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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

TIVAR overview. (A) The standard 7–10 day antibiotic treatment regimen is sufficient to clear most bacterial infections. (B) Antibiotic treatment of persistent infections may be ineffective at controlling bacterial proliferation as certain host microenvironments may stimulate changes in the bacterium that result in the induction of transient resistance to high doses of antibiotics. This creates a major bacterial population that is transiently resistant to certain antibiotics, from which drug-resistant mutants may arise via established mutational mechanisms.
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f0040: TIVAR overview. (A) The standard 7–10 day antibiotic treatment regimen is sufficient to clear most bacterial infections. (B) Antibiotic treatment of persistent infections may be ineffective at controlling bacterial proliferation as certain host microenvironments may stimulate changes in the bacterium that result in the induction of transient resistance to high doses of antibiotics. This creates a major bacterial population that is transiently resistant to certain antibiotics, from which drug-resistant mutants may arise via established mutational mechanisms.

Mentions: Although the standard 7–10 day antibiotic treatment regimen is usually sufficient to clear microbial infections, some patients fail to respond and require prolonged therapy, higher dosing or alternative antibiotics. This is particularly confounding in cases involving immune competent individuals where bacterial ID and AST results predict drug sensitivity. Why does this occur and what are the possible implications? Although bacteria may be susceptible to antibiotics in the laboratory, certain host sites may present a unique biochemical environment that induces changes in the bacterium so they become transiently resistant to high doses of certain antibiotics (Fig. 7). This results in a large, transiently-resistant bacterial population from which permanent drug-resistant mutants may arise via standard mutational mechanisms. Supporting this hypothesis, Salmonella exhibited PMB resistance only when derived from a subset of host tissues (lung, liver, spleen), but not from other host tissues or from biological samples routinely used to detect bacterial infection (blood, feces, urine). PMB treatment failed to control bacterial infection in a murine model of typhoid fever and was associated with an increased frequency of permanent drug-resistant bacteria. This was presumably due to the increased lifespan of treated mice, allowing for additional rounds of bacterial replication, selection, and mutagenesis during antibiotic exposure. Additionally, due to cross resistance between polymyxins and host antimicrobials (Band and Weiss, 2014), exposure to host cationic antimicrobial peptides may provide selective pressure for drug-resistant mutants to arise as soon as a bacterial infection is established and long before antibiotic therapy is even started.


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)

TIVAR overview. (A) The standard 7–10 day antibiotic treatment regimen is sufficient to clear most bacterial infections. (B) Antibiotic treatment of persistent infections may be ineffective at controlling bacterial proliferation as certain host microenvironments may stimulate changes in the bacterium that result in the induction of transient resistance to high doses of antibiotics. This creates a major bacterial population that is transiently resistant to certain antibiotics, from which drug-resistant mutants may arise via established mutational mechanisms.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0040: TIVAR overview. (A) The standard 7–10 day antibiotic treatment regimen is sufficient to clear most bacterial infections. (B) Antibiotic treatment of persistent infections may be ineffective at controlling bacterial proliferation as certain host microenvironments may stimulate changes in the bacterium that result in the induction of transient resistance to high doses of antibiotics. This creates a major bacterial population that is transiently resistant to certain antibiotics, from which drug-resistant mutants may arise via established mutational mechanisms.
Mentions: Although the standard 7–10 day antibiotic treatment regimen is usually sufficient to clear microbial infections, some patients fail to respond and require prolonged therapy, higher dosing or alternative antibiotics. This is particularly confounding in cases involving immune competent individuals where bacterial ID and AST results predict drug sensitivity. Why does this occur and what are the possible implications? Although bacteria may be susceptible to antibiotics in the laboratory, certain host sites may present a unique biochemical environment that induces changes in the bacterium so they become transiently resistant to high doses of certain antibiotics (Fig. 7). This results in a large, transiently-resistant bacterial population from which permanent drug-resistant mutants may arise via standard mutational mechanisms. Supporting this hypothesis, Salmonella exhibited PMB resistance only when derived from a subset of host tissues (lung, liver, spleen), but not from other host tissues or from biological samples routinely used to detect bacterial infection (blood, feces, urine). PMB treatment failed to control bacterial infection in a murine model of typhoid fever and was associated with an increased frequency of permanent drug-resistant bacteria. This was presumably due to the increased lifespan of treated mice, allowing for additional rounds of bacterial replication, selection, and mutagenesis during antibiotic exposure. Additionally, due to cross resistance between polymyxins and host antimicrobials (Band and Weiss, 2014), exposure to host cationic antimicrobial peptides may provide selective pressure for drug-resistant mutants to arise as soon as a bacterial infection is established and long before antibiotic therapy is even started.

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