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James E. Kirby - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Apramycin against spectinomycin-resistant and -susceptible strains of Neisseria gonorrhoeae.
    The Journal of antimicrobial chemotherapy, 2019
    Co-Authors: Stefan Riedel, Divya Vijayakumar, Gretchen Berg, Anthony D. Kang, Kenneth P. Smith, James E. Kirby
    Abstract:

    Background The emergence of Neisseria gonorrhoeae resistant to all currently available antimicrobial therapies poses a dire public health threat. New antimicrobial agents with activity against N. gonorrhoeae are urgently needed. Apramycin is an aminocyclitol aminoglycoside with broad-spectrum in vitro activity against MDR Gram-negative pathogens and Staphylococcus aureus. However, its activity against N. gonorrhoeae has not been described. Objectives The activity spectrum of Apramycin against a collection of MDR N. gonorrhoeae was assessed. Isolates tested included those susceptible and resistant to the structurally distinct aminocyclitol, spectinomycin. Results The modal MICs for Apramycin and spectinomycin were 16 mg/L and 32 mg/L, respectively. The epidemiological cut-off (ECOFF) for Apramycin was 64 mg/L. No strains among 77 tested had an MIC above this ECOFF, suggesting very low levels of acquired Apramycin resistance. In time-kill analysis, Apramycin demonstrated rapid bactericidal activity comparable to that of spectinomycin. Conclusions Apramycin has broad-spectrum, rapidly bactericidal activity against N. gonorrhoeae. Future pharmacokinetic and pharmacodynamic studies will be needed to determine whether Apramycin and/or Apramycin derivatives hold promise as new therapeutics for N. gonorrhoeae infection.

  • Evaluation of Apramycin activity against methicillin-resistant, methicillin-sensitive, and vancomycin-intermediate Staphylococcus aureus clinical isolates.
    Diagnostic microbiology and infectious disease, 2018
    Co-Authors: Katherine A Truelson, Kenneth P. Smith, Thea Brennan-krohn, James E. Kirby
    Abstract:

    We evaluated the in vitro activity of Apramycin against clinical strains of vancomycin-intermediate and methicillin-resistant and -susceptible Staphylococcus aureus. Apramycin demonstrated an MIC50/MIC90 of 8/16 μg/mL. No strains had an MIC above the epidemiological cutoff value of 32 μg/mL, suggesting Apramycin resistance mechanisms are rare in this strain population. The mounting evidence for broad-spectrum in vitro activity of Apramycin against S. aureus and other bacterial species suggests that further exploration of Apramycin or derivatives as repurposed human therapeutics is warranted.

  • Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model.
    Antimicrobial agents and chemotherapy, 2018
    Co-Authors: Anthony D. Kang, Kenneth P. Smith, Katherine A Truelson, Anders H. Berg, George M. Eliopoulos, Christopher Mccoy, James E. Kirby
    Abstract:

    Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum (Cmax)/MIC was ≈10 or higher. Based on these findings, we suggest that Apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii.

  • Invitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa
    Diagnostic microbiology and infectious disease, 2017
    Co-Authors: Anthony D. Kang, Kenneth P. Smith, Anders H. Berg, George M. Eliopoulos, Christopher Mccoy, James E. Kirby
    Abstract:

    The in vitro activity of Apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32μg/ml for A. baumannii and 16/32μg/ml for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiological cutoff value of 64μg/ml. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256μg/ml for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, respectively, and the MIC50/MIC90 were ≥8/256μg/ml for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, respectively. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clinical study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chemistry exploration.

  • Evaluation of Apramycin activity against carbapenem-resistant and -susceptible strains of Enterobacteriaceae
    Diagnostic microbiology and infectious disease, 2016
    Co-Authors: Kenneth P. Smith, James E. Kirby
    Abstract:

    We evaluated activity of Apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clinical Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were Apramycin susceptible, which compared favorably to aminoglycosides in current clinical use. Our data suggest that Apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.

Kenneth P. Smith - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Apramycin against spectinomycin-resistant and -susceptible strains of Neisseria gonorrhoeae.
    The Journal of antimicrobial chemotherapy, 2019
    Co-Authors: Stefan Riedel, Divya Vijayakumar, Gretchen Berg, Anthony D. Kang, Kenneth P. Smith, James E. Kirby
    Abstract:

    Background The emergence of Neisseria gonorrhoeae resistant to all currently available antimicrobial therapies poses a dire public health threat. New antimicrobial agents with activity against N. gonorrhoeae are urgently needed. Apramycin is an aminocyclitol aminoglycoside with broad-spectrum in vitro activity against MDR Gram-negative pathogens and Staphylococcus aureus. However, its activity against N. gonorrhoeae has not been described. Objectives The activity spectrum of Apramycin against a collection of MDR N. gonorrhoeae was assessed. Isolates tested included those susceptible and resistant to the structurally distinct aminocyclitol, spectinomycin. Results The modal MICs for Apramycin and spectinomycin were 16 mg/L and 32 mg/L, respectively. The epidemiological cut-off (ECOFF) for Apramycin was 64 mg/L. No strains among 77 tested had an MIC above this ECOFF, suggesting very low levels of acquired Apramycin resistance. In time-kill analysis, Apramycin demonstrated rapid bactericidal activity comparable to that of spectinomycin. Conclusions Apramycin has broad-spectrum, rapidly bactericidal activity against N. gonorrhoeae. Future pharmacokinetic and pharmacodynamic studies will be needed to determine whether Apramycin and/or Apramycin derivatives hold promise as new therapeutics for N. gonorrhoeae infection.

  • Evaluation of Apramycin activity against methicillin-resistant, methicillin-sensitive, and vancomycin-intermediate Staphylococcus aureus clinical isolates.
    Diagnostic microbiology and infectious disease, 2018
    Co-Authors: Katherine A Truelson, Kenneth P. Smith, Thea Brennan-krohn, James E. Kirby
    Abstract:

    We evaluated the in vitro activity of Apramycin against clinical strains of vancomycin-intermediate and methicillin-resistant and -susceptible Staphylococcus aureus. Apramycin demonstrated an MIC50/MIC90 of 8/16 μg/mL. No strains had an MIC above the epidemiological cutoff value of 32 μg/mL, suggesting Apramycin resistance mechanisms are rare in this strain population. The mounting evidence for broad-spectrum in vitro activity of Apramycin against S. aureus and other bacterial species suggests that further exploration of Apramycin or derivatives as repurposed human therapeutics is warranted.

  • Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model.
    Antimicrobial agents and chemotherapy, 2018
    Co-Authors: Anthony D. Kang, Kenneth P. Smith, Katherine A Truelson, Anders H. Berg, George M. Eliopoulos, Christopher Mccoy, James E. Kirby
    Abstract:

    Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum (Cmax)/MIC was ≈10 or higher. Based on these findings, we suggest that Apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii.

  • Invitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa
    Diagnostic microbiology and infectious disease, 2017
    Co-Authors: Anthony D. Kang, Kenneth P. Smith, Anders H. Berg, George M. Eliopoulos, Christopher Mccoy, James E. Kirby
    Abstract:

    The in vitro activity of Apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32μg/ml for A. baumannii and 16/32μg/ml for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiological cutoff value of 64μg/ml. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256μg/ml for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, respectively, and the MIC50/MIC90 were ≥8/256μg/ml for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, respectively. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clinical study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chemistry exploration.

  • Evaluation of Apramycin activity against carbapenem-resistant and -susceptible strains of Enterobacteriaceae
    Diagnostic microbiology and infectious disease, 2016
    Co-Authors: Kenneth P. Smith, James E. Kirby
    Abstract:

    We evaluated activity of Apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clinical Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were Apramycin susceptible, which compared favorably to aminoglycosides in current clinical use. Our data suggest that Apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.

Malcolm J. Bennett - One of the best experts on this subject based on the ideXlab platform.

  • Human isolates of Apramycin-resistant Escherichia coli which contain the genes for the AAC(3)IV enzyme
    Epidemiology and infection, 1993
    Co-Authors: J. E. B. Hunter, C. A. Hart, J. C. Shelley, J. R. Walton, Malcolm J. Bennett
    Abstract:

    Gentamicin-resistant Escherichia coli isolated at different periods from patients in two hospitals were tested for resistance to the aminoglycoside antibiotic Apramycin. Twenty-four of 93 (26%) gentamicin-resistant isolates collected from the Royal Liverpool Hospital between 1981 and 1990 were resistant to Apramycin. Thirteen isolates were highly resistant to Apramycin (minimal inhibitory concentration (MIC) > or = 1024 micrograms/ml), were also resistant to gentamicin, netilmicin and tobramycin, and hybridized with a DNA probe derived from the aminoglycoside acetyltransferase (3)IV (AAC(3)IV) gene. The proportion of gentamicin-resistant isolates which had high level resistance to Apramycin increased from 7% in 1981-5 to 24% in 1986-90. Twelve gentamicin-resistant E. coli from Guy's and St Thomas's Hospital isolated between 1977 and 1980 were also tested for resistance to Apramycin. For five of these isolates the MICs of Apramycin was 32-256 micrograms/ml. None was shown to have a conjugative plasmid carrying resistance to Apramycin and only one hybridized with the DNA probe for the AAC(3)IV enzyme.

  • Apramycin resistance plasmids in Escherichia coli: possible transfer to Salmonella typhimurium in calves.
    Epidemiology and infection, 1992
    Co-Authors: J. E. B. Hunter, C. A. Hart, J. C. Shelley, J. R. Walton, Malcolm J. Bennett
    Abstract:

    An outbreak of salmonellosis in calves was monitored for persistence of Salmonella typhimurium excretion in faeces and the effect of treatment with Apramycin. Prior to treatment Apramycin-resistant Escherichia coli were present but all S. typhimurium isolates were sensitive. Following the treatment of six calves with Apramycin, Apramycin-resistant S. typhimurium were isolated from two treated calves and one untreated calf. Plasmid profiles of E. coli and S. typhimurium were compared and plasmids conferring resistance to Apramycin and several other antibiotics were transferred by conjugation in vitro from calf E. coli and S. typhimurium isolates to E. coli K-12 and from E. coli to S. typhimurium. The plasmids conjugated with high frequency in vitro from E. coli to S. typhimurium, and hybridized to a DNA probe specific for the gene encoding aminoglycoside acetyltransferase 3-IV (AAC(3)-IV) which confers resistance to Apramycin, gentamicin, netilmicin and tobramycin.

Shelley C. Rankin - One of the best experts on this subject based on the ideXlab platform.

  • Antimicrobial resistance of Salmonella enterica typhimurium DT104 isolates and investigation of strains with transferable Apramycin resistance.
    Epidemiology and infection, 1997
    Co-Authors: J. C. Low, M. Angus, G. Hopkins, Donald S. Munro, Shelley C. Rankin
    Abstract:

    An examination of salmonella isolates collected by the Scottish Agricultural College Veterinary Services Division from April 1994 to May 1995 was conducted to determine the extent to which Salmonella enterica serotype Typhimurium phage type 104 (DT104) occurred and to investigate the antimicrobial resistance patterns of isolates. Typhimurium DT104 was the predominant salmonella and was isolated from nine species of animal. All isolates of this phage type possessed resistance to at least one antimicrobial and 98% of the isolates were resistant to multiple antimicrobials with R-type ACTSp the predominant resistance pattern. Various other resistance patterns were identified and transferable resistance to the veterinary aminoglycoside antimicrobial Apramycin was demonstrated in three strains. A retrospective study for gentamicin resistance in isolates from the Scottish Salmonella Reference Laboratory collection revealed a human isolate of Typhimurium DT104 resistant to gentamicin but sensitive to Apramycin and a bovine isolate with Apramycin and gentamicin resistance.

J. E. B. Hunter - One of the best experts on this subject based on the ideXlab platform.

  • Human isolates of Apramycin-resistant Escherichia coli which contain the genes for the AAC(3)IV enzyme
    Epidemiology and infection, 1993
    Co-Authors: J. E. B. Hunter, C. A. Hart, J. C. Shelley, J. R. Walton, Malcolm J. Bennett
    Abstract:

    Gentamicin-resistant Escherichia coli isolated at different periods from patients in two hospitals were tested for resistance to the aminoglycoside antibiotic Apramycin. Twenty-four of 93 (26%) gentamicin-resistant isolates collected from the Royal Liverpool Hospital between 1981 and 1990 were resistant to Apramycin. Thirteen isolates were highly resistant to Apramycin (minimal inhibitory concentration (MIC) > or = 1024 micrograms/ml), were also resistant to gentamicin, netilmicin and tobramycin, and hybridized with a DNA probe derived from the aminoglycoside acetyltransferase (3)IV (AAC(3)IV) gene. The proportion of gentamicin-resistant isolates which had high level resistance to Apramycin increased from 7% in 1981-5 to 24% in 1986-90. Twelve gentamicin-resistant E. coli from Guy's and St Thomas's Hospital isolated between 1977 and 1980 were also tested for resistance to Apramycin. For five of these isolates the MICs of Apramycin was 32-256 micrograms/ml. None was shown to have a conjugative plasmid carrying resistance to Apramycin and only one hybridized with the DNA probe for the AAC(3)IV enzyme.

  • Apramycin resistance plasmids in Escherichia coli: possible transfer to Salmonella typhimurium in calves.
    Epidemiology and infection, 1992
    Co-Authors: J. E. B. Hunter, C. A. Hart, J. C. Shelley, J. R. Walton, Malcolm J. Bennett
    Abstract:

    An outbreak of salmonellosis in calves was monitored for persistence of Salmonella typhimurium excretion in faeces and the effect of treatment with Apramycin. Prior to treatment Apramycin-resistant Escherichia coli were present but all S. typhimurium isolates were sensitive. Following the treatment of six calves with Apramycin, Apramycin-resistant S. typhimurium were isolated from two treated calves and one untreated calf. Plasmid profiles of E. coli and S. typhimurium were compared and plasmids conferring resistance to Apramycin and several other antibiotics were transferred by conjugation in vitro from calf E. coli and S. typhimurium isolates to E. coli K-12 and from E. coli to S. typhimurium. The plasmids conjugated with high frequency in vitro from E. coli to S. typhimurium, and hybridized to a DNA probe specific for the gene encoding aminoglycoside acetyltransferase 3-IV (AAC(3)-IV) which confers resistance to Apramycin, gentamicin, netilmicin and tobramycin.