isolated from cystic fibrosis (CF) patients is further enhanced by the occurrence of hypermutator strains, a hallmark of chronic CF infections. However, the within-patient genetic diversity of P. aeruginosa populations related to antibiotic resistance remains unexplored. Here, we show the evolution of the mutational resistome profile of a P. aeruginosa hypermutator lineage by performing longitudinal and transversal analyses of ...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: Colque CA, Albarracín Orio AG, Feliziani S, Marvig RL, Tobares AR, Johansen HK, Molin S, Smania AM Tags: Antimicrob Agents Chemother Source Type: research

Discordance between Etravirine Phenotype and Genotype-based Predicted Phenotype for Subtype C HIV-1 from First-line Antiretroviral Therapy Failures in South Africa.
Abstract Background: Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in treatment-experienced individuals. Genotypic resistance test-interpretation systems can predict ETR resistance; however, genotype-based algorithms are derived primarily from HIV-1 subtype B and may not accurately predict resistance in non-B subtypes. The frequency of ETR resistance among recombinant subtype C HIV-1 and accuracy of genotypic interpretation systems were investigated.Methods: HIV-1LAI containing full-length RT from HIV-1 subtype C-positive individuals experiencing virologic failure (>10,000 co...
Source: Antimicrobial Agents and Chemotherapy - February 18, 2020 Category: Microbiology Authors: McCormick KD, Penrose KJ, Brumme CJ, Harrigan R, Viana RV, Mellors JW, Parikh UM, Wallis CL Tags: Antimicrob Agents Chemother Source Type: research

Development of a multiplex real-time PCR assay for rapid detection of tigecycline resistance gene tet(X) variants from bacteria, faeces, and environment samples.
Abstract We developed a multiplex real-time SYBR Green-based PCR assay for rapid detection of tet(X) and its variants, including tet(X1), tet(X2), and high-level tigecycline resistance genes tet(X3), tet(X4) and tet(X5). High linearity (R2 ≥0.996), sensitivity (low detection limit) and specificity (only the target gene could be amplified significantly) were showed in developed real-time PCR assay and further evaluated using bacterial, faeces, and environmental samples. PMID: 32041710 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Fu Y, Liu D, Song H, Liu Z, Jiang H, Wang Y Tags: Antimicrob Agents Chemother Source Type: research

Preclinical Antimalarial Combination Studies: The Case of M5717, a P. falciparum Elongation Factor 2 Inhibitor and Pyronaridine, a Hemozoin Formation Inhibitor.
Abstract Antimalarial drug resistance in the Plasmodium falciparum parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a Plasmodium falciparum translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin format...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Rottmann M, Jonat B, Gumpp C, Dhingra SK, Giddins MJ, Yin X, Badolo L, Greco B, Fidock DA, Oeuvray C, Spangenberg T Tags: Antimicrob Agents Chemother Source Type: research

Efficacy of Ceftolozane/Tazobactam in combination with Colistin against Extensively drug-resistant Pseudomonas aeruginosa including High Risk Clones in an In Vitro Pharmacodynamic Model.
Conclusions: C/T plus colistin may be a useful treatment for XDR P. aeruginosa infections, including those caused by high risk-clones resistant to C/T. PMID: 32041712 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Montero M, Ochoa SD, López-Causapé C, VanScoy B, Luque S, Sorlí L, Campillo N, Angulo-Brunet A, Padilla E, Prim N, Pomar V, Rivera A, Grau S, Ambrose PG, Oliver A, Horcajada JP Tags: Antimicrob Agents Chemother Source Type: research

Antagonistic effect of colistin on vancomycin activity against methicillin-resistant Staphylococcus aureus in in vitro and in vivo studies.
This study suggests that exposure of colistin may reduce the susceptibility of vancomycin in certain MRSA strains. Combination therapy with vancomycin and colistin for multidrug-resistant pathogens might result in treatment failure for concurrent MRSA infection. PMID: 32041713 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Choi S, Moon SM, Park SJ, Lee SC, Jung KH, Sung HS, Kim MN, Jung J, Kim MJ, Kim SH, Lee SO, Choi SH, Jeong JY, Woo JH, Kim YS, Chong YP Tags: Antimicrob Agents Chemother Source Type: research

Multiple low-reactivity class B penicillin-binding proteins are required for cephalosporin resistance in enterococci.
Abstract Enterococcus faecalis and Enterococcus faecium are commensals of the gastrointestinal tract of most terrestrial organisms, including humans, and are major causes of healthcare-associated infections. Such infections are difficult or impossible to treat, as the enterococcal strains responsible are often resistant to multiple antibiotics. One intrinsic resistance trait that is conserved among E. faecalis and E. faecium is cephalosporin resistance, and prior exposure to cephalosporins is one of the most well-known risk factors for acquisition of an enterococcal infection. Cephalosporins inhibit peptidoglycan ...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Djorić D, Little JL, Kristich CJ Tags: Antimicrob Agents Chemother Source Type: research

Population pharmacokinetics of amikacin administered once-daily in patients with different renal function.
Conclusion: There is a wide variability in amikacin pharmacokinetic parameters in Mexican patients. This leads to inadequate dosing regimens specially in patients with augmented renal clearance (CLCr> 130 ml/min). Optimization based on final population pharmacokinetic model in Mexican patients may be useful since reliability and clinical applicability have been demonstrated in the current study. PMID: 32041715 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Aréchiga-Alvarado NA, Medellín-Garibay SE, Milán-Segovia RDC, Ortiz-Álvarez A, Magaña-Aquino M, Romano-Moreno S Tags: Antimicrob Agents Chemother Source Type: research

Synergistic interactions of indole-2-carboxamides and β-lactam antibiotics against Mycobacterium abscessus.
Synergistic interactions of indole-2-carboxamides and β-lactam antibiotics against Mycobacterium abscessus. Antimicrob Agents Chemother. 2020 Feb 10;: Authors: Raynaud C, Daher W, Roquet-Banères F, Johansen MD, Stec J, Onajole OK, Ordway D, Kozikowski AP, Kremer L Abstract New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus. We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activit...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Raynaud C, Daher W, Roquet-Banères F, Johansen MD, Stec J, Onajole OK, Ordway D, Kozikowski AP, Kremer L Tags: Antimicrob Agents Chemother Source Type: research

Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.
Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers. Antimicrob Agents Chemother. 2020 Feb 10;: Authors: Mallalieu NL, Winter E, Fettner S, Patel K, Zwanziger E, Attley G, Rodriguez I, Kano A, Salama SM, Bentley D, Geretti AM Abstract Nacubactam is a novel, β-lactamase inhibitor with dual mechanism of action as an inhibitor of serine β-lactamases (classes A, C, and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacok...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Mallalieu NL, Winter E, Fettner S, Patel K, Zwanziger E, Attley G, Rodriguez I, Kano A, Salama SM, Bentley D, Geretti AM Tags: Antimicrob Agents Chemother Source Type: research

Tissue distribution of doxycycline in animal models of tuberculosis.
Abstract Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in TB infected organs and lesions have not been con...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Gengenbacher M, Zimmerman MD, Sarathy JP, Kaya F, Wang H, Mina M, Carter C, Hossen MA, Su H, Trujillo C, Ehrt S, Schnappinger D, Dartois V Tags: Antimicrob Agents Chemother Source Type: research

Scope and Predictive Genetic/Phenotypic Signatures of 'Bicarbonate [NaHCO3]-Responsiveness' and β-Lactam Sensitization Among Methicillin-Resistant Staphylococcus aureus (MRSA).
Scope and Predictive Genetic/Phenotypic Signatures of 'Bicarbonate [NaHCO3]-Responsiveness' and β-Lactam Sensitization Among Methicillin-Resistant Staphylococcus aureus (MRSA). Antimicrob Agents Chemother. 2020 Feb 10;: Authors: Ersoy SC, Otmishi M, Milan VT, Li L, Pak Y, Mediavilla J, Chen L, Kreiswirth B, Chambers HF, Proctor RA, Xiong YQ, Fowler VG, Bayer AS Abstract Addition of sodium bicarbonate (NaHCO3) to standard antimicrobial susceptibility testing media reveals certain MRSA strains to be highly susceptible to β-lactams. We investigated the prevalence of this phenotype ("NaHCO3...
Source: Antimicrobial Agents and Chemotherapy - February 10, 2020 Category: Microbiology Authors: Ersoy SC, Otmishi M, Milan VT, Li L, Pak Y, Mediavilla J, Chen L, Kreiswirth B, Chambers HF, Proctor RA, Xiong YQ, Fowler VG, Bayer AS Tags: Antimicrob Agents Chemother Source Type: research

Comparison of MIC Test Strip and Sensititre YeastOne with the broth microdilution reference methods CLSI and EUCAST for in vitro antifungal susceptibility testing of Cryptococcus neoformans.
Abstract We compared MTS and SYO to EUCAST and CLSI methods for; amphotericin B, 5-fluocytosine, fluconazole, voriconazole and isavuconazole against 106 C.neoformans isolates. The overall EA ±1/±2 dilutions between EUCAST and CLSI were>72%/>94%. The EA between SYO and EUCAST/CLSI for the following drugs amphotericin B, 5-flucytosine, fluconazole, voriconazole were>89/>93%, and for MTS were>57/75% respectively. The VME rates were low for AMB and FCZ (
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Delma FZ, Al-Hatmi AMS, Buil JB, van der Lee H, Tehupeiory-Kooreman M, de Hoog GS, Meletiadis J, Verweij PE Tags: Antimicrob Agents Chemother Source Type: research

Assessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from United States and European Medical Centers (2016-2018).
Abstract High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium. Only 3.3% and 2.1% of E. faecalis showed elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4-40.3% of E. faecium exhibited these phenotypes. Tedizolid inhibited 98.9-100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the USA and Turkey. PMID: 32015026 [PubMed - as supplied by publi...
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Carvalhaes CG, Sader HS, Flamm RK, Streit JM, Mendes RE Tags: Antimicrob Agents Chemother Source Type: research

Activation of heme oxygenase expression by cobalt protoporphyrin treatment prevents pneumonic plague caused by inhalation of Yersinia pestis.
Abstract Pneumonic plague, caused by the gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection. Consequently, primary pneumonic plague is a multi-organ disease involving sepsis, necrosis of immune tissues and the liver, as well as bronchopneumonia and rampant bacterial growth. Given the likely role of the hyper-inflammatory response in accelerating the destruction of tissue, in this work we evaluated the therap...
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Willix JL, Stockton JL, Olson RM, Anderson PE, Anderson DM Tags: Antimicrob Agents Chemother Source Type: research

Potency of Vaborbactam is Less Affected than Avibactam in Strains Producing KPC-2 Mutations that Confer Resistance to Ceftazidime-Avibactam.
In this study we demonstrate that two substitutions in KPC-2, D179Y and L169P, reduce the ability of avibactam to enhance the activity of ceftazidime, cefepime or piperacillin against isogenic efflux deficient strains of P. aeruginosa, 8 to 32-fold and 4 to 16-fold for the D179Y and L169P variants, respectively, depending on antibiotic. In contrast, the potency of vaborbactam, the structurally unrelated beta-lactamase inhibitor that was recently approved by the FDA in combination with meropenem, is reduced no more than two-fold. Experiments with purified enzymes demonstrate that the D179Y substitution causes ∼20-fold i...
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Tsivkovski R, Lomovskaya O Tags: Antimicrob Agents Chemother Source Type: research

Efficacy of early oral switch with beta-lactams for low-risk Staphylococcus aureus bacteremia.
Conclusions. In this low MRSA prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings. PMID: 32015029 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Bupha-Intr O, Blackmore T, Bloomfield M Tags: Antimicrob Agents Chemother Source Type: research

Identification of antibiotics that diminish disease in a murine model of enterohemorrhagic Escherichia coli infection.
h P Abstract Infections with enterohemorrhagic Escherichia coli (EHEC) cause disease ranging from mild diarrhea to hemolytic uremic syndrome (HUS) and are the most common cause of renal failure in children in high income countries. The severity of the disease derives from the release of Shiga toxins (Stx). The use of antibiotics to treat EHEC infections is generally avoided as it can result in increased stx expression. Here, we systematically tested different classes of antibiotics and found that their influence on stx expression and release varies significantly. We assessed a selection of these antibiotics in viv...
Source: Antimicrobial Agents and Chemotherapy - February 3, 2020 Category: Microbiology Authors: Mühlen S, Ramming I, Pils MC, Koeppel M, Glaser J, Leong J, Flieger A, Stecher B, Dersch P Tags: Antimicrob Agents Chemother Source Type: research