Re-evaluation of FDA-approved antibiotics with increased diagnostic accuracy for assessment of antimicrobial resistance

Heithoff, Douglas M.; Barnes, Lucien; Mahan, Scott; Fried, Jeffrey; Fitzgibbons, Lynn; House, John K.; Mahan, Michael J.

doi:10.1016/j.xcrm.2023.101023

Cited by 9 publications

(12 citation statements)

References 64 publications

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“…Here, strain-specific differences in susceptibility to antibiotics were observed when E. faecalis isolates were grown in SSF compared to control conditions. This supports the broader idea that environmental conditions and media choice may impact antibiotic efficacy, which underscores the need to pursue susceptibility testing in conditions that closely resemble the host region [49][50][51][52] . In conclusion, our findings provide the first evidence of genetic heterogeneity among E. faecalis PJI isolates along with strain-specific differences in biofilm morphology and antibiotic resistance when grown in SSF.…”

Section: Discussionsupporting

confidence: 59%

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Genotypic and phenotypic characterization ofEnterococcus faecalisisolates from periprosthetic joint infections

Haeberle,

Greenwood-Quaintance,

Zar

et al. 2024

Preprint

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Over 2.5 million prosthetic joint implantation surgeries occur annually in the United States. Periprosthetic joint infections (PJIs), though occurring in only 1-2% of patients receiving replacement joints, are challenging to diagnose and treat and are associated with significant morbidity. The Gram-positive bacteriumEnterococcus faecalis, which can be highly antibiotic resistant and is a robust biofilm producer on indwelling medical devices, accounts for 2-11% of PJIs.E. faecalisPJIs are understudied compared to those caused by other pathogens, such asStaphylococcus aureus. This motivates the need to generate a comprehensive understanding ofE. faecalisPJIs to guide future treatments for these infections. To address this, we describe a panel ofE. faecalisstrains isolated from the surface of prosthetic joints in a cohort of individuals treated at Mayo Clinic in Rochester, MN. Here, we present the first complete genome assemblage ofE. faecalisPJI isolates. Comparative genomics shows differences in genome size, virulence factors, antimicrobial resistance genes, plasmids, and prophages, underscoring the genetic diversity of these strains. These isolates have strain-specific differences inin vitrobiofilm biomass, biofilm burden, and biofilm morphology. We measured robust changes in biofilm architecture and aggregation for all isolates when grown in simulated synovial fluid (SSF). Lastly, we evaluated antibiotic efficacy of these isolates and found strain specific changes across all strains when grown in SSF. Results of this study highlight the existence of genetic and phenotypic heterogeneity amongE. faecalisPJI isolates which will provide valuable insight and resources for futureE. faecalisPJI research.ImportancePeriprosthetic joint infections (PJIs) affect ∼1-2% of those who undergo joint replacement surgery.Enterococcus faecalisis a Gram-positive opportunistic pathogen that causes ∼10% of PJIs in the United States each year, but our understanding of how and whyE. faecaliscauses PJIs is limited.E. faecalisinfections are typically biofilm associated and can be difficult to clear with antibiotic therapy. Here, we provide complete genomes for fourE. faecalisPJI isolates from the Mayo Clinic. These isolates have strain-specific differences in biofilm formation, aggregation, and antibiotic susceptibility in simulated synovial fluid. These results provide important insight into genomic and phenotypic features ofE. faecalisisolates from PJI.

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Section: Discussionsupporting

confidence: 59%

“…Briefly, explanted prostheses from subjects undergoing arthroplasty resection due to PJI were placed in Ringer’s solution. Biofilms were removed using a previously published protocol for vortexing and sonication 53 . E. faecalis was cultured from resulting sonicate fluids and frozen in a microbank (Prolabs) at -80°C.…”

Section: Methodsmentioning

confidence: 99%

Genotypic and phenotypic characterization ofEnterococcus faecalisisolates from periprosthetic joint infections

Haeberle,

Greenwood-Quaintance,

Zar

et al. 2024

Preprint

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, the host microenvironment has been shown to affect antibiotic efficacy ( 68 ), and testing in media which mimics the in vivo physiological conditions of the host may increase the accuracy of MIC prediction ( 69 ). To account for this, we also determined the MIC and MBC of VesiX CPC in pooled human urine supplemented with 30% (vol/vol) MHB ( 69 ) ( Table 3 ). A twofold increase in MIC and MBC of VesiX CPC was observed for UPEC UTI89, E. faecalis ATCC 29212, P. mirabilis H14320, and K. pneumoniae TOP52 1721 in pooled human urine compared to MHB medium.…”

Section: Resultsmentioning

confidence: 99%

VesiX cetylpyridinium chloride is rapidly bactericidal and reduces uropathogenic Escherichia coli bladder epithelial cell invasion in vitro

Sawant,

Chang,

Pandit

et al. 2024

Microbiol Spectr

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Management of urinary tract infection (UTI) in postmenopausal women can be challenging. The recent rise in resistance to most of the available oral antibiotic options together with high recurrence rate in postmenopausal women has further complicated treatment of UTI. As such, intravesical instillations of antibiotics like gentamicin are being investigated as an alternative to oral antibiotic therapies. This study evaluates the efficacy of the candidate intravesical therapeutic VesiX, a solution containing the cationic detergent Cetylpyridinium chloride, against a broad range of uropathogenic bacterial species clinically isolated from postmenopausal women with recurrent UTI (rUTI). We also evaluate the cytotoxicity of VesiX against cultured bladder epithelial cells and find that low concentrations of 0.0063% and 0.0125% provide significant bactericidal effect toward diverse bacterial species including uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae , Enterococcus faecalis , Pseudomonas aeruginosa , and Proteus mirabilis while minimizing cytotoxic effects against cultured 5637 bladder epithelial cells. Lastly, to begin to evaluate the potential utility of using VesiX in combination therapy with existing intravesical therapies for rUTI, we investigate the combined effects of VesiX and the intravesical antibiotic gentamicin. We find that VesiX and gentamicin are not antagonistic and are able to reduce levels of intracellular UPEC in cultured bladder epithelial cells. IMPORTANCE When urinary tract infections (UTIs), which affect over 50% of women, become resistant to available antibiotic therapies dangerous complications like kidney infection and lethal sepsis can occur. New therapeutic paradigms are needed to expand our arsenal against these difficult to manage infections. Our study investigates VesiX, a Cetylpyridinium chloride (CPC)-based therapeutic, as a candidate broad-spectrum antimicrobial agent for use in bladder instillation therapy for antibiotic-resistant UTI. CPC is a cationic surfactant that is FDA-approved for use in mouthwashes and is used as a food additive but has not been extensively evaluated as a UTI therapeutic. Our study is the first to investigate its rapid bactericidal kinetics against diverse uropathogenic bacterial species isolated from postmenopausal women with recurrent UTI and host cytotoxicity. We also report that together with the FDA-approved bladder-instillation agent gentamicin, VesiX was able to significantly reduce intracellular populations of uropathogenic bacteria in cultured bladder epithelial cells.

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“…To capitalize on this to improve the accuracy of antibiotic testing, some groups have started exploring antibiotic testing in host-mimicking media. These media range from supplementing synthetic media with key in vivo molecules such as sodium bicarbonate ( 27 ), to using human serum, urine, or synovial fluid to replicate some aspect of the infection environment ( 28 – 31 ). Using mimetic media can better replicate the complex interplay between the infection environment and aspects of bacterial genetics ( 30 ), physiology ( 31 ), or phenotypic variability ( 32 ) that can lead to alterations in antibiotic susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

Davis,

Morales,

Ende

et al. 2024

mBio

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The rise in infections caused by multidrug-resistant (MDR) bacteria has necessitated a variety of clinical approaches, including the use of antibiotic combinations. Here, we tested the hypothesis that drug-drug interactions vary in different media, and determined which in vitro models best predict drug interactions in the lungs. We systematically studied pair-wise antibiotic interactions in three different media, CAMHB, (a rich lab medium standard for antibiotic susceptibility testing), a urine mimetic medium (UMM), and a minimal medium of M9 salts supplemented with glucose and iron (M9Glu) with three Gram-negative ESKAPE pathogens, Acinetobacter baumannii (Ab), Klebsiella pneumoniae (Kp), and Pseudomonas aeruginosa (Pa). There were pronounced differences in responses to antibiotic combinations between the three bacterial species grown in the same medium. However, within species, PaO1 responded to drug combinations similarly when grown in all three different media, whereas Ab17978 and other Ab clinical isolates responded similarly when grown in CAMHB and M9Glu medium. By contrast, drug interactions in Kp43816, and other Kp clinical isolates poorly correlated across different media. To assess whether any of these media were predictive of antibiotic interactions against Kp in the lungs of mice, we tested three antibiotic combination pairs. In vitro measurements in M9Glu, but not rich medium or UMM, predicted in vivo outcomes. This work demonstrates that antibiotic interactions are highly variable across three Gram-negative pathogens and highlights the importance of growth medium by showing a superior correlation between in vitro interactions in a minimal growth medium and in vivo outcomes. IMPORTANCE Drug-resistant bacterial infections are a growing concern and have only continued to increase during the SARS-CoV-2 pandemic. Though not routinely used for Gram-negative bacteria, drug combinations are sometimes used for serious infections and may become more widely used as the prevalence of extremely drug-resistant organisms increases. To date, reliable methods are not available for identifying beneficial drug combinations for a particular infection. Our study shows variability across strains in how drug interactions are impacted by growth conditions. It also demonstrates that testing drug combinations in tissue-relevant growth conditions for some strains better models what happens during infection and may better inform combination therapy selection.

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Re-evaluation of FDA-approved antibiotics with increased diagnostic accuracy for assessment of antimicrobial resistance

Cited by 9 publications

References 64 publications

Genotypic and phenotypic characterization ofEnterococcus faecalisisolates from periprosthetic joint infections

Genotypic and phenotypic characterization ofEnterococcus faecalisisolates from periprosthetic joint infections

VesiX cetylpyridinium chloride is rapidly bactericidal and reduces uropathogenic Escherichia coli bladder epithelial cell invasion in vitro

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

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