Nitrofurantoin: what is the evidence for current UK guidance?

Kashouris, Eleanor; Joseph, Amelia; Lewis, Tom

doi:10.1093/jac/dkad287

Cited by 3 publications

References 35 publications

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Improving Nitrofurantoin Resistance Prediction inEscherichia colifrom Whole Genome Sequence by Integrating NfsA/B Enzyme Assays

Dulyayangkul,

Sealey,

Lee

et al. 2024

Preprint

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Nitrofurantoin resistance in Escherichia coli is primarily caused by mutations damaging two enzymes, NfsA and NfsB. Studies based on small isolate collections with defined nitrofurantoin MICs have found significant random genetic drift in nfsA and nfsB making it extremely difficult to predict nitrofurantoin resistance from whole genome sequence (WGS) where both genes are not obviously disrupted by nonsense or frameshift mutations or insertional inactivation. Here we report a WGS survey of 200 E. coli from community urine samples, of which 34 were nitrofurantoin resistant. We characterised individual non-synonymous mutations seen in nfsA and nfsB among this collection using complementation cloning and assays of NfsA/B enzyme activity in cell extracts. We definitively identified R203C, H11Y, W212R, A112E, A112T and A122T in NfsA and R121C, Q142H, F84S, P163H, W46R, K57E and V191G in NfsB as amino acid substitutions that reduce enzyme activity sufficiently to cause resistance. In contrast, E58D, I117T, K141E, L157F, A172S, G187D and A188V in NfsA and G66D, M75I, V93A and A174E in NfsB, are functionally silent in this context. We identified that 9/166 (5.4%) of nitrofurantoin susceptible isolates were pre-resistant, defined as having loss of function mutations in nfsA or nfsB. Finally, using NfsA/B enzyme activity assay and proteomics we demonstrated that 9/34 (26.5%) of nitrofurantoin resistant isolates carried functionally wild-type nfsB or nfsB/nfsA. In these cases, enzyme activity was reduced through downregulated gene expression. Our biological understanding of nitrofurantoin resistance is greatly improved by this analysis, but is still insufficient to allow its reliable prediction from WGS data.

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Improving Nitrofurantoin Resistance Prediction inEscherichia colifrom Whole Genome Sequence by Integrating NfsA/B Enzyme Assays

Dulyayangkul,

Sealey,

Lee

et al. 2024

Preprint

View full text Add to dashboard Cite

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‘When all you have is a hammer, everything has to be a nail’: Managing diagnostic uncertainty in urinary tract infection

Kashouris

2024

Sociology Health & Illness

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Diagnosis of urinary tract infections (UTI) is a routine part of medical work and yet is well recognised to be an area of high clinical uncertainty. Meanwhile, diagnosis of UTI is becoming increasingly important to policymakers globally due to concerns about antibiotic over‐prescription. Drawing on Mol’s concept of ontological multiplicity in clinical work, I explore how diagnostic uncertainty is co‐ordinated into certainty by a UK national diagnostic algorithm for UTI. The diagnosis of UTI is produced or withheld as a post hoc rationalisation of a prior decision whether to prescribe antibiotics or not. Work in the sociology of diagnosis has already noted that diagnostic steps are often re‐ordered by health‐care professionals taking diverse actions in the best interest of their patients. This article contributes an argument that ordering diagnostic work around antimicrobial stewardship agendas has the effect of narrowing possible actions. Exploring the consequences and effects of doing diagnosis in this way for different groups, I argue that a greater creativity about what could be done to care for painful bladders could be found in a return to more clinical ways of working.

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Improving nitrofurantoin resistance prediction in Escherichia coli from whole-genome sequence by integrating NfsA/B enzyme assays

Dulyayangkul,

Sealey,

Lee

et al. 2024

Antimicrob Agents Chemother

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Nitrofurantoin resistance in Escherichia coli is primarily caused by mutations damaging two enzymes, NfsA and NfsB. Studies based on small isolate collections with defined nitrofurantoin MICs have found significant random genetic drift in nfsA and nfsB , making it extremely difficult to predict nitrofurantoin resistance from whole-genome sequence (WGS) where both genes are not obviously disrupted by nonsense or frameshift mutations or insertional inactivation. Here, we report a WGS survey of 200 oqxAB -negative E. coli from community urine samples, of which 34 were nitrofurantoin resistant. We characterized individual non-synonymous mutations seen in nfsA and nfsB among this collection using complementation cloning and NfsA/B enzyme assays in cell extracts. We definitively identified R203C, H11Y, W212R, A112E, and A112T in NfsA and R121C, Q142H, F84S, P163H, W46R, K57E, and V191G in NfsB as amino acid substitutions that reduce enzyme activity sufficiently to cause resistance. In contrast, E58D, I117T, K141E, L157F, A172S, G187D, and A188V in NfsA and G66D, M75I, V93A, and A174E in NfsB are functionally silent in this context. We identified that 9/166 (5.4%) nitrofurantoin-susceptible isolates were “pre-resistant,” defined as having loss of function mutations in nfsA or nfsB . Finally, using NfsA/B enzyme assays and proteomics, we demonstrated that 9/34 (26.5%) ribE wild-type nitrofurantoin-resistant isolates also carried functionally wild-type nfsB or nfsB / nfsA . In these cases, NfsA/B activity was reduced through downregulated gene expression. Our biological understanding of nitrofurantoin resistance is greatly improved by this analysis but is still insufficient to allow its reliable prediction from WGS data.

show abstract

Nitrofurantoin: what is the evidence for current UK guidance?

Cited by 3 publications

References 35 publications

Improving Nitrofurantoin Resistance Prediction inEscherichia colifrom Whole Genome Sequence by Integrating NfsA/B Enzyme Assays

Improving Nitrofurantoin Resistance Prediction inEscherichia colifrom Whole Genome Sequence by Integrating NfsA/B Enzyme Assays

‘When all you have is a hammer, everything has to be a nail’: Managing diagnostic uncertainty in urinary tract infection

Improving nitrofurantoin resistance prediction in Escherichia coli from whole-genome sequence by integrating NfsA/B enzyme assays

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