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Antimicrobial Agents and Chemotherapy
Journal Prestige (SJR): 2.291
Citation Impact (citeScore): 4
Number of Followers: 31  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0066-4804 - ISSN (Online) 1098-6596
Published by American Society for Microbiology Homepage  [17 journals]
  • Population Pharmacokinetics and Outcomes of Critically Ill Pediatric
           Patients Treated with Intravenous Colistin at Higher Than Recommended
           Doses [Pharmacology]

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      Authors: Antachopoulos, C; Geladari, A, Landersdorfer, C. B, Volakli, E, Ilia, S, Gikas, E, Gika, H, Sdougka, M, Nation, R. L, Roilides, E.
      Abstract: Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations that are frequently
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00002-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Editorial Board [Masthead]

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      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.masthead.65-6
      Issue No: Vol. 65, No. 6 (2021)
       
  • Role of Synonymous Mutations in the Evolution of TEM {beta}-Lactamase
           Genes [Mechanisms of Resistance]

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      Authors: Faheem, M; Zhang, C. J, Morris, M. N, Pleiss, J, Oelschlaeger, P.
      Abstract: Nonsynonymous mutations are well documented in TEM β-lactamases. The resulting amino acid changes often alter the conferred phenotype from broad spectrum (2b) conferred by TEM-1 to extended spectrum (2be), inhibitor resistant (2br), or both extended spectrum and inhibitor resistant (2ber). The encoding blaTEM genes also deviate in numerous synonymous mutations, which are not well understood. blaTEM-3 (2be), blaTEM-33 (2br), and blaTEM-109 (2ber) were studied in comparison to blaTEM-1. blaTEM-33 was chosen for more detailed studies because it deviates from blaTEM-1 by a single nonsynonymous mutation and three additional synonymous mutations. Genes encoding the enzymes with only nonsynonymous or all (including synonymous) mutations plus all permutations between blaTEM-1 and blaTEM-33 were expressed in Escherichia coli cells. In disc diffusion assays, genes encoding TEM-3, TEM-33, and TEM-109 with all synonymous mutations resulted in higher resistance levels than genes without synonymous mutations. Disc diffusion assays with the 16 genes carrying all possible nucleotide change combinations between blaTEM-1 and blaTEM-33 indicated different susceptibilities for different variants. Nucleotide BLAST searches did not identify genes without synonymous mutations but did identify some without nonsynonymous mutations. Energies of possible secondary mRNA structures calculated with mfold are generally higher with synonymous mutations, suggesting that their role could be to destabilize the mRNA and facilitate its unfolding for efficient translation. In summary, our data indicate that transition from blaTEM-1 to other variant genes by simply acquiring the nonsynonymous mutations is not favored. Instead, synonymous mutations seem to support the transition to other variant genes with nonsynonymous mutations leading to different phenotypes.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00018-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Quantitative Imaging Analysis of the Spatial Relationship between
           Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus
           RNA, and Collagen in the Mesenteric Lymph Nodes of Nonhuman Primates
           [Antiviral Agents]

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      Authors: Scholz, E. M. B; Mwangi, J. N, De la Cruz, G, Nekorchuk, M, Chan, C. N, Busman-Sahay, K, Adamson, L, Luciw, P, Fedoriw, Y, Estes, J. D, Rosen, E. P, Kashuba, A. D. M.
      Abstract: Human immunodeficiency virus (HIV) persistence in tissue reservoirs is a major barrier to HIV cure. While antiretrovirals (ARVs) suppress viral replication, antiretroviral therapy (ART) interruption results in rapid rebound viremia that may originate from lymphoid tissues. To understand the relationship between anatomic distribution of ARV exposure and viral expression in lymph nodes, we performed mass spectrometry imaging (MSI) of 6 ARVs, RNAscope in situ hybridization for viral RNA (vRNA), and immunohistochemistry of collagen in mesenteric lymph nodes from 8 uninfected and 10 reverse transcriptase simian/human immunodeficiency virus (RT-SHIV)-infected rhesus macaques dosed to steady state with combination ART. MATLAB-based quantitative imaging analysis was used to evaluate spatial and pharmacological relationships between these ARVs, viral RNA (both vRNA+ cells and follicular dendritic cell [FDC]-bound virions), and collagen deposition. Using MSI, 31% of mesenteric lymph node tissue area was found to be not covered by any ARV. Additionally, 28% of FDC-trapped virions and 21% of infected cells were not exposed to any detected ARV. Of the 69% of tissue area that was covered by cumulative ART exposure, nearly 100% of concentrations were greater than in vitro 50% inhibitory concentration (IC50) values; however, 52% of total tissue coverage was from only one ARV, primarily maraviroc. Collagen covered ~35% of tissue area but did not influence ARV distribution heterogeneity. Our findings are consistent with our hypothesis that ARV distribution, in addition to total-tissue drug concentration, must be considered when evaluating viral persistence in lymph nodes and other reservoir tissues.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00019-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Spontaneous Selection of Cryptosporidium Drug Resistance in a Calf Model
           of Infection [Mechanisms of Resistance]

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      Authors: Hasan, M. M; Stebbins, E. E, Choy, R. K. M, Gillespie, J. R, de Hostos, E. L, Miller, P, Mushtaq, A, Ranade, R. M, Teixeira, J. E, Verlinde, C. L. M. J, Sateriale, A, Zhang, Z, Osbourn, D. M, Griggs, D. W, Fan, E, Buckner, F. S, Huston, C. D.
      Abstract: The intestinal protozoan Cryptosporidium is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ~10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA (Cryptosporidium parvum MetRS [CpMetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance. Dairy calves experimentally infected with Cryptosporidium parvum initially improved with 2093 treatment, but parasite shedding resumed in two of three calves on treatment day 5. Parasites shed by each recrudescent calf had different amino acid-altering mutations in the gene encoding CpMetRS (CpMetRS), yielding either an aspartate 243-to-glutamate (D243E) or a threonine 246-to-isoleucine (T246I) mutation. Transgenic parasites engineered to have either the D243E or T246I CpMetRS mutation using CRISPR/Cas9 grew normally but were highly 2093 resistant; the D243E and T246I mutant-expressing parasites, respectively, had 2093 half-maximal effective concentrations (EC50s) that were 613- and 128-fold that of transgenic parasites with wild-type CpMetRS. In studies using recombinant enzymes, the D243E and T246I mutations shifted the 2093 IC50>170-fold. Structural modeling of CpMetRS based on an inhibitor-bound Trypanosoma brucei MetRS crystal structure suggested that the resistance mutations reposition nearby hydrophobic residues, interfering with compound binding while minimally impacting substrate binding. This is the first report of naturally emerging Cryptosporidium drug resistance, highlighting the need to address the potential for anticryptosporidial resistance and establish strategies to limit its occurrence.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00023-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Antimicrobial Resistance Hidden within Multiserovar Salmonella Populations
           [Epidemiology and Surveillance]

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      Authors: Siceloff, A. T; Ohta, N, Norman, K. N, Loneragan, G. H, Norby, B, Scott, H. M, Shariat, N. W.
      Abstract: Salmonella enterica can exist in food animals as multiserovar populations, and different serovars can harbor diverse antimicrobial resistance (AMR) profiles. Conventional Salmonella isolation assesses AMR only in the most abundant members of a multiserovar population, which typically reflects their relative abundance in the initial sample. Therefore, AMR in underlying serovars is an undetected reservoir that can readily be expanded upon antimicrobial use. CRISPR-SeroSeq profiling demonstrated that 60% of cattle fecal samples harbored multiple serovars, including low levels of Salmonella serovar Reading in 11% of samples, which were not found by culture-based Salmonella isolation. An in vitro challenge revealed that Salmonella serovar Reading was tetracycline resistant, while more abundant serovars were susceptible. This study highlights the importance of AMR surveillance in multiserovar populations.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00048-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Clinical Impact of the Revised 2019 CLSI Levofloxacin Breakpoints in
           Patients with Enterobacterales Bacteremia [Clinical Therapeutics]

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      Authors: Huang, H.-Y; Wang, C.-F, Lu, P.-L, Tseng, S.-P, Wang, Y.-L, Chen, T.-C, Chang, K, Tu, H.-P, Lin, S.-Y.
      Abstract: The Clinical and Laboratory Standards Institute (CLSI) revised the fluoroquinolone MIC breakpoints for Enterobacterales in 2019, based on pharmacokinetic/pharmacodynamic analyses. However, clinical evidence supporting these breakpoint revisions is limited. A retrospective study was conducted at 3 hospitals in Taiwan between January 2017 and March 2019. Patients treated with levofloxacin for bacteremia caused by members of the Enterobacterales with high MICs (1 or 2 μg/ml; levofloxacin susceptible by pre-2019 CLSI breakpoints) were compared with those with low-MIC bacteremia (≤0.5 μg/ml; levofloxacin susceptible by 2019 CLSI breakpoints) to assess therapeutic effectiveness by multivariable logistic regression. The primary outcome was 30-day mortality, and the secondary outcome was the emergence of levofloxacin-resistant isolates within 90 days after levofloxacin initiation. A total of 308 patients were eligible for the study. Kaplan-Meier analysis showed that patients infected with high-MIC isolates (n = 63) had a significantly lower survival rate than those infected with low-MIC isolates (n = 245) (P = 0.001). Multivariable logistic regression revealed that high levofloxacin MIC was a predictor of 30-day mortality (odds ratio [OR], 6.05; 95% confidence interval [CI], 1.51 to 24.18; P = 0.011). We consistently found similar results in a propensity score-matched cohort (OR, 5.38; 95% CI, 1.06 to 27.39; P = 0.043). The emergence of levofloxacin-resistant isolates was more common in the high-MIC group than the low-MIC group (25.0% versus 7.5%; P = 0.065). An estimated area under the concentration-time curve/MIC ratio of ≥87 was significantly associated with better survival (P = 0.002). In conclusion, patients infected with isolates with levofloxacin MICs within the pre-2019 CLSI susceptible range of 1 or 2 μg/ml exhibited higher mortality than those infected with isolates with MICs of ≤0.5 μg/ml.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00074-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • In Vitro Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa
           following Treatment-Emergent Resistance to Ceftolozane-Tazobactam
           [Mechanisms of Resistance]

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      Authors: Rubio, A. M; Kline, E. G, Jones, C. E, Chen, L, Kreiswirth, B. N, Nguyen, M. H, Clancy, C. J, Cooper, V. S, Haidar, G, Van Tyne, D, Shields, R. K.
      Abstract: We compared the in vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa isolates collected before and after treatment-emergent resistance to ceftolozane-tazobactam. Median baseline and postexposure ceftolozane-tazobactam MICs were 2 and 64 μg/ml, respectively. Whole-genome sequencing identified treatment-emergent mutations in ampC among 79% (11/14) of paired isolates. AmpC mutations were associated with cross-resistance to ceftazidime-avibactam but increased susceptibility to piperacillin-tazobactam and imipenem. A total of 81% (12/16) of ceftolozane-tazobactam-resistant isolates with ampC mutations were susceptible to imipenem-relebactam.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00084-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • RNA Interference Screening Reveals Requirement for Platelet-Derived Growth
           Factor Receptor Beta in Japanese Encephalitis Virus Infection [Antiviral
           Agents]

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      Authors: Zhou, M; Wang, S, Guo, J, Liu, Y, Cao, J, Lan, X, Jia, X, Zhang, B, Xiao, G, Wang, W.
      Abstract: Mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide and is associated with high morbidity and mortality. To identify potential host therapeutic targets, a high-throughput receptor tyrosine kinase small interfering RNA library screening was performed with recombinant JEV particles. Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a hit after two rounds of screening. Knockdown of PDGFRβ blocked JEV infection and transcomplementation of PDGFRβ could partly restore its infectivity. The PDGFRβ inhibitor imatinib, which has been approved for the treatment of malignant metastatic cancer, protected mice against JEV-induced lethality by decreasing the viral load in the brain while abrogating the histopathological changes associated with JEV infection. These findings demonstrated that PDGFRβ is important in viral infection and provided evidence for the potential to develop imatinib as a therapeutic intervention against JEV infection.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00113-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Activity of Lysin CF-296 Alone and in Addition to Daptomycin in a Rat
           Model of Experimental Methicillin-Resistant Staphylococcus aureus
           Osteomyelitis [Letters]

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      Authors: Karau, M. J; Schmidt-Malan, S. M, Mandrekar, J, Lehoux, D, Schuch, R, Cassino, C, Patel, R.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00117-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Emergence of Resistance to Ceftazidime-Avibactam in a Pseudomonas
           aeruginosa Isolate Producing Derepressed blaPDC in a Hollow-Fiber
           Infection Model [Experimental Therapeutics]

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      Authors: Drusano, G. L; Bonomo, R. A, Marshall, S. M, Rojas, L. J, Adams, M. D, Mojica, M. F, Kreiswirth, B. N, Chen, L, Mtchedlidze, N, Bacci, M, Vicchiarelli, M, Bulitta, J. B, Louie, A.
      Abstract: Ceftazidime (CAZ)-avibactam (AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and type C β-lactamases. Resistance emergence has been seen, with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic hollow-fiber infection model, delineating the linkage between drug exposure and both the rate of bacterial kill and resistance emergence by all mechanisms. The Pseudomonas aeruginosa isolate had MICs of 1.0 mg/liter (CAZ) and 4 mg/liter (AVI). We demonstrated that the time at ≥4.0 mg/liter AVI was linked to the rate of bacterial kill. Linkage to resistance emergence/suppression was more complex. In one experiment in which CAZ and AVI administration was intermittent and continuous, respectively, and in which AVI was given in unitary steps from 1 to 8 mg/liter, AVI at up to 3 mg/liter allowed resistance emergence, whereas higher values did not. The threshold value was 3.72 mg/liter as a continuous infusion to counterselect resistance (AVI area under the concentration-time curve [AUC] of 89.3 mg · h/liter). The mechanism involved a 7-amino-acid deletion in the -loop region of the Pseudomonas-derived cephalosporinase (PDC) β-lactamase. Further experiments in which CAZ and AVI were both administered intermittently with regimens above and below the AUC of 89.3 mg · h/liter resulted in resistance in the lower-exposure groups. Deletion mutants were not identified. Finally, in an experiment in which paired exposures as both continuous and intermittent infusions were performed, the lower value of 25 mg · h/liter by both profiles allowed selection of deletion mutants. Of the five instances in which these mutants were recovered, four had a continuous-infusion profile. Both continuous-infusion administration and low AVI AUC exposures have a role in selection of this mutation.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00124-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Molecular Epidemiology of Third-Generation-Cephalosporin-Resistant
           Enterobacteriaceae in Southeast Queensland, Australia [Mechanisms of
           Resistance]

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      Authors: Stewart, A. G; Price, E. P, Schabacker, K, Birikmen, M, Harris, P. N. A, Choong, K, Subedi, S, Sarovich, D. S.
      Abstract: Third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. In addition to routine mass spectrometry and antibiotic sensitivity testing, isolates were examined using rapid (~40-min) real-time PCR assays targeting the most common extended-spectrum β-lactamases (ESBLs; blaCTX-M-1 and blaCTX-M-9 groups, plus blaTEM, blaSHV, and an internal 16S rRNA gene control). AmpC CMY β-lactamase (blaCMY) prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes, and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one β-lactamase gene, with 144 (50%) harboring blaCTX-M-1 group, 92 (31.9%) harboring blaCTX-M-9 group, 48 (16.7%) harboring blaSHV, 133 (46.2%) harboring blaTEM, and 34 (11.8%) harboring blaCMY genes. A subset of isolates (n = 98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants and to verify genotyping accuracy. WGS of β-lactamase-negative or carbapenem-resistant isolates identified uncommon ESBL and carbapenemase genes, including blaNDM and blaIMP, and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00130-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Cefepime Population Pharmacokinetics and Target Attainment in Critically
           Ill Patients on Continuous Renal Replacement Therapy [Clinical
           Therapeutics]

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      Authors: Al-Shaer, M. H; Philpott, C. D, Droege, C. A, Courter, J. D, Healy, D. P, Droege, M. E, Ernst, N. E, Mueller, E. W, Peloquin, C. A.
      Abstract: Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT), which will affect their antimicrobial exposure. We aimed to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, were admitted to the ICU, and received cefepime 2 g every 8 h as a 4-h infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer ports, postdialyzer ports, and effluent fluid at 1, 2, 3, 4, and 8 h after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% of the dosing interval during which the free beta-lactam concentration is above the MIC (fT>MIC). Ten patients were included; their mean age was 53 years, and mean weight was 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates, which were used to describe the rates of transfer between the compartments. At MICs of ≤8 mg/liter, intermittent infusion of 2 g cefepime every 8 h achieved good target attainment both early in therapy and at steady state. Only extended- and continuous-infusion regimens achieved good target attainment at MICs of 16 mg/liter. In conclusion, 2 g cefepime infused over 30 min followed by extended infusion of 2 g every 8 h achieved good target attainment at MICs of ≤16 mg/liter with different CRRT flow rates and may be considered in resistant bacterial infections.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00144-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Distinguishing blaKPC Gene-Containing IncF Plasmids from Epidemiologically
           Related and Unrelated Enterobacteriaceae Based on Short- and Long-Read
           Sequence Data [Epidemiology and Surveillance]

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      Authors: Stohr, J. J. J. M; Kluytmans-van den Bergh, M. F. Q, Weterings, V. A. T. C, Rossen, J. W. A, Kluytmans, J. A. J. W.
      Abstract: Limited information is available on whether blaKPC-containing plasmids from isolates in a hospital outbreak can be differentiated from epidemiologically unrelated blaKPC-containing plasmids based on sequence data. This study aimed to evaluate the performance of three approaches to distinguish epidemiologically related from unrelated blaKPC-containing pKpQiL-like IncFII(k2)-IncFIB(pQiL) plasmids. Epidemiologically related isolates were subjected to short- and long-read whole-genome sequencing. A hybrid assembly was performed, and plasmid sequences were extracted from the assembly graph. Epidemiologically unrelated plasmid sequences were extracted from GenBank. Pairwise comparisons of epidemiologically related and unrelated plasmids based on SNPs using snippy and of phylogenetic distance using Roary and using a similarity index that penalizes size differences between plasmids (Stoesser index) were performed. The percentage of pairwise comparisons misclassified as genetically related or as clonally unrelated was determined using different genetic thresholds for genetic relatedness. The ranges of number of SNPs, Roary phylogenetic distance, and Stoesser index overlapped between the epidemiologically related and unrelated plasmids. When a genetic similarity threshold that classified 100% of epidemiologically related plasmid pairs as genetically related was used, the percentages of plasmids misclassified as epidemiologically related ranged from 6.7% (Roary) to 20.8% (Stoesser index). Although epidemiologically related plasmids can be distinguished from unrelated plasmids based on genetic differences, blaKPC-containing pKpQiL-like IncFII(k2)-IncFIB(pQiL) plasmids show a high degree of sequence similarity. The phylogenetic distance as determined using Roary showed the highest degree of discriminatory power between the epidemiologically related and unrelated plasmids.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00147-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Antimicrobial Resistance Conferred by OXA-48 {beta}-Lactamases: Towards a
           Detailed Mechanistic Understanding [Minireviews]

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      Authors: Hirvonen, V. H. A; Spencer, J, van der Kamp, M. W.
      Abstract: OXA-48-type β-lactamases are now routinely encountered in bacterial infections caused by carbapenem-resistant Enterobacterales. These enzymes are of high and growing clinical significance due to the importance of carbapenems in treatment of health care-associated infections by Gram-negative bacteria, the wide and increasing dissemination of OXA-48 enzymes on plasmids, and the challenges posed by their detection. OXA-48 confers resistance to penicillin (which is efficiently hydrolyzed) and carbapenem antibiotics (which is more slowly broken down). In addition to the parent enzyme, a growing array of variants of OXA-48 is now emerging. The spectrum of activity of these variants varies, with some hydrolyzing expanded-spectrum oxyimino-cephalosporins. The growth in importance and diversity of the OXA-48 group has motivated increasing numbers of studies that aim to elucidate the relationship between structure and specificity and establish the mechanistic basis for β-lactam turnover in this enzyme family. In this review, we collate recently published structural, kinetic, and mechanistic information on the interactions between clinically relevant β-lactam antibiotics and inhibitors and OXA-48 β-lactamases. Collectively, these studies are starting to form a detailed picture of the underlying bases for the differences in β-lactam specificity between OXA-48 variants and the consequent differences in resistance phenotype. We focus specifically on aspects of carbapenemase and cephalosporinase activities of OXA-48 β-lactamases and discuss β-lactamase inhibitor development in this context. Throughout the review, we also outline key open research questions for future investigation.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00184-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Novel Specific Metallo-{beta}-Lactamase Inhibitor ANT2681 Restores
           Meropenem Activity to Clinically Effective Levels against NDM-Positive
           Enterobacterales [Susceptibility]

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      Authors: Zalacain, M; Lozano, C, Llanos, A, Sprynski, N, Valmont, T, De Piano, C, Davies, D, Leiris, S, Sable, C, Ledoux, A, Morrissey, I, Lemonnier, M, Everett, M.
      Abstract: The global dissemination of metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-β-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. The addition of ANT2681 at 8 μg/ml reduced the MEM MIC50/MIC90 from>32/>32 μg/ml to 0.25/8 μg/ml. Moreover, the combination of 8 μg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)-positive and 85.7% of the imipenem hydrolyzing β-lactamase (IMP)-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favorably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC90 1 μg/ml), in contrast to ATM-AVI (MIC90 4 μg/ml), FDC (MIC90>32 μg/ml), and FEP-taniborbactam (MIC90>32 μg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00203-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • In Vitro Activity of the Ultrabroad-Spectrum Beta-Lactamase Inhibitor
           QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against
           Pseudomonas aeruginosa [Mechanisms of Resistance]

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      Authors: Lomovskaya, O; Rubio-Aparicio, D, Nelson, K, Sun, D, Tsivkovski, R, Castanheira, M, Lindley, J, Loutit, J, Dudley, M.
      Abstract: QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase-producing Enterobacterales and Acinetobacter spp. In this study, we evaluated the in vitro activity of QPX7728 (QPX; 8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with various beta-lactam resistance mechanisms. Seven hundred ninety clinical isolates were included in this study; 500 isolates, termed a "representative panel," were selected to be representative of the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data. An additional 290 selected isolates ("challenge panel") that were either nonsusceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo-beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD, and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was>90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in ~90% and ~80% of strains, respectively, versus 68% to 70% for QPX-MEM and QPX-PIP and 63% to 65% for TOL-TAZ and CAZ-AVI, respectively. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ~70% of strains versus 2% to 40% for other combinations. Increased efflux and impaired OprD had various effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varied results according to beta-lactamase production and other intrinsic resistance mechanisms.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00210-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Continued Low Efficacy of Artemether-Lumefantrine in Angola' [Letters]

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      Authors: Rasmussen, C; Ringwald, P.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00220-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Analyzing Possible Native Functions of the Quinolone Resistance Gene qnr
           in Vibrio vulnificus [Mechanisms of Resistance]

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      Authors: Gil-Marques, M. L; Jacoby, G. A, Hooper, D. C.
      Abstract: The worldwide distribution of qnr genes found on plasmids and their presence on the chromosomes of aquatic bacteria, such as Vibrio vulnificus, one of the suspected sources, suggests an origin before the development of synthetic quinolones. However, their native function remains unknown. Previous work indicated that expression of qnrVv in V. vulnificus was induced by cold shock. To investigate its role further, we constructed single in-frame deletion mutants in qnrVv and cspA (the gene for cold shock protein) and a double mutant in qnrVv and cspA in V. vulnificus ATCC 17562 to evaluate the response to different environmental conditions and stresses and to exposure to various DNA-damaging agents. We found that qnrVv is involved in resistance to ciprofloxacin, levofloxacin, and mitomycin C and in the cold shock response in V. vulnificus. Moreover, qnrVv and cspA mutants showed slower growth when they were treated with bile salts at 37°C and then shifted to 15°C (cold shock) without bile salts in the medium, with the effect being stronger in the double mutant. This transition may mimic what happens when V. vulnificus is ingested into the gastrointestinal tract and released in its natural environment. Cold shock and bile salts induced the expression of cspA and DNA gyrase and topoisomerase IV genes. However, no induction was found in the qnrVv mutant, suggesting that the qnrVv gene is involved in the response to DNA damage and nucleic acid secondary structure.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00232-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Antifungal Susceptibility Profiles of Olorofim (Formerly F901318) and
           Currently Available Systemic Antifungals against Mold and Yeast Phases of
           Talaromyces marneffei [Susceptibility]

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      Authors: Zhang, J; Liu, H, Xi, L, Chang, Y. C, Kwon-Chung, K. J, Seyedmousavi, S.
      Abstract: In vitro antifungal susceptibility profiling of 32 clinical and environmental Talaromyces marneffei isolates recovered from southern China was performed against olorofim and 7 other systemic antifungals, including amphotericin B, 5-flucytosine, posaconazole, voriconazole, caspofungin, and terbinafine, using CLSI methodology. In comparison, olorofim was the most active antifungal agent against both mold and yeast phases of all tested Talaromyces marneffei isolates, exhibiting an MIC range, MIC50, and MIC90 of 0.0005 to 0.002 μg/ml, 0.0005 μg/ml, and 0.0005 μg/ml, respectively.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00256-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Clinical and Pharmacological Considerations for Concomitant Administration
           of Posaconazole and Isavuconazole with Letermovir [Pharmacology]

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      Authors: Terrier, J; Zanella, M.-C, Masouridi-Levrat, S, Kronig, I, Chalandon, Y, Vernaz, N, Van Delden, C, Papanicolaou, G, Neofytos, D.
      Abstract: We sought in this case-control retrospective study to compare posaconazole and isavuconazole (PCZ and IVC, respectively) plasma trough concentration (Ctrough) levels in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC Ctrough levels were not found to be significantly different between cases and controls, as they were 1.31 mg/liter (median) (interquartile range [IQR], 0.90) versus 1.36 mg/liter (IQR, 1.16) (P = 0.31) and 3.20 mg/liter (IQR, 2.40) versus 2.35 mg/liter (IQR, 1.50) (P = 0.17), respectively. In conclusion, we observed PCZ/IVC Ctrough levels within the expected range and no significant effect of LET coadministration.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00274-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • In Vitro and In Vivo Antifungal Activity of AmBisome Compared to
           Conventional Amphotericin B and Fluconazole against Candida auris
           [Susceptibility]

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      Authors: Herrada, J; Gamal, A, Long, L, Sanchez, S. P, McCormick, T. S, Ghannoum, M. A.
      Abstract: Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/ml, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg treatment group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data show that AmBisome has significant antifungal activity against C. auris infection in vitro and in vivo.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00306-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Reply to Rasmussen and Ringwald, "Continued Low Efficacy of
           Artemether-Lumefantrine in Angola'" [Letters]

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      Authors: Dimbu, P. R; Horth, R, Candido, A. L. M, Ferreira, C. M, Caquece, F, Garcia, L. E. A, Andre, K, Pembele, G, Jandondo, D, Bondo, B. J, Nieto Andrade, B, Labuda, S, Ponce de Leon, G, Kelley, J, Patel, D, Svigel, S. S, Talundzic, E, Lucchi, N, Morais, J. F. M, Fortes, F, Martins, J. F, Plucinski, M. M.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00338-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Fluconazole Underexposure in Critically Ill Patients: a Matter of Using
           the Right Targets' [Letters]

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      Authors: Van Daele, R; Debaveye, Y, Lagrou, K, Spriet, I.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00430-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Reply to Van Daele et al., "Fluconazole Underexposure in Critically Ill
           Patients: a Matter of Using the Right Targets'" [Letters]

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      Authors: Märtson, A.- G; Boonstra, J. M, Sandaradura, I, Kosterink, J. G. W, van der Werf, T. S, Marriott, D. J. E, Zijlstra, J. G, Touw, D. J, Alffenaar, J. W. C.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00465-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Buehrle et al. "Decreased Overall and Inappropriate Antibiotic
           Prescribing in a Veterans Affairs Hospital Emergency Department following
           a Peer Comparison-Based Stewardship Intervention" [Errata]

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      Authors: Buehrle, D. J; Phulpoto, R. H, Wagener, M. M, Clancy, C. J, Decker, B. K.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00528-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • In Vitro and In Vivo Activities, Absorption, Tissue Distribution, and
           Excretion of OBP-4, a Potential Anti-Clostridioides difficile Agent
           [Pharmacology]

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      Authors: Liu, L; Zhou, X, Li, B, Cheng, F, Cui, H, Li, J, Zhang, J.
      Abstract: Clostridioides difficile infection (CDI) is considered a major concern of the health care system globally, with an increasing need for alternative therapies. OBP-4, a new oxazolidinone-fluoroquinolone hybrid with excellent in vitro activities and good safety, shows promising features as an antibacterial agent. Here, we further evaluated the in vitro and in vivo activities of OBP-4 against C. difficile and its absorption (A), distribution (D), and excretion (E) profiles in rats. In vitro assays indicated that OBP-4 was active against all tested C. difficile strains, with MICs ranging from 0.25 to 1 mg/liter. In addition, OBP-4 showed complete inhibition of spore formation at 0.5x MIC. In the mouse model of CDI, 5-day oral treatment with OBP-4 provided complete protection from death and CDI recurrence in infected mice. However, cadazolid (CZD) and vancomycin (VAN) showed less protection of infected mice than did OBP-4 in terms of diarrhea and weight loss, especially VAN. Subsequently, ADE investigations of OBP-4 with a reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method showed extremely low systemic exposure and predominantly fecal excretion, resulting in a high local concentration of OBP-4 in the intestinal tract—the site of CDI. These results demonstrated that OBP-4 possesses good activity against C. difficile and favorable ADE characteristics for oral treatment of CDI, which support further development of OBP-4 as a potential anti-CDI agent.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00581-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Identification of Two Plasmids Coharboring Carbapenemase Genes and
           tmexCD1-toprJ1 in Clinical Klebsiella pneumoniae ST2667 [Letters]

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      Authors: Qin, S; Peng, J, Deng, R, Peng, K, Yan, T, Chen, F, Li, R.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00625-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Herring et al., "Inhibition of Arenaviruses by Combinations of
           Orally Available Approved Drugs" [Errata]

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      Authors: Herring, S; Oda, J. M, Wagoner, J, Kirchmeier, D, OConnor, A, Nelson, E. A, Huang, Q, Liang, Y, DeWald, L. E, Johansen, L. M, Glass, P. J, Olinger, G. G, Ianevski, A, Aittokallio, T, Paine, M. F, Fink, S. L, White, J. M, Polyak, S. J.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00653-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Khan et al., "Evaluation of the Performance of Manual
           Antimicrobial Susceptibility Testing Methods and Disk Breakpoints for
           Stenotrophomonas maltophilia" [Errata]

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      Authors: Khan, A; Pettaway, C. H, Dien Bard, J, Arias, C. A, Bhatti, M. M, Humphries, R. M.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00770-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Herrera-Hidalgo et al., "Ampicillin and Ceftriaxone Solution
           Stability at Different Temperatures in Outpatient Parenteral Antimicrobial
           Therapy" [Errata]

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      Authors: Herrera-Hidalgo, L; Lopez-Cortes, L. E, Luque-Marquez, R, Galvez-Acebal, J, de Alarcon, A, Lopez-Cortes, L. F, Gutierrez-Valencia, A, Gil-Navarro, M. V.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00784-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Herrera-Hidalgo et al., "Is Once-Daily High-Dose Ceftriaxone
           plus Ampicillin an Alternative for Enterococcus faecalis Infective
           Endocarditis in Outpatient Parenteral Antibiotic Therapy Programs'"
           [Errata]

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      Authors: Herrera-Hidalgo, L; de Alarcon, A, Lopez-Cortes, L. E, Luque-Marquez, R, Lopez-Cortes, L. F, Gutierrez-Valencia, A, Gil-Navarro, M. V, on behalf of Grupo para el Estudio de las Infecciones Cardiovasculares de la Sociedad Andaluza de Enfermedades Infecciosas
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00785-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • Erratum for Miranda-Cadena et al., "Development and Characterization of
           Monoolein-Based Liposomes of Carvacrol, Cinnamaldehyde, Citral, or Thymol
           with Anti-Candida Activities" [Errata]

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      Authors: Miranda-Cadena, K; Dias, M, Costa-Barbosa, A, Collins, T, Marcos-Arias, C, Eraso, E, Pais, C, Quindos, G, Sampaio, P.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.00800-21
      Issue No: Vol. 65, No. 6 (2021)
       
  • New Insight into Vitamins E and K1 as Anti-Quorum-Sensing Agents against
           Pseudomonas aeruginosa [Mechanisms of Resistance]

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      Authors: Soltani, S; Fazly Bazzaz, B. S, Hadizadeh, F, Roodbari, F, Soheili, V.
      Abstract: Today, antivirulence compounds that attenuate bacterial pathogenicity and have no interference with bacterial viability or growth are introduced as the next generation of antibacterial agents. However, the development of such compounds that can be used by humans is restricted by various factors, including the need for extensive economic investments, the inability of many molecules to penetrate the membrane of Gram-negative bacteria, and unfavorable pharmacological properties and cytotoxicity. Here, we take a new and different look into two frequent supplements, vitamin E and K1, as anti-quorum-sensing agents against Pseudomonas aeruginosa, a pathogen that is hazardous to human life and responsible for several diseases. Both vitamins showed significant anti-biofilm activity (62% and 40.3% reduction by vitamin E and K1, respectively), and the expression of virulence factors, including pyocyanin, pyoverdine, and protease, was significantly inhibited, especially in the presence of vitamin E. Cotreatment of constructed biofilms with these vitamins plus tobramycin significantly reduced the number of bacterial cells sheltered inside the impermeable matrix (71.6% and 69% by a combination of tobramycin and vitamin E or K1, respectively). The in silico studies, besides the similarities of chemical structures, reinforce the possibility that both vitamins act through inhibition of the PqsR protein. This is the first report of the antivirulence and antipathogenic activity of vitamin E and K1 against P. aeruginosa and confirms their potential for further research against other multidrug-resistant bacteria.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.01342-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Identification of a Novel Ciprofloxacin Tolerance Gene, aciT, Which
           Contributes to Filamentation in Acinetobacter baumannii [Mechanisms of
           Resistance]

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      Authors: Naidu, V; Shah, B, Kamath, K. S, Chien, A, Nagy, S, Pokhrel, A, Molloy, M, Hassan, K. A, Paulsen, I. T.
      Abstract: Fluoroquinolones are one of the most prescribed broad-spectrum antibiotics. However, their effectiveness is being compromised by high rates of resistance in clinically important organisms, including Acinetobacter baumannii. We sought to investigate the transcriptomic and proteomic responses of the clinical A. baumannii strain AB5075-UW upon exposure to subinhibitory concentrations of ciprofloxacin. Our transcriptomics and proteomics analyses found that the most highly expressed genes and proteins were components of the intact prophage phiOXA. The next most highly expressed gene (and its protein product) under ciprofloxacin stress was a hypothetical gene, ABUW_0098, named here the Acinetobacter ciprofloxacin tolerance (aciT) gene. Disruption of this gene resulted in higher susceptibility to ciprofloxacin, and complementation of the mutant with a cloned aciT gene restored ciprofloxacin tolerance to parental strain levels. Microscopy studies revealed that aciT is essential for filamentation during ciprofloxacin stress in A. baumannii. Sequence analysis of aciT indicates the encoded protein is likely to be localized to the cell membrane. Orthologs of aciT are found widely in the genomes of species from the Moraxellaceae family and are well conserved in Acinetobacter species, suggesting an important role. With these findings taken together, this study has identified a new gene conferring tolerance to ciprofloxacin, likely by enabling filamentation in response to the antibiotic.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.01400-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Experience with Liposomal Amphotericin B in Outpatient Parenteral
           Antimicrobial Therapy [Clinical Therapeutics]

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      Authors: Burnett, Y. J; Spec, A, Ahmed, M. M, Powderly, W. G, Hamad, Y.
      Abstract: Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The most common doses of L-AMB were 3 mg/kg (n = 16, 38%) or 5 mg/kg (n = 14, 33%) based on actual body weight. Twenty-six (62%) patients completed their anticipated course of L-AMB. Twenty-two (52%) patients were readmitted within 30 days of discharge; median time to readmission was 11 days (interquartile range [IQR] 5 to 18). While hypokalemia and acute kidney injury (AKI) were common, occurring in 26 (62%) and 20 (48%) patients, respectively, only 5 (12%) were readmitted to the hospital due to L-AMB-associated AEs. Ninety percent of patients achieved at least partial renal recovery within 30 days after L-AMB discontinuation. Factors significantly associated with AKI include higher L-AMB dose, lower serum potassium levels after therapy initiation, and receipt of potassium supplementation at discharge. L-AMB is associated with significant AEs; however, these results suggest that treatment is feasible in the outpatient setting with close monitoring, as the majority of AEs were managed effectively in an outpatient without long-term sequelae.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.01876-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Atypical Genetic Basis of Pyrazinamide Resistance in Monoresistant
           Mycobacterium tuberculosis [Mechanisms of Resistance]

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      Authors: Modlin, S. J; Marbach, T, Werngren, J, Mansjö, M, Hoffner, S. E, Valafar, F.
      Abstract: Pyrazinamide (PZA) is a widely used antitubercular chemotherapeutic. Typically, PZA resistance (PZA-R) emerges in Mycobacterium tuberculosis strains with existing resistance to isoniazid and rifampin (i.e., multidrug resistance [MDR]) and is conferred by loss-of-function pncA mutations that inhibit conversion to its active form, pyrazinoic acid (POA). PZA-R departing from this canonical scenario is poorly understood. Here, we genotyped pncA and purported alternative PZA-R genes (panD, rpsA, and clpC1) with long-read sequencing of 19 phenotypically PZA-monoresistant isolates collected in Sweden and compared their phylogenetic and genomic characteristics to a large set of MDR PZA-R (MDRPZA-R) isolates. We report the first association of ClpC1 mutations with PZA-R in clinical isolates, in the ClpC1 promoter (clpC1p–138) and the N terminus of ClpC1 (ClpC1Val63Ala). Mutations have emerged in both these regions under POA selection in vitro, and the N-terminal region of ClpC1 has been implicated further, through its POA-dependent efficacy in PanD proteolysis. ClpC1Val63Ala mutants spanned 4 Indo-Oceanic sublineages. Indo-Oceanic isolates invariably harbored ClpC1Val63Ala and were starkly overrepresented (odds ratio [OR] = 22.2, P < 0.00001) among PZA-monoresistant isolates (11/19) compared to MDRPZA-R isolates (5/80). The genetic basis of Indo-Oceanic isolates’ overrepresentation in PZA-monoresistant tuberculosis (TB) remains undetermined, but substantial circumstantial evidence suggests that ClpC1Val63Ala confers low-level PZA resistance. Our findings highlight ClpC1 as potentially clinically relevant for PZA-R and reinforce the importance of genetic background in the trajectory of resistance development.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.01916-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Laboratory Variants GESG170L, GESG170K, and GESG170H Increase Carbapenem
           Hydrolysis and Confer Resistance to Clavulanic Acid [Mechanisms of
           Resistance]

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      Authors: Piccirilli, A; Mercuri, P. S, Segatore, B, Galleni, M, Brisdelli, F, Kerff, F, Amicosante, G, Perilli, M.
      Abstract: The Guiana extended-spectrum (GES) β-lactamase GESG170H, GESG170L, and GESG170K mutants showed kcat, Km, and kcat/Km values very dissimilar to those of GES-1 and GES-5. The enhancement of the hydrolytic activity against carbapenems is potentially due to a shift of the substrate in the active site that provides better positioning of the deacylating water molecule caused by the presence of the imidazole ring of H170 and of the long side chain of K170 and L170.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.01931-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Efficacy of Topical Vancomycin- and Gentamicin-Loaded Calcium Sulfate
           Beads or Systemic Antibiotics in Eradicating Polymicrobial Biofilms
           Isolated from Diabetic Foot Infections within an In Vitro Wound Model
           [Experimental Therapeutics]

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      Authors: Crowther, G. S; Callaghan, N, Bayliss, M, Noel, A, Morley, R, Price, B.
      Abstract: Diabetic foot ulcers are notoriously difficult to heal, with ulcers often becoming chronic, in many cases leading to amputation despite weeks or months of antibiotic therapy in addition to debridement and offloading. Alternative wound biofilm management options, such as topical rather than systemic delivery of antimicrobials, have been investigated by clinicians in order to improve treatment outcomes. Here, we collected blood and tissue from six subjects with diabetic foot infections, measured the concentrations of antibiotics in the samples after treatment, and compared the microbiota within the tissue before treatment and after 7 days of antibiotic therapy. We used an in vitro model of polymicrobial biofilm infection inoculated with isolates from the tissue we collected to simulate different methods of antibiotic administration by simulated systemic therapy or topical release from calcium sulfate beads. We saw no difference in biofilm bioburden in the models after simulated systemic therapy (representative of antibiotics used in the clinic), but we did see reductions in bioburden of between 5 and 8 logs in five of the six biofilms that we tested with topical release of antibiotics via calcium sulfate beads. Yeast is insensitive to antibiotics and was a component of the sixth biofilm. These data support further studies of the topical release of antibiotics from calcium sulfate beads in diabetic foot infections to combat the aggregate issues of infectious organisms taking the biofilm mode of growth, compromised immune involvement, and poor systemic delivery of antibiotics via the bloodstream to the site of infection in patients with diabetes.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02012-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Coproduction of Tet(X7) Conferring High-Level Tigecycline Resistance,
           Fosfomycin FosA4, and Colistin Mcr-1.1 in Escherichia coli Strains from
           Chickens in Egypt [Epidemiology and Surveillance]

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      Authors: Soliman, A. M; Ramadan, H, Zarad, H, Sugawara, Y, Yu, L, Sugai, M, Shimamoto, T, Hiott, L. M, Frye, J. G, Jackson, C. R, Shimamoto, T.
      Abstract: The plasmid-mediated tet(X7) conferring high-level tigecycline resistance was identified in five mcr-1.1-positive Escherichia coli strains (ST10 [n = 3] and ST155 [n = 2]) isolated from chickens in Egypt. Two fosfomycin-resistant fosA4-carrying IncFII plasmids (~79 kb in size) were detected. Transposase ISCR3 (IS91 family) is syntenic with tet(X7) in all isolates, suggesting its role in the mobilization of tet(X7). To our knowledge, this is the first global report of ST4-IncHI2 plasmids cocarrying tet(X7) and mcr-1.1 from chickens.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02084-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1
           Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in
           Healthy Participants [Pharmacology]

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      Authors: Pene Dumitrescu, T; Joshi, S. R, Xu, J, Zhan, J, Johnson, M, Butcher, L, Zimmerman, E, Webster, L, Davidson, A. M, Lataillade, M, Min, S.
      Abstract: GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on days 15 through 21. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time zero to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMRs (90% CI) of 0.886 (0.75 to 1.04) and 0.874 (0.68 to 1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV. (This study has been registered at ClinicalTrials.gov under identifier NCT03836729.)
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02173-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Nebulized Micafungin Treatment for Scopulariopsis/Microascus
           Tracheobronchitis in Lung Transplant Recipients [Clinical Therapeutics]

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      Authors: Los-Arcos, I; Berastegui, C, Martin-Gomez, M. T, Grau, S, Campany-Herrero, D, Deu, M, Sacanell, J, Campillo, N, Bravo, C, Len, O.
      Abstract: Scopulariopsis/Microascus isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of Scopulariopsis/Microascus tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02174-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • In Vitro Susceptibility of Kinetoplastids to Celastroloids from Maytenus
           chiapensis [Susceptibility]

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      Authors: Nunez, M. J; Martinez, M. L, Lopez-Arencibia, A, Bethencourt-Estrella, C. J, San Nicolas-Hernandez, D, Jimenez, I. A, Lorenzo-Morales, J, Pinero, J. E, Bazzocchi, I. L.
      Abstract: Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastid drugs has become an urgent issue. In the present work, a bioassay-guided investigation of the root bark of Maytenus chiapensis on Leishmania amazonensis and Trypanosoma cruzi led to the identification of two D:A-friedo-nor-oleanane triterpenoids (celastroloids), 20β-hydroxy-tingenone (celastroloid 5) and 3-O-methyl-6-oxo-tingenol (celastroloid 8), as promising antikinetoplastid leads. They displayed higher potency on L. amazonensis promastigotes (50% inhibitory concentrations [IC50s], 0.44 and 1.12 μM, respectively), intracellular amastigotes (IC50s, 0.83 and 1.91 μM, respectively), and T. cruzi epimastigote stage (IC50s, 2.61 and 3.41 μM, respectively) than reference drugs miltefosine and benznidazole. This potency was coupled with an excellent selectivity index on murine macrophages. Mechanism of action studies, including mitochondrial membrane potential (m) and ATP-level analysis, revealed that celastroloids could induce apoptotic cell death in L. amazonensis triggered by the mitochondria. In addition, the structure-activity relationship is discussed. These findings strongly underline the potential of celastroloids as lead compounds to develop novel antikinetoplastid drugs.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02236-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Thin-Layer-Agar-Based Direct Phenotypic Drug Susceptibility Testing on
           Sputum in Eswatini Rapidly Detects Mycobacterium tuberculosis Growth and
           Rifampicin Resistance Otherwise Missed by WHO-Endorsed Diagnostic Tests
           [Susceptibility]

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      Authors: Ardizzoni, E; Ariza, E, Mulengwa, D, Mpala, Q, de La Tour, R, Maphalala, G, Varaine, F, Kerschberger, B, Graulus, P, Page, A. L, Niemann, S, Dreyer, V, Van Deun, A, Decroo, T, Rigouts, L, de Jong, B. C.
      Abstract: Xpert MTB/RIF rapidly detects resistance to rifampicin (RR); however, this test misses I491F-RR conferring rpoB mutation, common in southern Africa. In addition, Xpert MTB/RIF does not distinguish between viable and dead Mycobacterium tuberculosis (MTB). We aimed to investigate the ability of thin-layer agar (TLA) direct drug-susceptibility testing (DST) to detect MTB and its drug-resistance profiles in field conditions in Eswatini. Consecutive samples were tested in parallel with Xpert MTB/RIF and TLA for rifampicin (1.0 μg/ml) and ofloxacin (2.0 μg/ml). TLA results were compared at the Reference Laboratory in Antwerp with indirect-DST on Löwenstein-Jensen or 7H11 solid media and additional phenotypic and genotypic testing to resolve discordance. TLA showed a positivity rate for MTB detection of 7.1% versus 10.0% for Xpert MTB/RIF. Of a total of 4,547 samples included in the study, 200 isolates were available for comparison to the composite reference. Within a median of 18.4 days, TLA detected RR with 93.0% sensitivity (95% confidence interval [CI], 77.4 to 98.0) and 99.4% specificity (95% CI, 96.7 to 99.9) versus 62.5% (95% CI, 42.7 to 78.8) and 99.3% (95% CI, 96.2 to 99.9) for Xpert MTB/RIF. Eight isolates, 28.6% of all RR-confirmed isolates, carried the I491F mutation, all detected by TLA. TLA also correctly identified 183 of the 184 ofloxacin-susceptible isolates (99.5% specificity; 95% CI, 97.0 to 99.9). In field conditions, TLA rapidly detects RR, and in this specific setting, it contributed to detection of additional RR patients over Xpert MTB/RIF, mainly but not exclusively due to I491F. TLA also accurately excluded fluoroquinolone resistance.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02263-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Activity of {beta}-Lactam Antibiotics against
           Metallo-{beta}-Lactamase-Producing Enterobacterales in Animal Infection
           Models: a Current State of Affairs [Minireviews]

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      Authors: Asempa, T. E; Abdelraouf, K, Nicolau, D. P.
      Abstract: Metallo-β-lactamases (MBLs) result in resistance to nearly all β-lactam antimicrobial agents, as determined by currently employed susceptibility testing methods. However, recently reported data demonstrate that variable and supraphysiologic zinc concentrations in conventional susceptibility testing media compared with physiologic (bioactive) zinc concentrations may be mediating discordant in vitro-in vivo MBL resistance. While treatment outcomes in patients appear suggestive of this discordance, these limited data are confounded by comorbidities and combination therapy. To that end, the goal of this review is to evaluate the extent of β-lactam activity against MBL-harboring Enterobacterales in published animal infection model studies and provide contemporary considerations to facilitate the optimization of current antimicrobials and development of novel therapeutics.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02271-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Finafloxacin Is an Effective Treatment for Inhalational Tularemia and
           Plague in Mouse Models of Infection [Experimental Therapeutics]

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      Authors: Barnes, K. B; Richards, M. I, Laws, T. R, Nunez, A, Thwaite, J. E, Bentley, C, Harding, S. V.
      Abstract: Infection with aerosolized Francisella tularensis or Yersinia pestis can lead to lethal disease in humans if treatment is not initiated promptly. Finafloxacin is a novel fluoroquinolone which has demonstrated broad-spectrum activity against a range of bacterial species in vitro, in vivo, and in humans, activity which is superior in acidic, infection-relevant conditions. Human-equivalent doses of finafloxacin or ciprofloxacin were delivered at 24 h (representing prophylaxis) or at 72 or 38 h (representing treatment) postchallenge with F. tularensis or Y. pestis, respectively, in BALB/c mouse models. In addition, a short course of therapy (3 days) was compared to a longer course (7 days). Both therapies provided a high level of protection against both infections when administered at 24 h postchallenge, irrespective of the length of the dosing regimen; however, differences were observed when therapy was delayed. A benefit was demonstrated with finafloxacin compared to ciprofloxacin in both models when therapy was delivered later in the infection. These studies suggest that finafloxacin is an effective alternative therapeutic for the prophylaxis and treatment of inhalational infections with F. tularensis or Y. pestis.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02294-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Core Antibiotic-Induced Transcriptional Signatures Reflect Susceptibility
           to All Members of an Antibiotic Class [Susceptibility]

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      Authors: Martinsen, M. A; Jaramillo Cartagena, A, Bhattacharyya, R. P.
      Abstract: Current growth-based antibiotic susceptibility testing (AST) is too slow to guide early therapy. We previously developed a diagnostic approach that quantifies antibiotic-induced transcriptional signatures to distinguish susceptible from resistant isolates, providing phenotypic AST 24 to 36 h faster than current methods. Here, we show that 10 transcripts optimized for AST of one fluoroquinolone, aminoglycoside, or beta-lactam reflect susceptibility when the organism is exposed to other members of that class. This finding will streamline development and implementation of this strategy, facilitating efficient antibiotic deployment.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02296-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Manogepix, the Active Moiety of the Investigational Agent Fosmanogepix,
           Demonstrates In Vitro Activity against Members of the Fusarium oxysporum
           and Fusarium solani Species Complexes [Susceptibility]

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      Authors: Badali, H; Patterson, H. P, Sanders, C. J, Mermella, B, Gibas, C. F. C, Ibrahim, A. S, Shaw, K. J, Wiederhold, N. P.
      Abstract: We evaluated the in vitro activity of manogepix against Fusarium oxysporum and Fusarium solani species complex (FOSC and FSSC, respectively) isolates per CLSI document M38 broth microdilution methods. Manogepix demonstrated activity against both FOSC (MEC [minimum effective concentration] range, ≤0.015 to 0.03 μg/ml; MIC50 range, ≤0.015 to 0.125 μg/ml) and FSSC (MEC, ≤0.015 μg/ml; MIC50, ≤0.015 to 0.25 μg/ml). Amphotericin B was also active (MIC, 0.25 to 4 μg/ml), whereas the triazoles (MIC, 1 to>16 μg/ml) and micafungin (MEC, ≥8 μg/ml) had limited activity.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02343-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Efficacy and Associated Drug Exposures of Isavuconazole and Fluconazole in
           an Experimental Model of Coccidioidomycosis [Pharmacology]

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      Authors: Kovanda, L. L; Sass, G, Martinez, M, Clemons, K. V, Nazik, H, Kitt, T. M, Wiederhold, N, Hope, W. W, Stevens, D. A.
      Abstract: Coccidioides spp. are important pathogens in regions where they are endemic, and new treatment options are needed. Here, isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy. Broth macrodilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days postinoculation. In model 1, mice were treated for 19 days, followed by 30 days of off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug; 186, 279, or 372 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Model 2 included 7-day treatment with ISAVUSULF (prodrug; 74.4, 111.6, or 148.8 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Serial plasma and tissues samples were obtained for pharmacokinetics (PK) and fungal burden measurement, respectively. Fifty percent minimal effective concentration (MEC50) values were 0.39 mg/liter (isavuconazole [ISAV]) and 12.5 mg/liter (FLU). Treatment with ISAVUSULF186 or with either FLU dose resulted in higher survival compared to that in the untreated group. Treatment with ISAVUSULF186 or ISAVUSULF279 twice daily or FLU100 reduced fungal burden in all organs (model 1). In model 2, a>1 log10 CFU/organ reduction was demonstrated, with ISAV area under the concentration-time curve (AUC) values achieved with 111.6 mg/kg twice daily (56.8 mg · h/liter) in the spleen and liver. FLU AUC values of 100 and 500 mg·h/liter for 20 and 100 mg/kg doses, respectively, resulted in a>1 log10 CFU/organ mean reduction in all organs. ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02344-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Development and Validation of an In Silico Decision Tool To Guide
           Optimization of Intravenous Artesunate Dosing Regimens for Severe
           Falciparum Malaria Patients [Clinical Therapeutics]

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      Authors: Zaloumis, S. G; Whyte, J. M, Tarning, J, Krishna, S, McCaw, J. M, Cao, P, White, M. T, Dini, S, Fowkes, F. J. I, Maude, R. J, Kremsner, P, Dondorp, A, Price, R. N, White, N. J, Simpson, J. A.
      Abstract: Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02346-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Impact of Accelerate Pheno and BacT/Alert Virtuo on Clinical Processes and
           Outcomes in Patients with Sepsis and Concurrent Gram-Negative Bacteremia
           [Clinical Therapeutics]

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      Authors: Babowicz, F; LaPlante, R, Mitchell, C, ODonnell, J. N, Tobin, E, George, M, Carreno, J. J.
      Abstract: The Accelerate Pheno and BacT/Alert Virtuo systems may improve bacteremia management. Here, we evaluated the impact of both devices on outcomes in patients with sepsis and concurrent Gram-negative bacteremia. This quasiexperimental study included a retrospective preimplementation and a prospective postimplementation group. Patients ≥18 years old with Gram-negative bacteremia were included. Patients with neutropenia, pregnant patients, those who were transferred from an outside hospital with active bloodstream infections, and those with polymicrobial bacteremia were excluded. Blood culture incubation in the BacT/Alert 3D device and microdilution antimicrobial susceptibility testing from culture plate growth were used prior to implementation of the BacT/Alert Virtuo and Accelerate Pheno systems. Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) identification directly from blood culture was used pre- and postimplementation. Time to Gram stain results, identification, susceptibility reporting, initiation of narrow-spectrum Gram-negative therapy at 72 h, 30-day inpatient mortality, sepsis resolution, and length of hospital stay were evaluated. A total of 116 patients were included (63 preimplementation, 53 postimplementation). Median times to Gram stain and susceptibility results were significantly shorter postimplementation (P < 0.001). The postimplementation group had an improved hazard ratio for narrow-spectrum Gram-negative therapy at 72 h (hazard ratio [HR], 2.685 [95% confidence interval {CI}, 1.348 to 5.349]), a reduced hazard ratio for 30-day inpatient mortality (adjusted HR [aHR], 0.150 [95% CI, 0.026 to 0.846]), and improved sepsis resolution (92.5% versus 77.8% [P = 0.030]). The length of hospital stay was unchanged after implementation. We conclude that implementation of the BacT/Alert Virtuo and Accelerate Pheno systems improved microbiology laboratory processes, antibiotic utilization processes, and clinical outcomes. These data support the use of rapid diagnostics in sepsis with concurrent Gram-negative bacteremia.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02364-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Two Functionally Redundant FK506-Binding Proteins Regulate Multidrug
           Resistance Gene Expression and Govern Azole Antifungal Resistance
           [Mechanisms of Resistance]

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      Authors: Moirangthem, R; Kumar, K, Kaur, R.
      Abstract: Increasing resistance to antifungal therapy is an impediment to the effective treatment of fungal infections. Candida glabrata is an opportunistic human fungal pathogen that is inherently less susceptible to cost-effective azole antifungals. Gain-of-function mutations in the Zn-finger pleiotropic drug resistance transcriptional activator-encoding gene CgPDR1 are the most prevalent causes of azole resistance in clinical settings. CgPDR1 is also transcriptionally activated upon azole exposure; however, factors governing CgPDR1 gene expression are not yet fully understood. Here, we have uncovered a novel role for two FK506-binding proteins, CgFpr3 and CgFpr4, in the regulation of the CgPDR1 regulon. We show that CgFpr3 and CgFpr4 possess a peptidyl-prolyl isomerase domain and act redundantly to control CgPDR1 expression, as a Cgfpr34 mutant displayed elevated expression of the CgPDR1 gene along with overexpression of its target genes, CgCDR1, CgCDR2, and CgSNQ2, which code for ATP-binding cassette multidrug transporters. Furthermore, CgFpr3 and CgFpr4 are required for the maintenance of histone H3 and H4 protein levels, and fluconazole exposure leads to elevated H3 and H4 protein levels. Consistent with the role of histone proteins in azole resistance, disruption of genes coding for the histone demethylase CgRph1 and the histone H3K36-specific methyltransferase CgSet2 leads to increased and decreased susceptibility to fluconazole, respectively, with the Cgrph1 mutant displaying significantly lower basal expression levels of the CgPDR1 and CgCDR1 genes. These data underscore a hitherto unknown role of histone methylation in modulating the most common azole antifungal resistance mechanism. Altogether, our findings establish a link between CgFpr-mediated histone homeostasis and CgPDR1 gene expression and implicate CgFpr in the virulence of C. glabrata.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02415-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Mutations in the HIV-1 3'-Polypurine Tract and Integrase Strand Transfer
           Inhibitor Resistance [Letters]

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      Authors: Wei, Y; Sluis-Cremer, N.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02432-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Identification of a Novel Hybrid Plasmid Encoding KPC-2 and Virulence
           Factors in Klebsiella pneumoniae Sequence Type 11 [Epidemiology and
           Surveillance]

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      Authors: Jin, L; Wang, R, Gao, H, Wang, Q, Wang, H.
      Abstract: Recent emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) coharboring blaKPC-2 and pLVPK-like virulence plasmids represented a novel clinical challenge. In the present study, we characterized a blaKPC-2 and virulence hybrid plasmid, designated pCRHV-C2244, from a clinical ST11-K64 CRKP strain. pCRHV-C2244 was non-self-transmissible due to incomplete conjugative elements but mobilizable together with a conjugative helper. Enhanced virulence and stable maintenance without significant fitness loss in its original host were confirmed in vitro and in vivo.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02435-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • A Yeast-Based Drug Discovery Platform To Identify Plasmodium falciparum
           Type II NADH Dehydrogenase Inhibitors [Pharmacology]

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      Authors: Cao, Y; Sun, C, Wen, H, Wang, M, Zhu, P, Zhong, M, Li, J, Chen, X, Tang, Y, Wang, J, Zhou, B.
      Abstract: Conventional methods utilizing in vitro protein activity assay or in vivo parasite survival to screen for malaria inhibitors suffer from high experimental background and/or inconvenience. Here, we introduce a yeast-based system to facilitate chemical screening for specific protein or pathway inhibitors. The platform comprises several isogeneic Pichia strains that differ only in the target of interest, so that a compound which inhibits one strain but not the other is implicated in working specifically against the target. We used Plasmodium falciparum NDH2 (PfNDH2), a type II NADH dehydrogenase, as a proof of principle to show how well this works. Three isogenic Pichia strains harboring, respectively, exogeneously introduced PfNDH2, its own complex I (a type I NADH dehydrogenase), and PfNDH2 with its own complex I, were constructed. In a pilot screen of more than 2,000 compounds, we identified a highly specific inhibitor that acts on PfNDH2. This compound poorly inhibits the parasites at the asexual blood stage; however, is highly effective in repressing oocyst maturation in the mosquito stage. Our results demonstrate that the yeast cell-based screen platform is feasible, efficient, economical, and has very low background noise. Similar strategies could be extended to the functional screen for interacting molecules of other targets.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02470-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Trends of Antimicrobial Resistance and Combination Susceptibility Testing
           of Multidrug-Resistant Pseudomonas aeruginosa Isolates from Cystic
           Fibrosis Patients: a 10-Year Update [Susceptibility]

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      Authors: Okoliegbe, I. N; Hijazi, K, Cooper, K, Ironside, C, Gould, I. M.
      Abstract: Antimicrobial combination therapy is a time/resource-intensive procedure commonly employed in the treatment of cystic fibrosis (CF) pulmonary exacerbations caused by Pseudomonas aeruginosa. Ten years ago, the most promising antimicrobial combinations were proposed, but there has since been the introduction of new β-lactam plus β-lactamase inhibitor antimicrobial combinations. The aims of this study were to (i) compare in vitro activity of these new antimicrobials with other antipseudomonal agents and suggest their most synergistic antimicrobial combinations and (ii) determine antimicrobial resistance rates and study inherent trends of antimicrobials over 10 years. A total of 721 multidrug-resistant P. aeruginosa isolates from 183 patients were collated over the study period. Antimicrobial susceptibility and combination testing were carried out using the Etest method. The results were further assessed using the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI). Resistance to almost all antimicrobial agents maintained a similar level during the studied period. Colistin (P < 0.001) and tobramycin (P = 0.001) were the only antimicrobials with significant increasing isolate susceptibility, while an increasing resistance trend was observed for levofloxacin. The most active antimicrobials were colistin, ceftolozane-tazobactam, ceftazidime-avibactam, and gentamicin. All combinations with β-lactam plus β-lactamase inhibitors produced some synergistic results. Ciprofloxacin plus ceftolozane-tazobactam (40%) and amikacin plus ceftazidime (36.7%) were the most synergistic combinations, while colistin combinations gave the best median SBPI (50.11). This study suggests that effective fluoroquinolone stewardship should be employed for CF patients. It also presents in vitro data to support the efficacy of novel combinations for use in the treatment of chronic P. aeruginosa infections.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02483-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Dosage Individualization of Linezolid: Precision Dosing of Linezolid To
           Optimize Efficacy and Minimize Toxicity [Pharmacology]

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      Authors: Luque, S; Hope, W, Sorli, L, Munoz-Bermudez, R, Campillo, N, Barcelo-Vidal, J, Alvarez-Lerma, F, Horcajada, J. P, Masclans-Enviz, J. R, Neely, M, Grau, S.
      Abstract: The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time>MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02490-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Physiological Responses of Aspergillus niger Challenged with Itraconazole
           [Mechanisms of Resistance]

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      Authors: Poulsen, J. S; Madsen, A. M, White, J. K, Nielsen, J. L.
      Abstract: Aspergillus niger is an opportunistic pathogen commonly found in a variety of indoor and outdoor environments. An environmental isolate of A. niger from a pig farm was resistant to itraconazole, and in-depth investigations were conducted to better understand cellular responses that occur during growth when this pathogen is exposed to an antifungal. Using a combination of cultivation techniques, antibiotic stress testing, and label-free proteomics, this study investigated the physiological and metabolic responses of A. niger to sublethal levels of antifungal stress. Challenging A. niger with itraconazole inhibited growth, and the MIC was estimated to be> 16 mg · liter–1. Through the proteome analysis, 1,305 unique proteins were identified. During growth with 2 and 8 mg · liter–1 itraconazole, a total of 91 and 50 proteins, respectively, were significantly differentially expressed. When challenged with itraconazole, A. niger exhibited decreased expression of peroxidative enzymes, increased expression of an ATP-binding cassette (ABC) transporter most likely involved as an azole efflux pump, and inhibited ergosterol synthesis; however, several ergosterol biosynthesis proteins increased in abundance. Furthermore, reduced expression of proteins involved in the production of ATP and reducing power from both the tricarboxylic acid (TCA) and glyoxylate cycles was observed. The mode of action of triazoles in A. niger therefore appears more complex than previously anticipated, and these observations may help highlight future targets for antifungal treatment.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02549-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Assessing the Bioactive Profile of Antifungal-Loaded Calcium Sulfate
           against Fungal Biofilms [Experimental Therapeutics]

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      Authors: Butcher, M. C; Brown, J. L, Hansom, D, Wilson-van Os, R, Delury, C, Laycock, P. A, Ramage, G.
      Abstract: Calcium sulfate (CS) has been used clinically as a bone- or void-filling biomaterial, and its resorptive properties have provided the prospect for its use as a release mechanism for local antibiotics to control biofilms. Here, we aimed to test CS beads loaded with three antifungal drugs against planktonic and sessile fungal species to assess whether these antifungal beads could be harnessed to provide consistent release of antifungals at biofilm-inhibitory doses. A panel of different fungal species (n = 15) were selected for planktonic broth microdilution testing with fluconazole (FLZ), amphotericin B (AMB), and caspofungin (CSP). After establishing planktonic inhibition, antifungal CS beads were introduced to fungal biofilms (n = 5) to assess biofilm formation and cell viability through a combination of standard quantitative and qualitative biofilm assays. Inoculation of a hydrogel substrate, packed with antifungal CS beads, was also used to assess diffusion through a semidry material, to mimic active infection in vivo. In general, antifungals released from loaded CS beads were all effective at inhibiting the pathogenic fungi over 7 days within standard MIC ranges for these fungi. We observed a significant reduction of pregrown fungal biofilms across key fungal pathogens following treatment, with visually observable changes in cell morphology and biofilm coverage provided by scanning electron microscopy. Assessment of biofilm inhibition also revealed reductions in total and viable cells across all organisms tested. These data show that antifungal-loaded CS beads produce a sustained antimicrobial effect that inhibits and kills clinically relevant fungal species in vitro as planktonic and biofilm cells.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02551-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Influence of Fluconazole Administration on Gut Microbiome, Intestinal
           Barrier, and Immune Response in Mice [Biologic Response Modifiers]

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      Authors: Heng, X; Jiang, Y, Chu, W.
      Abstract: Antibiotics that can treat or prevent infectious diseases play an important role in medical therapy. However, the use of antibiotics has potentially negative effects on the health of the host. For example, antibiotics use may affect the host's immune system by altering the gut microbiota. Therefore, the aim of the study was to investigate the influence of antifungal (fluconazole) treatment on the gut microbiota and immune system of mice. Results showed that the gut microbial composition of mice receiving fluconazole treatment was significantly changed after the trial. Fluconazole did not affect the relative abundance of bacteria but significantly reduced the diversity of bacterial flora. In the bacteriome, Firmicutes and Proteobacteria significantly increased, while Bacteroidetes, Deferribacteres, Patescibacteria, and Tenericutes showed a remarkable reduction in the fluconazole-treated group compared with the control group. In the mycobiome, the relative abundance of Ascomycota was significantly decreased and Mucoromycota was significantly increased in the intestine of mice treated with fluconazole compared to the control group. Reverse transcription-quantitative PCR (RT-qPCR) results showed that the relative gene expression of ZO-1, occludin, MyD88, interleukin-1β (IL-1β), and IL-6 was decreased in the fluconazole-treated group compared to the control. Serum levels of IL-2, LZM, and IgM were significantly increased, while the IgG level was considerably downregulated in the fluconazole-treated compared to the control group. These results suggest that the administration of fluconazole can influence the gut microbiota and that a healthy gut microbiome is important for the regulation of the host immune responses.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02552-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Validation of Available Extended-Spectrum-Beta-Lactamase Clinical Scoring
           Models in Predicting Drug Resistance in Patients with Enteric
           Gram-Negative Bacteremia Treated at South Texas Veterans Health Care
           System [Mechanisms of Resistance]

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      Authors: Madrid-Morales, J; Sharma, A, Reveles, K, Velez-Mejia, C, Hopkins, T, Yang, L, Walter, E, Cadena, J.
      Abstract: Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae are increasingly common; however, predicting which patients are likely to be infected with an ESBL pathogen is challenging, leading to increased use of carbapenems. To date, five prediction models have been developed to distinguish between patients infected with ESBL pathogens. The aim of this study was to validate and compare each of these models to better inform antimicrobial stewardship. This was a retrospective cohort study of patients with Gram-negative bacteremia treated at the South Texas Veterans Health Care System over 3 months from 2018 to 2019. We evaluated isolate, clinical syndrome, and score variables for the five published prediction models/scores: Italian "Tumbarello," Duke, University of South Carolina (USC), Hopkins clinical decision tree, and modified Hopkins. Each model was assessed using the area under the receiver operating characteristic curve (AUROC) and Pearson correlation. One hundred forty-five patients were included for analysis, of which 20 (13.8%) were infected with an ESBL Escherichia coli or Klebsiella spp. The most common sources of infection were genitourinary (55.8%) and gastrointestinal/intraabdominal (24.1%), and the most common pathogen was E. coli (75.2%). The prediction model with the strongest discriminatory ability (AUROC) was Tumbarello (0.7556). The correlation between prediction model score and percent ESBL was strongest with the modified Hopkins model (R2 = 0.74). In this veteran population, the modified Hopkins and Duke prediction models were most accurate in discriminating between Gram-negative bacteremia patients when considering both AUROC and correlation. However, given the moderate discriminatory ability, many patients with ESBL Enterobacteriaceae (at least 25%) may still be missed empirically.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02562-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Discovery of a Novel Respiratory Syncytial Virus Replication Inhibitor
           [Antiviral Agents]

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      Authors: Wang, L; Zhu, Q, Xiang, K, Zhang, Y, Li, B, Yu, X, Yang, G, Liang, C, Yun, H, Zhang, M, Qin, N, Gao, L.
      Abstract: A high-throughput screen of a Roche internal chemical library based on inhibition of the respiratory syncytial virus (RSV)-induced cytopathic effect (CPE) on HEp-2 cells was performed to identify RSV inhibitors. Over 2,000 hits were identified and confirmed to be efficacious against RSV infection in vitro. Here, we report the discovery of a triazole-oxadiazole derivative, designated triazole-1, as an RSV replication inhibitor, and we characterize its mechanism of action. Triazole-1 inhibited the replication of both RSV A and B subtypes with 50% inhibitory concentration (IC50) values of approximately 1 μM, but it was not effective against other viruses, including influenza virus A, human enterovirus 71 (EV71), and vaccinia virus. Triazole-1 was shown to inhibit RSV replication when added at up to 8 h after viral entry, suggesting that it inhibits RSV after viral entry. In a minigenome reporter assay in which RSV transcription regulatory sequences flanking a luciferase gene were cotransfected with RSV N/P/L/M2-1 genes into HEp-2 cells, triazole-1 demonstrated specific and dose-dependent RSV transcription inhibitory effects. Consistent with these findings, deep sequencing of the genomes of triazole-1-resistant mutants revealed a single point mutation (A to G) at nucleotide 13546 of the RSV genome, leading to a T-to-A change at amino acid position 1684 of the L protein, which is the RSV RNA polymerase for both viral transcription and replication. The effect of triazole-1 on minigenome transcription, which was mediated by the L protein containing the T1684A mutation, was significantly reduced, suggesting that the T1684A mutation alone conferred viral resistance to triazole-1.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02576-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Azole Susceptibility Profiles of More than 9,000 Clinical Yeast Isolates
           Belonging to 40 Common and Rare Species [Susceptibility]

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      Authors: Desnos-Ollivier, M; Lortholary, O, Bretagne, S, Dromer, F, on behalf of the French Mycoses Study Group
      Abstract: Invasive yeast infections represent a major global public health issue, and only few antifungal agents are available. Azoles are one of the classes of antifungals used for treatment of invasive candidiasis. The determination of antifungal susceptibility profiles using standardized methods is important to identify resistant isolates and to uncover the potential emergence of intrinsically resistant species. Here, we report data on 9,319 clinical isolates belonging to 40 pathogenic yeast species recovered in France over 17 years. The antifungal susceptibility profiles were all determined at the National Reference Center for Invasive Mycoses and Antifungals based on the EUCAST broth microdilution method. The centralized collection and analysis allowed us to describe the trends of azole susceptibility of isolates belonging to common species, confirming the high susceptibility for Candida albicans (n = 3,295), Candida tropicalis (n = 641), and Candida parapsilosis (n = 820) and decreased susceptibility for Candida glabrata (n = 1,274) and Pichia kudriavzevii (n = 343). These profiles also provide interesting data concerning azole susceptibility of Cryptococcus neoformans species complex, showing comparable MIC distributions for the three species but lower MIC50s and MIC90s for serotype D (n = 208) compared to serotype A (n = 949) and AD hybrids (n = 177). Finally, these data provide useful information for rare and/or emerging species, such as Clavispora lusitaniae (n = 221), Saprochaete clavata (n = 184), Meyerozyma guilliermondii complex (n = 150), Candida haemulonii complex (n = 87), Rhodotorula mucilaginosa (n = 55), and Wickerhamomyces anomalus (n = 36).
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02615-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Antioxidant Molecules as a Source of Mitigation of Antibiotic Resistance
           Gene Dissemination [Mechanisms of Resistance]

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      Authors: Ortiz de la Rosa, J. M; Nordmann, P, Poirel, L.
      Abstract: Escherichia coli is the most commonly identified human pathogen and a prominent microorganism of the gut microbiota. Acquired resistance to antibiotics in this species is driven mainly by horizontal gene transfer and plasmid acquisition. Currently, the main concern is the acquisition of extended-spectrum β-lactamases of the CTX-M type in E. coli, a worldwide-observed phenomenon. Plasmids encoding CTX-M enzymes have different scaffolds and conjugate at different frequencies. Here, we show that the conjugation rates of several plasmid types encoding broad-spectrum β-lactamases are increased when the E. coli donor strain is exposed to subinhibitory concentrations of diverse orally given antibiotics, including fluoroquinolones, such as ciprofloxacin and levofloxacin, but also trimethoprim and nitrofurantoin. This study provides insights into underlying mechanisms leading to increased plasmid conjugation frequency in relation to DNA synthesis inhibitor-type antibiotics, involving reactive oxygen species (ROS) production and probably increased expression of genes involved in the SOS response. Furthermore, we show that some antioxidant molecules currently approved for unrelated clinical uses, such as edaravone, p-coumaric acid, and N-acetylcysteine, may antagonize the ability of antibiotics to increase plasmid conjugation rates. These results suggest that several antioxidative molecules might be used in combination with these "inducer" antibiotics to mitigate the unwanted increased resistance plasmid dissemination.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02658-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Ibrexafungerp Demonstrates In Vitro Activity against Fluconazole-Resistant
           Candida auris and In Vivo Efficacy with Delayed Initiation of Therapy in
           

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      Authors: Wiederhold, N. P; Najvar, L. K, Olivo, M, Morris, K. N, Patterson, H. P, Catano, G, Patterson, T. F.
      Abstract: Candida auris is an emerging pathogen that has rapidly spread to many countries on multiple continents. Invasive infections caused by this species are associated with significant mortality, and treatment options are limited due to antifungal resistance. Ibrexafungerp is the first-in-class member of the triterpenoids, which inhibit the production of (1,3)-β-d-glucan and can be administered orally. We evaluated the in vitro activity and in vivo efficacy of ibrexafungerp against C. auris. Antifungal susceptibility was tested by broth microdilution against 54 C. auris isolates. Neutropenic mice were intravenously infected with a clinical isolate, and a 7-day treatment course was begun 24 h postinoculation with vehicle control, ibrexafungerp (20, 30, and 40 mg/kg orally twice daily), fluconazole (20 mg/kg orally once daily), or caspofungin (10 mg/kg intraperitoneally once daily). Fungal burden was assessed by colony counts in the kidneys on day 8 and on day 21 or as mice became moribund in the survival arm. Ibrexafungerp demonstrated consistent activity, with MICs ranging between 0.25 and 2 μg/ml against all isolates. Marked improvements in survival were observed in mice treated with the higher doses of ibrexafungerp and caspofungin. Similarly, reductions in kidney fungal burden were also observed in these groups. No improvements in survival or reductions in fungal burden were observed with fluconazole, consistent with the in vitro resistance of the isolate used to establish infection to this azole. These results demonstrate that ibrexafungerp is effective in vivo against C. auris even when the start of therapy is delayed.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02694-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Whole-Genome Analysis Surveillance of Influenza A Virus Resistance to
           Polymerase Complex Inhibitors in Eastern Spain from 2016 to 2019
           [Antiviral Agents]

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      Authors: Mengual-Chulia; B., Alonso-Cordero, A., Cano, L., Mosquera, M. d. M., de Molina, P., Vendrell, R., Reyes-Prieto, M., Jane, M., Torner, N., Martinez, A. I., Vila, J., Diez-Domingo, J., Marcos, M. A., Lopez-Labrador, F. X., on behalf of the Valencia Hospital Network for the Study of Influenza Respiratory Viruses Disease (VAHNSI)
      Abstract: Molecular surveillance by whole-genome sequencing was used to monitor the susceptibility of circulating influenza A viruses to three polymerase complex inhibitors. A total of 12 resistance substitutions were found among 285 genomes analyzed, but none were associated with high levels of resistance. Natural resistance to these influenza A antivirals is currently uncommon.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02718-20
      Issue No: Vol. 65, No. 6 (2021)
       
  • Antibiotic-Dispensing Practice in Community Pharmacies: Results of a
           Cross-Sectional Study in Italy [Epidemiology and Surveillance]

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      Authors: Bianco, A; Licata, F, Trovato, A, Napolitano, F, Pavia, M.
      Abstract: Inappropriate use of antibiotics in the community contributes to the development of antibiotic resistance (ABR), one of the most concerning issues in modern medicine. The objectives of the study were to investigate the knowledge and attitudes regarding ABR and dispensing antibiotics without prescription (DAwP) and to assess the extent of the practice of DAwP among Italian community pharmacists (CPs). A nationwide cross-sectional study using an anonymous, structured, validated, and pilot-tested questionnaire was conducted. The five sections gathered data on demographic and professional characteristics, knowledge and attitudes toward ABR and DAwP, practices regarding dispensing antibiotics with or without prescription and their reasons, counselling on the potential antibiotic side effects and the importance of adherence to medication regimen, and the information sources used to update the knowledge about ABR. About 4 in 10 CPs (37.1%) reported being involved in DAwP, although 93.7% knew that it is illegal in Italy. The vast majority affirmed to have always/often asked clients about their drug allergies (95.5%) and about their medication history (82.5%). Two-thirds (66.2%) warned their clients about the potential side effects of the drugs, and 55% informed them about the importance of completing the full course of antibiotics. Complacency with clients who found it difficult to consult the physician was the most significant predictor of DAwP. A considerable proportion of DAwP was described, so it could be easy for patients to misuse these drugs. Future policies need to enhance the enforcement of existing prescription-only regulations and to develop monitoring strategies to ensure their establishment in real-life practices.
      PubDate: 2021-05-18T08:00:59-07:00
      DOI: 10.1128/AAC.02729-20
      Issue No: Vol. 65, No. 6 (2021)
       
 
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