In Vitro Activity of Iclaprim against Isolates in Two Phase 3 Clinical Trials (REVIVE-1 and -2) for Acute Bacterial Skin and Skin Structure Infections (ABSSSI).
Abstract Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two Phase 3 studies of ABSSSI (REVIVE-1 and -2). Seven hundred-ninety baseline isolates, including S. aureus, beta-hemolytic streptococci, and S. anginosus Group, underwent antibacterial susceptibility testing. Iclaprim had MIC90 of 0.12μg/mL for S. aureus (0.12μg/mL for methicillin-susceptible, 0.25μg/mL for methicillin-resistant), 0.25μg/mL for beta-hemolytic streptococci and 0.008μg/mL for S. anginosus Group. Iclaprim demonstrated potent activity agains...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Noviello S, Magnet S, Hawser S, Huang DB Tags: Antimicrob Agents Chemother Source Type: research

Biocide Exposure Induces Changes in Susceptibility, Pathogenicity and Biofilm Formation in Uropathogenic Escherichia coli.
Conclusion: Biocide exposure in UPEC may lead to reductions in biocide and antibiotic susceptibility, changes in biofilm-formation and alterations relative-pathogenicity. These data indicate the multiple consequences of biocide adaptation that should be considered when selecting an anti-infective catheter-coating agent. PMID: 30642923 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Henly EL, Dowling JAR, Maingay JB, Lacey MM, Smith TJ, Forbes S Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetic Data Are Predictive of in vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model.
This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESCS strain requiring doses that yielded an fTMIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCR strain and were useful in designing effective dosing regimens. PMID: 30642924 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Connolly KL, Eakin AE, Gomez C, Osborn BL, Unemo M, Jerse AE Tags: Antimicrob Agents Chemother Source Type: research

Race/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202.
We report an analysis on the contribution of participant characteristics to the disposition of tenofovir plasma concentrations.Methods Tenofovir concentration data from a total of 817 individuals (88%) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of inter-individual variability (IIV), and a proportional and mixed error model was assessed for residual variability.Results The final structural model contained t...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Bednasz CJ, Venuto CS, Ma Q, Daar ES, Sax PE, Fischl M, Collier AC, Smith KY, Tierney C, Acosta EP, Mager DE, Morse GD, AIDS Clinical Trials Group Study A5202 Team Tags: Antimicrob Agents Chemother Source Type: research

Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2'-C-methyladenosine prevents death in a mouse model of West Nile virus infection.
In this study, we demonstrate that 2'-C-methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C2'-methylated nucleosides, 7-deaza-2'-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days post-infection, at the time of a peak of viremia, ...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Eyer L, Fojtíková M, Nencka R, Rudolf I, Hubálek Z, Ruzek D Tags: Antimicrob Agents Chemother Source Type: research

In vivo efficacy of novel monobactam LYS228 in murine models of carbapenemase-producing Klebsiella pneumoniae infection.
Abstract LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with K. pneumoniae producing either KPC-2 or NDM-1; pre-treatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in the kidney, urine and bladder. The successful treatment of murine infection models established with carbapenem resistant K. pneumoniae further supports the clinical development of LYS228. PMID: 30642927 [PubMed - as supplied by pu...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Weiss WJ, Pulse ME, Nguyen P, Growcott EJ Tags: Antimicrob Agents Chemother Source Type: research

Moxifloxacin in COPD: pharmacokinetics and penetration into bronchial secretions in ward and ICU patients.
This study aims to evaluate moxifloxacin's (MXF's) pharmacokinetic profile in serum and sputum/bronchial secretions of 22 patients, with acute exacerbation of COPD (AECOPD), hospitalized in ward and ICU. The data showed that ICU patients had lower concentration in secretions (p=0.01).Thought, no other statistically significant differences were observed in pharmacokinetic parameters and penetration in secretions between less and critically ill. MXF showed a favorable pharmacokinetic profile and the pharmacodynamic targets for common pathogens for AECOPD were achieved. PMID: 30642928 [PubMed - as supplied by publisher] ...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Sionidou M, Manika K, Pitsiou G, Kontou P, Chatzika K, Zarogoulidis P, Kioumis I Tags: Antimicrob Agents Chemother Source Type: research

Population pharmacokinetics and dosing optimization of linezolid in pediatric patients.
Conclusion: The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization. PMID: 30642929 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Li SC, Ye Q, Xu H, Zhang L, Wang Y Tags: Antimicrob Agents Chemother Source Type: research

ClyJ, a novel pneumococcal chimeric lysin with a CHAP catalytic domain.
In this study, we identified a putative lysin (gp20) encoded by the Streptococcus phage SPSL1 using the LytA autolysin as a template. Molecular dissection of gp20 revealed a binding domain (GPB) containing choline-binding repeats (CBRs) that are high specificity for S. pneumoniae By fusing GPB to the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) catalytic domain of the PlyC lysin, we constructed a novel chimeric lysin, ClyJ, with improved activity to the pneumococcal Cpl-1 lysin. No resistance was observed in S. pneumoniae strains after exposure to incrementally doubling concentrations of ClyJ for 8 continu...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Yang H, Gong Y, Zhang H, Etobayeva I, Miernikiewicz P, Luo D, Li X, Zhang X, Dabrowska K, Nelson DC, He J, Wei H Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetics and pharmacodynamics of murepavadin in neutropenic mice models.
PHARMACOKINETICS AND PHARMACODYNAMICS OF MUREPAVADIN IN NEUTROPENIC MICE MODELS. Antimicrob Agents Chemother. 2019 Jan 14;: Authors: Melchers MJ, Teague J, Warn P, Hansen J, Bernardini F, Wach A, Obrecht D, Dale GE, Mouton JW Abstract Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein targeting antibiotics. It specifically interacts with LptD and inhibits LPS transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding, the pharmacokinetics of murepavadin in plasma and ELF ...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Melchers MJ, Teague J, Warn P, Hansen J, Bernardini F, Wach A, Obrecht D, Dale GE, Mouton JW Tags: Antimicrob Agents Chemother Source Type: research

Vacuolar sequestration of azoles: A novel strategy of azole antifungal resistance conserved across pathogenic and non-pathogenic yeast.
Abstract Target alteration and over production, drug efflux by overexpression of plasma membrane localized multidrug transporters comprise the conventional mechanisms of azole antifungal resistance. Here, we identify a novel and conserved mechanism of azole resistance not only in the budding yeast, Saccharomyces cerevisiae but also in the pathogenic yeast, Candida albicans We observe that the vacuolar membrane localized, MRP subfamily ABC transporter, of S. cerevisiae, Ybt1, can import azoles into the vacuole. Interestingly, the Ybt1 homologue in C. albicans, Mlt1p, could also complement this function. The underpi...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Khandelwal NK, Wasi M, Nair R, Gupta M, Kumar M, Mondal AK, Gaur NA, Prasad R Tags: Antimicrob Agents Chemother Source Type: research

Detection of mcr-mediated colistin resistance in Escherichia coli isolated from pigs in small-scale farms in Cambodia.
usson U Abstract Colistin is today considered a last-line antimicrobial for the treatment of infections in humans caused by multidrug-resistant Enterobacteriaceae [1]. The dissemination of colistin resistance has received increased attention since a mobilized gene conferring resistance to colistin, mcr-1, was described in Enterobacteriaceae from humans and food-producing animals in China in 2015 [2], and additional gene homologs have since been identified [3-15]. PMID: 30642933 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Ström Hallenberg G, Börjesson S, Sokerya S, Sothyra T, Magnusson U Tags: Antimicrob Agents Chemother Source Type: research

Small molecule inhibitor of FosA expands fosfomycin activity to multidrug-resistant Gram-negative pathogens.
In this study, we describe the discovery and biochemical and structural characterization of 3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one (ANY1), a small molecule active site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains. PMID: 30642934 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Tomich AD, Klontz EH, Deredge D, Barnard JP, McElheny CL, Eshbach ML, Weisz OA, Wintrode P, Doi Y, Sundberg EJ, Sluis-Cremer N Tags: Antimicrob Agents Chemother Source Type: research

Turning the Tide against Antibiotic Resistance by Evaluating Novel, Halogenated Phenazine, Quinoline, and NH125 Compounds against Ureaplasma spp. Clinical Isolates and Mycoplasma Type Strains.
Abstract Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium, have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics such as beta-lactams, vancomycin, sulfonamides and trimethoprim of no value. To address this shortage, we screened nitroxoline, triclosan, and a library of 20 novel, halogenated phenazine, quinoline, and NH125 analogues against Ureaplasma spp. and M. hominis clinical isolates from urine. We tested a subset of these compounds (n = 9) a...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Valentine-King MA, Cisneros K, James MO, Huigens RW, Brown MB Tags: Antimicrob Agents Chemother Source Type: research

Ceftolozane-tazobactam pharmacokinetics during extracorporeal membrane oxygenation in a lung transplant recipient.
Abstract Ceftolozane-tazobactam (C/T) pharmacokinetics during extracorporeal membrane oxygenation (ECMO) has not been previously studied. In this work we report on the C/T plasmatic levels in a lung transplant (LTX) recipient during ECMO, treated with C/T (i.v., 2 g ceftolozane and 1 g tazobactam, every 8 hours]) for a Pseudomonas aeruginosa pulmonary infection. PMID: 30642936 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Arena F, Marchetti L, De Angelis LH, Maglioni E, Contorni M, Cassetta MI, Novelli A, Rossolini GM Tags: Antimicrob Agents Chemother Source Type: research

Isoniazid bactericidal activity involves electron transport chain perturbation.
This study implicates mycobacterial ETC perturbation through NDHs, SDHs, cytochrome bc1 and F0F1 ATP synthase in INH's bactericidal activity and pinpoints the participation of the cytochrome bd oxidase in protection against this drug under stress conditions. PMID: 30642937 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Zeng S, Soetaert K, Ravon F, Vandeput M, Bald D, Kauffmann JM, Mathys V, Wattiez R, Fontaine V Tags: Antimicrob Agents Chemother Source Type: research

Clofazimine exposure in vitro selects efflux pump mutants and bedaquiline resistance.
Abstract Six in-vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harbouring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants, however atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway. PMID: 30642938 [PubMed - as...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Ismail N, Peters RPH, Ismail NA, Omar SV Tags: Antimicrob Agents Chemother Source Type: research

The roles of efflux pumps from different superfamilies in the surface-associated motility and virulence of Acinetobacter baumannii ATCC 17978.
bé J Abstract While the relationship between Acinetobacter baumannii efflux pumps and antimicrobial resistance is well-documented, less is known about the involvement of these proteins in the pathogenicity of this nosocomial pathogen. In previous work, we identified the AbaQ MFS efflux pump and demonstrated its participation in the motility and virulence of A. baumannii In the present study, we examined the role in these processes of A. baumannii transporters belonging to different superfamilies of efflux pumps. Genes encoding known or putative permeases belonging to efflux pump superfamilies other than MFS...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Pérez-Varela M, Corral J, Aranda J, Barbé J Tags: Antimicrob Agents Chemother Source Type: research

Aspergillus fumigatus thioredoxin reductase: structure, mechanism, and inhibition.
Abstract Aspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen (2-phenyl-1,2-benzoselenazol-3(2H)-one) is an inhibitor of A. fumigatus TrxR (Ki = 0.22 μM) and inhibits growth of Aspergillus spp. with in vitro MIC values of 16-64 μg/mL. Mass spectrometry analysis demonstrates that ebselen interacts co...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Marshall AC, Kidd SE, Lamont-Friedrich SJ, Arentz G, Hoffmann P, Coad BR, Bruning JB Tags: Antimicrob Agents Chemother Source Type: research

Use of Letermovir as Salvage Therapy for Drug-resistant CMV Retinitis: A Case Series.
Abstract Treatment options for drug-resistant CMV are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically-confirmed resistance to letermovir while on therapy. PMID: 30642941 [PubMed...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW, Maziarz EK, Saullo JH, Wolfe CR Tags: Antimicrob Agents Chemother Source Type: research

Dose-dependent Synergistic Interactions of Colistin with Rifampicin, Meropenem and Tigecycline against Carbapenem-resistant Klebsiella pneumoniae Biofilms.
Abstract Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampicin (RIF), meropenem (MEM), gentamicin (GEN) and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN or TGC against CR-Kp mature biofilms. Twenty CR-Kp blood isolates were derived from equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0.4% crystal violet and measuring optical density spectrophotometr...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Geladari A, Simitsopoulou M, Antachopoulos C, Roilides E Tags: Antimicrob Agents Chemother Source Type: research

In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates.
The objective of the present study was to evaluate the in vitro activity of various marketed β-lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both β-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem/vaborbactam combination is now marketed and an imipenem/relebactam combination is currently in phase III trials, these fixed combinations may become the β-la...
Source: Antimicrobial Agents and Chemotherapy - January 14, 2019 Category: Microbiology Authors: Kaushik A, Ammerman NC, Lee J, Martins O, Kreiswirth BN, Lamichhane G, Parrish NM, Nuermberger EL Tags: Antimicrob Agents Chemother Source Type: research

Linezolid pharmacokinetics in South African patients with drug resistant tuberculosis and a high prevalence of HIV co-infection.
Abstract WHO recently recommended linezolid should be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in this population. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady-state. Non-compartmental analysis was performed. Thirty participants were included: 15 HIV-posi...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Wasserman S, Denti P, Brust JCM, Tareq M, Hlungulu S, Wiesner L, Norman J, Sirgel FA, Warren RM, Esmail A, Dheda K, Gandhi NR, Meintjes G, Maartens G Tags: Antimicrob Agents Chemother Source Type: research

Effects of KPC variant and porin genotype on the in vitro activity of meropenem-vaborbactam against carbapenem-resistant Enterobacteriaceae.
We described the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory engineered E. coli harboring mutant bla KPC genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam minimum inhibitory concentrations (MICs) were 1 and 0.03μg/mL, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MIC ≤4μg/mL). Against K. pneumoniae harboring mutant bla ...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Wilson WR, Kline EG, Jones CE, Morder KT, Mettus RT, Doi Y, Nguyen MH, Clancy CJ, Shields RK Tags: Antimicrob Agents Chemother Source Type: research

In Vitro Activity of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa: Results from a Multicenter Study in China, 2017.
Abstract The in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers across China in 2017. Antimicrobial susceptibility testing was performed by CLSI broth microdilution. And bla KPC and bla NDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE). Ceftazidime-avibactam demonstrated potent activity against almost all Enterobacteriaceae (94.6% susceptibility; MIC50≤0.25 mg/L; MIC90, ≤0.25->32 mg/L) and good against P. aerugino...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Yin D, Wu S, Yang Y, Shi Q, Dong D, Zhu D, Hu F Tags: Antimicrob Agents Chemother Source Type: research

Antimicrobial Activity of Omadacycline Tested against Clinical Bacterial Isolates from Hospitals in China (including Hong Kong) and Taiwan: Results from the SENTRY Antimicrobial Surveillance Program (2013-2016).
Abstract Omadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (one per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan. Susceptibility testing was performed by broth microdilution methods in a central laboratory (JMI Laboratories). The collection included Gram-positive and Gram-negative organisms from patients with pneumonia, bloodstream, skin, community-acquired respiratory, and other infections. Omadacycline was very potent against Staphylococcus aureus (n=689; MIC50/90, 0.12/0.25 mg/...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Carvalhaes CG, Huband MD, Reinhart HH, Flamm RK, Sader HS Tags: Antimicrob Agents Chemother Source Type: research

A First-in-human Safety, Tolerability and Pharmacokinetics study of Benapenem in Healthy Chinese Volunteers.
The objective of this trial is to investigate the safety, tolerability and pharmacokinetics (PK) of benapenem administrated by single or multiple intravenous infusions in healthy Chinese volunteers.Methods: The trial was divided into 3 parts. Part A: 94 subjects were enrolled in a double-blind, placebo-controlled, sequential ascending single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1000, 2000 or 3000 mg, respectively. The effects of intravenous infusion time on the subjects of 250, 500 and 1000 mg group were explored. Part B: 12 ...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Zhao CY, Lv Y, Zhu Y, Wei MJ, Liu MY, Ji XW, Kang ZS, Xia YH, Tian JH, Ma Y, Liu Y Tags: Antimicrob Agents Chemother Source Type: research

Adjuvant β-lactam therapy combined with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: Does β-lactam class matter?
Adjuvant β-lactam therapy combined with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: Does β-lactam class matter? Antimicrob Agents Chemother. 2019 Jan 07;: Authors: Dilworth TJ, Casapao AM, Ibrahim OM, Jacobs DM, Bowers DR, Beyda ND, Mercier RC Abstract We analyzed the impact of vancomycin (VAN) combined with adjuvant β-lactam therapy (COMBO) on persistent methicillin-resistant Staphylococcus aureus bacteremia (≥5 days) compared to VAN using pooled data from two previously published, observational studies (n=156). COMBO was inversely associated with p...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Dilworth TJ, Casapao AM, Ibrahim OM, Jacobs DM, Bowers DR, Beyda ND, Mercier RC Tags: Antimicrob Agents Chemother Source Type: research

Evolution of daptomycin resistance in coagulase negative staphylococci involves mutations of the essential two component regulator WalKR.
This study highlights the significance of CoNS in evolving daptomycin resistance and showed that walKR is shared among the staphylococcal species as being involved in antibiotic resistance development. Notably, we did not observe mutations in genes responsible for phospholipid biosynthesis or an altered cell surface charge, suggesting that reduced daptomycin susceptibility in CoNS may emerge in a fashion distinct from S. aureus. PMID: 30617095 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Jiang JH, Dexter C, Cameron DR, Monk IR, Baines S, Abbott IJ, Spelman DW, Kostoulias X, Nethercott C, Howden BP, Peleg AY Tags: Antimicrob Agents Chemother Source Type: research

Investigation of novel pmrB and eptA mutations in isogenic Acinetobacter baumannii isolates associated with colistin resistance and increased virulence in vivo.
In this study we investigate the mechanisms of colistin resistance in four isogenic pairs of A. baumannii isolates displaying an increase in colistin MICs. A mutation in pmrB was detected in each colistin-resistant isolate, three of which were novel (A28V, I232T, ΔL9-G12). Increased expression of pmrC was shown by qRT-PCR for three colistin-resistant isolates, and the addition of phosphoethanolamine (PEtN) to lipid A by PmrC was revealed by mass spectrometry. Interestingly, PEtN addition was also observed in some colistin-susceptible isolates, indicating that this resistance mechanism might be strain-specific and tha...
Source: Antimicrobial Agents and Chemotherapy - January 7, 2019 Category: Microbiology Authors: Gerson S, Betts JW, Lucaßen K, Nodari CS, Wille J, Josten M, Göttig S, Nowak J, Stefanik D, Roca I, Vila J, Cisneros JM, La Ragione RM, Seifert H, Higgins PG Tags: Antimicrob Agents Chemother Source Type: research

Structure-activity relationships of wollamide cyclic hexapeptides with activity against drug-resistant and intracellular Mycobacterium tuberculosis.
Abstract Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces, that exhibit promising in vitro anti-mycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin, without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and anti-mycobacterial activity of ×36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth inhibitory activity against Mycobacterium tuberculosis (Mtb) (H37Rv, H37Ra, CDC1551, HN878, HN353). The m...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Khalil ZG, Hill TA, De Leon Rodriguez LM, Lohman RJ, Hoang HN, Reiling N, Hillemann D, Brimble MA, Fairlie D, Blumenthal A, Capon RJ Tags: Antimicrob Agents Chemother Source Type: research

Understanding the components, calculation and impact of monthly and seasonal variation of the SAAR: Illustrative Data.
This study sought to characterize the impact of 3 types of variation on the Standardized Antimicrobial Administration Ratio (SAAR) utilizing local NHSN data. SAAR and antimicrobial days per 1000 days present (AD/1000DP) were compiled monthly for Northwestern Memorial Hospital from 2014 to 2016. Antimicrobial consumption was aggregated into agent categories (via NHSN criteria). Month-to-month changes in SAAR and AD/1000DP were evaluated. Azithromycin and oseltamivir AD/1000DP from 2012 through 2017 were explored for seasonal variation. A sensitivity analysis was performed to explore the effect of seasonality and altered con...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Avedissian SN, Rhodes NJ, Liu J, Aljefri D, Postelnick MJ, Sutton SH, Zembower TR, Martin D, Pais G, Cruce CE, Scheetz MH Tags: Antimicrob Agents Chemother Source Type: research

Are standard dosing regimens of ceftriaxone adapted for critically ill patients with augmented creatinine clearance? A prospective observational study.
Conclusion: When targeting 100%fT>MIC of the less susceptible pathogens, patients with ClCr ≥ 150 ml/min remain at risk of empirical ceftriaxone underdosing. These data emphasize the need of therapeutic drug monitoring in ARC patients. PMID: 30602511 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Ollivier J, Carrié C, d'Houdain N, Djabarouti S, Petit L, Xuereb F, Legeron R, Biais M, Breilh D Tags: Antimicrob Agents Chemother Source Type: research

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus.
This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tb through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tb (MIC 0.02 µM) and Mycobacterium abscessus (MIC 0.4 µM). Spontaneously generated mutants resistant to RUFI involved seven unique SNP mutations at three distinct codons within the NTD domain of clpC1 (V13, H77, F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, wh...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Choules MP, Wolf NM, Lee H, Anderson JR, Grzelak EM, Wang Y, Ma R, Gao W, McAlpine JB, Jin YY, Cheng J, Lee H, Suh JW, Duc NM, Paik S, Choe JH, Jo EK, Chang CL, Lee JS, Jaki BU, Pauli GF, Franzblau SG, Cho S Tags: Antimicrob Agents Chemother Source Type: research

Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women using the Dapivirine Vaginal Ring.
Abstract Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but are rarely included in trials. The 25 mg dapivirine vaginal ring (VR) reduced women's risk of sexually transmitted HIV infection in two Phase 3 trials conducted in Africa. MTN-029/IPM 039 was a Phase 1, open-label study of dapivirine VR use among lactating women. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) s...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Noguchi LM, Hoesley C, Kelly C, Scheckter R, Bunge K, Nel A, Marzinke MA, Hendrix CW, Dezzutti CS, Hillier SL, Bogen DL, Piper JM, Beigi RH Tags: Antimicrob Agents Chemother Source Type: research

Barrier to resistance of dolutegravir in two-drug combinations.
Abstract A major concern when using two-drug anti-HIV regimens is the risk of viral resistance. However, no techniques to evaluate the barrier to resistance of two-drug combinations in vitro have been reported. We evaluated the emergence of drug-resistant mutants in a passage study with constant concentrations of two drugs simultaneously. The barrier to resistance of dolutegravir-containing two-drug combinations was higher than the other combinations evaluated in this study. PMID: 30602514 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Yoshinaga T, Miki S, Kawauchi-Miki S, Seki T, Fujiwara T Tags: Antimicrob Agents Chemother Source Type: research

Relationship of Ganciclovir Therapeutic Drug Monitoring with Clinical Efficacy and Patient Safety.
Conclusions: We did not observe any associations between ganciclovir TDM and clinical efficacy or safety endpoints. Routine ganciclovir TDM may be of limited value. Future studies may be warranted to identify specific populations with unpredictable pharmacokinetic and pharmacodynamics profiles in whom ganciclovir TDM may be of benefit. PMID: 30602515 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Ritchie BM, Barreto JN, Frazee E, Crow SA, Dierkhising RA, Jannetto PJ, Tosh PK, Razonable RR Tags: Antimicrob Agents Chemother Source Type: research

Emergence of a multidrug-resistant hypervirulent Klebsiella pneumoniae of ST23 with a rare bla CTX-M-24-harboring virulence plasmid.
We reported a MDR-HvKP strain of ST23 with a rare hybrid plasmid harboring virulence genes and bla CTX-M-24, and analyzed the genetic basis for relationship between genotypes and "MDR-hypervirulence" phenotypes. Further analysis indicates that the hybrid plasmid is formed by the IS903D-mediated intermolecular transposition of bla CTX-M-24 gene into the virulent plasmid. The emergence of MDR-HvKP strains, especially drug-resistant virulent plasmids poses unprecedented threats/challenges to public health. This is a dangerous tendency and should be closely monitored. PMID: 30602516 [PubMed - as supplied by publ...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Shen D, Ma G, Li C, Jia X, Qin C, Yang T, Wang L, Jiang X, Ding N, Zhang X, Yue L, Yin Z, Zeng L, Zhao Y, Zhou D, Chen F Tags: Antimicrob Agents Chemother Source Type: research

Small IncQ1 and Col-like Plasmids Harboring bla KPC-2 and non-Tn4401 Elements (NTEKPC-IId) in High-Risk Lineages of Klebsiella pneumoniae CG258.
Abstract A retrospective genomic study led to the identification of two carbapenem-resistant K. pneumoniae isolates (KPN535 and KPC45) carrying bla KPC-2 genes on non-conjugative plasmids.…. PMID: 30602517 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Cerdeira LT, Lam MMC, Wyres KL, Wick RR, Judd LM, Lopes R, Ribas RM, Morais MM, Holt KE, Lincopan N Tags: Antimicrob Agents Chemother Source Type: research

A rapid unravelling of mycobacterial activity and of their susceptibility to antibiotics.
Abstract The development of antibiotic-resistant bacteria is a worldwide health-related emergency that calls for new tools to study the bacterial metabolism and to obtain fast diagnoses. Indeed, the conventional analysis timescale is too long and affects our ability to fight infections. Slowly growing bacteria represent a bigger challenge, since their analysis may require up to months. Among these bacteria, Mycobacterium tuberculosis, the causative agent of tuberculosis has caused, only in 2016 more than 10 million new cases and 1.7 million deaths. We employed a particularly powerful nanomechanical oscillator, the...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Mustazzolu A, Venturelli L, Dinarelli S, Brown K, Floto RA, Dietler G, Fattorini L, Kasas S, Girasole M, Longo G Tags: Antimicrob Agents Chemother Source Type: research

Indole-2-carboxamides are Active Against an Acute Mycobacterium abscessus Infected Mouse Model.
This study discloses in vivo data for two lead molecules (5 and 25) that were advanced for efficacy studies in Mycobacterium abscessus infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial load in lung and spleen of M. abscessus-infected mice. PMID: 30602519 [PubMed - as supplied by publisher] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Pandya AN, Prathipati PK, Hegde P, Li W, Graham KF, Mandal S, Drescher KM, Destache CJ, Ordway D, Jackson M, North EJ Tags: Antimicrob Agents Chemother Source Type: research

Efficacy and safety of pyronaridine-artesunate plus single-dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Cambodia.
Abstract In Cambodia, multi-drug resistant Plasmodium falciparum undermines the treatment of uncomplicated malaria and new therapeutic options are needed. Pyronaridine-artesunate has not previously been evaluated in eastern Cambodia. This single-arm, open-label, prospective study was conducted July-December 2017 at Koh Gnek (Mondulkiri) and Veun Sai (Rattanakiri) health centers in eastern Cambodia. Eligible patients were aged ≥7 years (females 12-18 years excluded), weighing ≥20 kg, with microscopically confirmed P. falciparum mono-infection and fever. Oral pyronaridine-artesunate was administered once daily...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Leang R, Mairet-Khedim M, Chea H, Huy R, Khim N, Mey Bouth D, Dorina Bustos M, Ringwald P, Witkowski B Tags: Antimicrob Agents Chemother Source Type: research

High Prevalence of Bedaquiline Resistance in Treatment-na ïve Tuberculosis Patients and Verapamil Effectiveness.
High Prevalence of Bedaquiline Resistance in Treatment-naïve Tuberculosis Patients and Verapamil Effectiveness. Antimicrob Agents Chemother. 2019 Jan 02;: Authors: Ghajavand H, Kargarpour Kamakoli M, Khanipour S, Pourazar Dizaji S, Masoumi M, Rahimi Jamnani F, Fateh A, Siadat SD, Vaziri F Abstract In the regions that Bedaquiline is introduced into regimen, analysis of the MIC and screening for pre-existing resistant mutations could be crucial. The high prevalence of isolates with high BDQ MICs without prior exposure to BDQ was worrisome. It was also concluded that efflux pumps play pivotal role i...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Ghajavand H, Kargarpour Kamakoli M, Khanipour S, Pourazar Dizaji S, Masoumi M, Rahimi Jamnani F, Fateh A, Siadat SD, Vaziri F Tags: Antimicrob Agents Chemother Source Type: research

Screening The Pathogen Box for Identification of New Chemicals Agents With Anti Fasciola hepatica Activity.
Abstract Fascioliasis is an infectious parasitic disease distributed globally and caused by the liver flukes Fasciola hepatica or F. gigantica This neglected tropical disease affects both animals and humans and it represents a latent public health problem due to the significant economic losses related to animal husbandry. For decades, Triclabendazole has been the unique anti-Fasciola drug that can effectively treat this disease. However, triclabendazole resistance in Fascioliasis has been more recently reported around the world, and thus the discovery of novel drugs is an urgent need. The aim of this study was to ...
Source: Antimicrobial Agents and Chemotherapy - January 2, 2019 Category: Microbiology Authors: Machicado C, Soto MP, Timoteo O, Vaisberg A, Pajuelo M, Ortiz P, Marcos LA Tags: Antimicrob Agents Chemother Source Type: research

Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient.
We report a case of a 24-year-old liver transplant recipient who developed hepatic artery thrombosis and graft failure, which was complicated by subphrenic abscess and persistent Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteremia. Ceftazidime-avibactam treatment led to emergence of resistance, and alternative combination therapy failed due to persistent infection and toxicity. The infection resolved after initiation of meropenem-vaborbactam, which created a bridge to retransplantation. Treatment-emergent ceftazidime-avibactam resistance is increasingly recognized, suggesting a role for meropenem-v...
Source: Antimicrobial Agents and Chemotherapy - December 24, 2018 Category: Microbiology Authors: Athans V, Neuner EA, Hassouna H, Richter SS, Keller G, Castanheira M, Brizendine KD, Mathers AJ Tags: Antimicrob Agents Chemother Source Type: research

Myelosuppression with Oxazolidinones: Are There Differences?
PMID: 30578404 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 24, 2018 Category: Microbiology Authors: Hardalo C, Lodise TP, De Anda C Tags: Antimicrob Agents Chemother Source Type: research

Reply to Hardalo et al., "Myelosuppression with Oxazolidinones: Are There Differences?"
Reply to Hardalo et al., "Myelosuppression with Oxazolidinones: Are There Differences?" Antimicrob Agents Chemother. 2019 Jan;63(1): Authors: Caffrey AR, Lee EY PMID: 30578405 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 24, 2018 Category: Microbiology Authors: Caffrey AR, Lee EY Tags: Antimicrob Agents Chemother Source Type: research

Erratum for Parvez et al., "Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro".
Erratum for Parvez et al., "Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro". Antimicrob Agents Chemother. 2019 Jan;63(1): Authors: Parvez MM, Kaisar N, Shin HJ, Lee YJ, Shin JG PMID: 30578406 [PubMed - in process] (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - December 24, 2018 Category: Microbiology Authors: Parvez MM, Kaisar N, Shin HJ, Lee YJ, Shin JG Tags: Antimicrob Agents Chemother Source Type: research

Oxazolidinones Can Replace Clarithromycin in Combination with Rifampin in a Mouse Model of Buruli Ulcer.
Abstract Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control reg...
Source: Antimicrobial Agents and Chemotherapy - December 17, 2018 Category: Microbiology Authors: Almeida DV, Omansen TF, Li SY, Lee J, Grosset JH, Converse PJ, Nuermberger EL Tags: Antimicrob Agents Chemother Source Type: research

Mass Balance and Drug Interaction Potential of IV Eravacycline Administered to Healthy Subjects.
We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (IV) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of IV eravacycline. In the mass balance study, the majority of total radioactivity from [14C]-eravacycline was recovered in the feces, suggesting biliary/fecal elimination is the major route of excretion for eravacycline and its metabolites after IV administration. The volume of distribution (217 L) was greater than extracellular fluid, which suggests distribution beyond ...
Source: Antimicrobial Agents and Chemotherapy - December 17, 2018 Category: Microbiology Authors: Newman JV, Zhou J, Izmailyan S, Tsai L Tags: Antimicrob Agents Chemother Source Type: research