The Influence of Urine on the in vitro Antimicrobial Activity of Various Antibiotics against Different &lt;i&gt;Escherichia coli&lt;/i&gt; Phenotypes

Büyükbaba-Boral, Özden; Gönüllü, Nevriye; Küçükbasmacı, Ömer; Anğ-Küçüker, Mine; Anǧ, Özdem

doi:10.1159/000077283

Cited by 4 publications

(3 citation statements)

References 5 publications

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“…To study the potential impact that the physiological environment may have on phage-antibiotic interactions, medical simulators such as human urine and human serum were employed in place of the LB medium. Urine has been shown to increase the apparent MIC of E. coli to several classes of antibiotics ( 54 ), and this phenomenon was observed here. We also found that urine affected the efficacy of phages.…”

Section: Discussionsupporting

confidence: 70%

Phage-Antibiotic Synergy Is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

mBio

222

139

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a few studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real-time microtiter plate readout with a matrix-like heat map of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of extraintestinal pathogenic Escherichia coli (ExPEC) with antibiotic levels blanketing the MIC across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, two different related phages that differed in their burst sizes produced drastically different synograms. Collectively, these data suggest lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria while also synergizing with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. IMPORTANCE Bacteriophage (phage) therapy is a promising approach to combat the rise of multidrug-resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

show abstract

Section: Discussionsupporting

confidence: 70%

Phage-Antibiotic Synergy Is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

mBio

222

139

View full text Add to dashboard Cite

show abstract

“…To study the potential impact that the physiological environment may have on phage-antibiotic interactions, medical simulators such as human urine and human serum were employed in place of the LB media. Urine has been shown to increase the apparent MIC of E. coli to several classes of antibiotics (52), and this phenomenon was observed here. We also found that urine affected the efficacy of phages.…”

Section: The Host Physiological Environment Changes the Efficacy Of Passupporting

confidence: 71%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics.However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drugresistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism.Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

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“…Urine itself has a signifi cant effect on the bactericidal activity of antibiotics. MICs are usually elevated if they are determined in urine instead of the standard medium [9,10] . The susceptible bacteria had signifi cantly higher titers than resistant bacteria.…”

Section: Discussionmentioning

confidence: 99%

Urinary Bactericidal Activity of Oral Antibiotics against Common Urinary Tract Pathogens in an ex vivo Model

et al. 2006

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Background: In this investigation, the urine samples obtained in a single oral-dose pharmacokinetic study were examined for their bactericidal activity against a range of relevant urinary tract pathogens. Methods: Six healthy volunteers received a single oral dose of ten oral antibiotics available in Croatia. Urine samples were taken every 2 h during the whole dosing interval of the particular antibiotic. The urinary bactericidal activity was tested by determination of urinary bactericidal titers. Results: All antibiotics showed a significant urinary bactericidal activity against non-extended spectrum β-lactamase Escherichia coli and Proteus mirabilis. Fluoroquinolones displayed high and persisting levels of urinary bactericidal activity against all gram-negative bacteria and Staphylococcus saprophyticus. Conclusions: Average urinary bactericidal activity can be predicted from in vitro susceptibility testing, but we expect that there will be patients with a low level of urinary bactericidal activity.

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The Influence of Urine on the in vitro Antimicrobial Activity of Various Antibiotics against Different <i>Escherichia coli</i> Phenotypes

Cited by 4 publications

References 5 publications

Phage-Antibiotic Synergy Is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Phage-Antibiotic Synergy Is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Urinary Bactericidal Activity of Oral Antibiotics against Common Urinary Tract Pathogens in an ex vivo Model

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