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Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

Kubicek-Sutherland JZ, Heithoff DM, Ersoy SC, Shimp WR, House JK, Marth JD, Smith JW, Mahan MJ - EBioMedicine (2015)

Bottom Line: This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells.Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance.This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.

ABSTRACT
Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

No MeSH data available.


Related in: MedlinePlus

Antibiotic treatment is ineffective at controlling Salmonella infection and promotes the emergence of drug-resistant mutants. (A) BALB/c mice infected with TIVAR + S. Typhimurium 14028 or TIVAR − S. Typhimurium var. 5 (04)-9639 (i.p. dose 102 CFU) were treated (or mock-treated) with a twice-daily PMB or ciprofloxacin dosing regimen (30 mg/kg/day; i.p. route; 10 mice/cohort). Mouse survival was assessed for 10 days post-infection. Statistical significance for difference in proportions of animal survival was calculated using Chi-square; ***P < 0.001. (B) TIVAR + or TIVAR − Salmonella derived from overnight LB culture (in vitro) or from the spleens of septic mice (in vivo), obtained from untreated (day 5) and treated animals (TIVAR +, day 7; TIVAR −, day 10), were plated on LB medium containing PMB (16 μg/ml). TIVAR + S. Typhimurium MT2057 (kanamycin resistant derivative of S. Typhimurium 14028) and TIVAR − S. Typhimurium var. 5 (04)-9639 were used in these studies. Values given are the average mutation frequency (no. of PMBr colonies/total no. of colonies plated) ± SEM derived from 10 independent determinations. NA (not applicable): successful antibiotic treatment of mice infected with TIVAR − bacteria precluded recovery of PMBr mutants from these animals. Log transformed intracellular PMBr mutation frequency data were analyzed for statistical significance using ANOVA; ***P < 0.001.
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f0035: Antibiotic treatment is ineffective at controlling Salmonella infection and promotes the emergence of drug-resistant mutants. (A) BALB/c mice infected with TIVAR + S. Typhimurium 14028 or TIVAR − S. Typhimurium var. 5 (04)-9639 (i.p. dose 102 CFU) were treated (or mock-treated) with a twice-daily PMB or ciprofloxacin dosing regimen (30 mg/kg/day; i.p. route; 10 mice/cohort). Mouse survival was assessed for 10 days post-infection. Statistical significance for difference in proportions of animal survival was calculated using Chi-square; ***P < 0.001. (B) TIVAR + or TIVAR − Salmonella derived from overnight LB culture (in vitro) or from the spleens of septic mice (in vivo), obtained from untreated (day 5) and treated animals (TIVAR +, day 7; TIVAR −, day 10), were plated on LB medium containing PMB (16 μg/ml). TIVAR + S. Typhimurium MT2057 (kanamycin resistant derivative of S. Typhimurium 14028) and TIVAR − S. Typhimurium var. 5 (04)-9639 were used in these studies. Values given are the average mutation frequency (no. of PMBr colonies/total no. of colonies plated) ± SEM derived from 10 independent determinations. NA (not applicable): successful antibiotic treatment of mice infected with TIVAR − bacteria precluded recovery of PMBr mutants from these animals. Log transformed intracellular PMBr mutation frequency data were analyzed for statistical significance using ANOVA; ***P < 0.001.

Mentions: Polymyxin B is a last-line therapy to treat infections caused by multidrug-resistant Gram-negative bacteria in critically ill patients (Sandri et al., 2013; Zavascki et al., 2008). Thus, we evaluated whether PMB treatment was able to control TIVAR + Salmonella infection in a murine model of typhoid fever. All untreated mice infected with TIVAR + or TIVAR − bacteria died within 5 days of infection (Fig. 6A). PMB treated mice infected with TIVAR − bacteria survived at least 10 days post-infection, whereas all PMB treated mice infected with TIVAR + bacteria died within 7 days of infection (P < 0.001). Since the PMB dose given (30 mg/kg/day) was 6 to 20-fold higher than that used to treat human or experimental rat infections (1.5 to 5 mg/kg/day (Abdelraouf et al., 2012; Bergen et al., 2012; Landman et al., 2008)), human infection with TIVAR + bacteria would likely not be controlled by prescribed dosages. In contrast, ciprofloxacin (CIP) treated mice infected with TIVAR + Salmonella survived at least 10 days post-infection at dosages used to treat human or experimental mouse infections (30 mg/kg/day (Fantin et al., 2009; Guillard et al., 2013)). These data are consistent with the bacterium's susceptibility to CIP in MIC testing under LPM pH 5.5 conditions (Fig. 1A), and the drug's established intracellular activity (Carryn et al., 2003).


Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

Kubicek-Sutherland JZ, Heithoff DM, Ersoy SC, Shimp WR, House JK, Marth JD, Smith JW, Mahan MJ - EBioMedicine (2015)

Antibiotic treatment is ineffective at controlling Salmonella infection and promotes the emergence of drug-resistant mutants. (A) BALB/c mice infected with TIVAR + S. Typhimurium 14028 or TIVAR − S. Typhimurium var. 5 (04)-9639 (i.p. dose 102 CFU) were treated (or mock-treated) with a twice-daily PMB or ciprofloxacin dosing regimen (30 mg/kg/day; i.p. route; 10 mice/cohort). Mouse survival was assessed for 10 days post-infection. Statistical significance for difference in proportions of animal survival was calculated using Chi-square; ***P < 0.001. (B) TIVAR + or TIVAR − Salmonella derived from overnight LB culture (in vitro) or from the spleens of septic mice (in vivo), obtained from untreated (day 5) and treated animals (TIVAR +, day 7; TIVAR −, day 10), were plated on LB medium containing PMB (16 μg/ml). TIVAR + S. Typhimurium MT2057 (kanamycin resistant derivative of S. Typhimurium 14028) and TIVAR − S. Typhimurium var. 5 (04)-9639 were used in these studies. Values given are the average mutation frequency (no. of PMBr colonies/total no. of colonies plated) ± SEM derived from 10 independent determinations. NA (not applicable): successful antibiotic treatment of mice infected with TIVAR − bacteria precluded recovery of PMBr mutants from these animals. Log transformed intracellular PMBr mutation frequency data were analyzed for statistical significance using ANOVA; ***P < 0.001.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588393&req=5

f0035: Antibiotic treatment is ineffective at controlling Salmonella infection and promotes the emergence of drug-resistant mutants. (A) BALB/c mice infected with TIVAR + S. Typhimurium 14028 or TIVAR − S. Typhimurium var. 5 (04)-9639 (i.p. dose 102 CFU) were treated (or mock-treated) with a twice-daily PMB or ciprofloxacin dosing regimen (30 mg/kg/day; i.p. route; 10 mice/cohort). Mouse survival was assessed for 10 days post-infection. Statistical significance for difference in proportions of animal survival was calculated using Chi-square; ***P < 0.001. (B) TIVAR + or TIVAR − Salmonella derived from overnight LB culture (in vitro) or from the spleens of septic mice (in vivo), obtained from untreated (day 5) and treated animals (TIVAR +, day 7; TIVAR −, day 10), were plated on LB medium containing PMB (16 μg/ml). TIVAR + S. Typhimurium MT2057 (kanamycin resistant derivative of S. Typhimurium 14028) and TIVAR − S. Typhimurium var. 5 (04)-9639 were used in these studies. Values given are the average mutation frequency (no. of PMBr colonies/total no. of colonies plated) ± SEM derived from 10 independent determinations. NA (not applicable): successful antibiotic treatment of mice infected with TIVAR − bacteria precluded recovery of PMBr mutants from these animals. Log transformed intracellular PMBr mutation frequency data were analyzed for statistical significance using ANOVA; ***P < 0.001.
Mentions: Polymyxin B is a last-line therapy to treat infections caused by multidrug-resistant Gram-negative bacteria in critically ill patients (Sandri et al., 2013; Zavascki et al., 2008). Thus, we evaluated whether PMB treatment was able to control TIVAR + Salmonella infection in a murine model of typhoid fever. All untreated mice infected with TIVAR + or TIVAR − bacteria died within 5 days of infection (Fig. 6A). PMB treated mice infected with TIVAR − bacteria survived at least 10 days post-infection, whereas all PMB treated mice infected with TIVAR + bacteria died within 7 days of infection (P < 0.001). Since the PMB dose given (30 mg/kg/day) was 6 to 20-fold higher than that used to treat human or experimental rat infections (1.5 to 5 mg/kg/day (Abdelraouf et al., 2012; Bergen et al., 2012; Landman et al., 2008)), human infection with TIVAR + bacteria would likely not be controlled by prescribed dosages. In contrast, ciprofloxacin (CIP) treated mice infected with TIVAR + Salmonella survived at least 10 days post-infection at dosages used to treat human or experimental mouse infections (30 mg/kg/day (Fantin et al., 2009; Guillard et al., 2013)). These data are consistent with the bacterium's susceptibility to CIP in MIC testing under LPM pH 5.5 conditions (Fig. 1A), and the drug's established intracellular activity (Carryn et al., 2003).

Bottom Line: This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells.Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance.This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.

ABSTRACT
Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

No MeSH data available.


Related in: MedlinePlus