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  • 1
    Online Resource
    Online Resource
    Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure
    American Society for Microbiology ; 2016
    In:  Antimicrobial Agents and Chemotherapy Vol. 60, No. 3 ( 2016-03), p. 1584-1591
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 3 ( 2016-03), p. 1584-1591
    Abstract: Staphylococcus aureus possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the in vitro evolution of S. aureus in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (10 8 CFU/ml) of methicillin-resistant S. aureus (MRSA) USA300 and USA400. Host-pathogen interactions using Galleria mellonella and accessory gene regulator ( agr ) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC ( f AUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas f AUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in G. mellonella mortality ( P = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in agr expression and virulence during therapy may be an adaptive mechanism of S. aureus persistence.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02657-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
    detail.hit.zdb_id: 1496156-8
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    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam–β-Lactamase Inhibitor Combinations
    American Society for Microbiology ; 2016
    In:  Antimicrobial Agents and Chemotherapy Vol. 60, No. 4 ( 2016-04), p. 1967-1973
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 4 ( 2016-04), p. 1967-1973
    Abstract: Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains of Escherichia coli that differed in the type of β-lactamase they expressed. The four investigational strains included 2805 (no β-lactamase), 2890 (AmpC β-lactamase), 2842 (CMY-10 β-lactamase), and 2807 (CTX-M-15 β-lactamase), with MICs to ceftolozane of 0.25, 4, 8, and 〉 128 mg/liter with no tazobactam, and MICs of 0.25, 1, 4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0, 1, 4, 16, 64, and 256 mg/liter) and tazobactam (0, 1, 4, 16, and 64 mg/liter) over 48 h using starting inocula of 10 6 and 10 8 CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ≥3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots ( R 2 〉 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC 50 s) at tazobactam concentrations of ≤4 mg/liter than those at concentrations of ≥16 mg/liter ( P 〈 0.01). Moreover, the EC 50 s at 10 8 CFU/ml were 2.81 to 66.5 times greater than the EC 50 s at 10 6 CFU/ml (median, 10.7-fold increase; P = 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of β-lactamase-producing E. coli strains.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02635-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    High-Dose Ampicillin-Sulbactam Combinations Combat Polymyxin-Resistant Acinetobacter baumannii in a Hollow-Fiber Infection Model
    American Society for Microbiology ; 2017
    In:  Antimicrobial Agents and Chemotherapy Vol. 61, No. 3 ( 2017-03)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 61, No. 3 ( 2017-03)
    Abstract: Acinetobacter baumannii is emerging with resistance to polymyxins. In 24-h time-kill experiments, high-dose ampicillin-sulbactam in combination with meropenem and polymyxin B achieved additivity or synergy against 10 8 CFU/ml of two clinical A. baumannii isolates resistant to all three drugs (maximum reductions, 1.6 and 3.1 logs). In a 14-day hollow-fiber infection model, high-dose ampicillin-sulbactam (8/4 g every 8 h, respectively) in combination with meropenem (2 g every 8 h) and polymyxin B (1.43 mg/kg of body weight every 12 h with loading dose) resulted in rapid (96 h) eradication of A. baumannii .
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01268-16
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 1496156-8
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  • 4
    Online Resource
    Online Resource
    A coup d'état by NDM-producing Klebsiella pneumoniae overthrows the major bacterial population during KPC-directed therapy
    Elsevier BV ; 2020
    In:  Diagnostic Microbiology and Infectious Disease Vol. 98, No. 1 ( 2020-09), p. 115080-
    Details
    In: Diagnostic Microbiology and Infectious Disease, Elsevier BV, Vol. 98, No. 1 ( 2020-09), p. 115080-
    Type of Medium: Online Resource
    ISSN: 0732-8893
    URL: Article
    DOI: 10.1016/j.diagmicrobio.2020.115080
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2026024-6
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  • 5
    Online Resource
    Online Resource
    Optimizing Polymyxin Combinations Against Resistant Gram-Negative Bacteria
    Springer Science and Business Media LLC ; 2015
    In:  Infectious Diseases and Therapy Vol. 4, No. 4 ( 2015-12), p. 391-415
    Details
    In: Infectious Diseases and Therapy, Springer Science and Business Media LLC, Vol. 4, No. 4 ( 2015-12), p. 391-415
    Type of Medium: Online Resource
    ISSN: 2193-8229 , 2193-6382
    URL: Article
    DOI: 10.1007/s40121-015-0093-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2701611-0
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  • 6
    Online Resource
    Online Resource
    Escaping ESKAPE resistance: in vitro and in silico studies of multifunctional carbamimidoyl-tethered indoles against antibiotic-resistant bacteria
    The Royal Society ; 2023
    In:  Royal Society Open Science Vol. 10, No. 4 ( 2023-04)
    Details
    In: Royal Society Open Science, The Royal Society, Vol. 10, No. 4 ( 2023-04)
    Abstract: Combining the hybridization and repurposing strategies, six compounds from our in-house library and having a designed hybrid structure of MBX-1162, pentamidine and MMV688271 were repurposed as potential antibacterial agents. Among, compounds 1a and 1d elicited potential sub-µg ml −1 activity against the high-priority antibiotic-resistant Gram-positive members of ESKAPE bacteria as well as antibiotic-susceptible Gram-positive bacteria. Furthermore, they showed potential low µg ml −1 activity against the explored critical-priority antibiotic-resistant Gram-negative members of ESKAPE bacteria. In time–kill assay, compound 1a has effective 0.5 and 0.25 µg ml −1 antibacterial lethal concentrations against MRSA in exponential growth phase. In silico investigations predicted compounds 1a and 1d as inhibitors of the open conformation of undecaprenyl diphosphate synthase involved in bacterial isoprenoid synthesis. In addition, compounds 1a and 1d were predicted as inhibitors of NADPH-free but not NADPH-bound form of ketol-acid reductoisomerase and may also serve as potential B-DNA minor groove binders with possible differences in the molecular sequence recognition. Overall, compounds 1a and 1d are presented as multifunctional potential antibacterial agents for further development against high- and critical-priority Gram-positive and Gram-negative antibiotic-resistant ESKAPE bacterial pathogens as well as antibiotic-susceptible Gram-positive bacterial pathogens.
    Type of Medium: Online Resource
    ISSN: 2054-5703
    URL: Article
    DOI: 10.1098/rsos.230020
    Language: English
    Publisher: The Royal Society
    Publication Date: 2023
    detail.hit.zdb_id: 2787755-3
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  • 7
    Online Resource
    Online Resource
    Losing the Battle but Winning the War: Can Defeated Antibacterials Form Alliances to Combat Drug-Resistant Pathogens?
    MDPI AG ; 2021
    In:  Antibiotics Vol. 10, No. 6 ( 2021-05-28), p. 646-
    Details
    In: Antibiotics, MDPI AG, Vol. 10, No. 6 ( 2021-05-28), p. 646-
    Abstract: Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have investigated the potential utility of combinations that consist of one or more antibacterials that individually are incapable of killing the relevant pathogen. The current review summarizes in vitro, in vivo, and clinical studies that evaluate combinations that include at least one drug that is not active individually against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or Staphylococcus aureus. Polymyxins were often included in combinations against all three of the Gram-negative pathogens, and carbapenems were commonly incorporated into combinations against K. pneumoniae and A. baumannii. Minocycline, sulbactam, and rifampin were also frequently investigated in combinations against A. baumannii, whereas the addition of ceftaroline or another β-lactam to vancomycin or daptomycin showed promise against S. aureus with reduced susceptibility to vancomycin or daptomycin. Although additional clinical studies are needed to define the optimal combination against specific drug-resistant pathogens, the large amount of in vitro and in vivo studies available in the literature may provide some guidance on the rational design of antibacterial combinations.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics10060646
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2681345-2
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  • 8
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    Online Resource
    Evolution of Staphylococcus aureus under Vancomycin Selective Pressure: the Role of the Small-Colony Variant Phenotype
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 2 ( 2015-02), p. 1347-1351
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 2 ( 2015-02), p. 1347-1351
    Abstract: Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10 8 -CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log 10 CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model ( R 2 〉 0.90).
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.04508-14
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 9
    Online Resource
    Online Resource
    Inoculum effect of β-lactam antibiotics
    Oxford University Press (OUP) ; 2019
    In:  Journal of Antimicrobial Chemotherapy Vol. 74, No. 10 ( 2019-10-01), p. 2825-2843
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 74, No. 10 ( 2019-10-01), p. 2825-2843
    Abstract: The phenomenon of attenuated antibacterial activity at inocula above those utilized for susceptibility testing is referred to as the inoculum effect. Although the inoculum effect has been reported for several decades, it is currently debatable whether the inoculum effect is clinically significant. The aim of the present review was to consolidate currently available evidence to summarize which β-lactam drug classes demonstrate an inoculum effect against specific bacterial pathogens. Review of the literature showed that the majority of studies that evaluated the inoculum effect of β-lactams were in vitro investigations of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Across all five pathogens, cephalosporins consistently displayed observable inoculum effects in vitro, whereas carbapenems were less susceptible to an inoculum effect. A handful of animal studies were available that validated that the in vitro inoculum effect translates into attenuated pharmacodynamics of β-lactams in vivo. Only a few clinical investigations were available and suggested that an in vitro inoculum effect of cefazolin against MSSA may correspond to an increased likeliness of adverse clinical outcomes in patients receiving cefazolin for bacteraemia. The presence of β-lactamase enzymes was the primary mechanism responsible for an inoculum effect, but the observation of an inoculum effect in multiple pathogens lacking β-lactamase enzymes indicates that there are likely multiple mechanisms that may result in an inoculum effect. Further clinical studies are needed to better define whether interventions made in the clinic in response to organisms displaying an in vitro inoculum effect will optimize clinical outcomes.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkz226
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1467478-6
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  • 10
    Online Resource
    Online Resource
    Capability of Enterococcus faecalis to shield Gram-negative pathogens from aminoglycoside exposure
    Oxford University Press (OUP) ; 2021
    In:  Journal of Antimicrobial Chemotherapy Vol. 76, No. 10 ( 2021-09-15), p. 2610-2614
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 76, No. 10 ( 2021-09-15), p. 2610-2614
    Abstract: Enterococcus faecalis commonly produce aminoglycoside-modifying enzymes (AMEs) and are implicated in polymicrobial infections. Objectives To determine if AME-producing E. faecalis is capable of protecting Enterobacteriaceae and Pseudomonas aeruginosa from gentamicin exposure. Methods Two Klebsiella pneumoniae isolates, two Escherichia coli isolates, and two Pseudomonas aeruginosa isolates were investigated in monoculture time–kill experiments, and each Gram-negative organism was also evaluated during co-culture with either AME-producing or AME-deficient E. faecalis. A pharmacokinetic/pharmacodynamics analysis that utilized Log Ratio Areas and a Hill-type mathematical model was used to determine if the maximal killing or potency of gentamicin against the Gram-negative organisms was altered by the presence of the E. faecalis. Results The maximal killing and potency of gentamicin was the same during monoculture and co-culture experiments for both K. pneumoniae isolates and one E. coli isolate (P  & gt; 0.05). In contrast, the maximal killing of gentamicin was attenuated against one E. coli isolate and both P. aeruginosa isolates during co-culture with E. faecalis (P  & lt; 0.05). The potency of gentamicin was variable against the three aforementioned isolates. Against the E. coli isolate, the potency of gentamicin was significantly reduced by the presence of either E. faecalis isolate (EC50 95% CI = 4.23–4.43 mg/L monoculture versus 3.86–4.19 mg/L and 3.55–3.96 mg/L during co-culture with AME-producing and AME-deficient E. faecalis, respectively). The potency of gentamicin increased or decreased for P. aeruginosa depending on which E. faecalis isolate was investigated. Conclusions The AME-producing E. faecalis did not provide a consistent protective effect from aminoglycosides for the Gram-negative pathogens.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkab211
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1467478-6
    SSG: 15,3
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