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Excess length of hospital stay, mortality and cost attributable to Clostridioides (Clostridium) difficile infection and recurrence: a nationwide analysis in Japan.

ABSTRACT: Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of infectious diarrhoea in hospitalised patients, representing a substantial economic burden driven mainly by increased length of hospital stay (LoS). Currently in Japan, limited evidence on CDI-associated excess LoS is available. We conducted a retrospective, matched-cohort study using a large, Japanese, hospital-based administrative database. CDI was defined as CDI treatment plus either CDI diagnosis or positive enzyme immunoassay result. Propensity score matching at the time of CDI or recurrent CDI (rCDI) onset was applied to adjust baseline confounding and immortal time bias. The analysis included 5 994 054 hospitalisation records during 2008-2017, of which 11 823 were identified as CDI and 1359 as rCDI. The median excess LoS attributable to CDI and rCDI was 3 days and 6.5 days, respectively. The excess mortality attributable to CDI was 6.9%; there was no excess mortality attributable to rCDI (-1.9%). The median difference in costs attributable to CDI and rCDI during the residual stay was JPY 130 296 (USD 1185) and JPY 81 054 (USD 737) per hospitalisation, respectively. By adjusting the biases, the burden of CDI in Japan was evaluated. The findings could support decision making and resource allocation for CDI management in Japanese hospitals.

SUBMITTER: Kimura T

PROVIDER: S-EPMC7118723 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Excess length of hospital stay, mortality and cost attributable to Clostridioides (Clostridium) difficile infection and recurrence: a nationwide analysis in Japan.

Kimura T T Stanhope S S Sugitani T T

Epidemiology and infection 20200302

Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of infectious diarrhoea in hospitalised patients, representing a substantial economic burden driven mainly by increased length of hospital stay (LoS). Currently in Japan, limited evidence on CDI-associated excess LoS is available. We conducted a retrospective, matched-cohort study using a large, Japanese, hospital-based administrative database. CDI was defined as CDI treatment plus either CDI diagnosis or positive enzyme ...[more]

PMID: 32115019

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Project description:BackgroundClostridioides difficile infection (CDI) is the most common hospital acquired infection in the USA, with recurrence rates > 15%. Although primary CDI has been extensively linked to gut microbial dysbiosis, less is known about the factors that promote or mitigate recurrence. Moreover, previous studies have not shown that microbial abundances in the gut measured by 16S rRNA amplicon sequencing alone can accurately predict CDI recurrence.ResultsWe conducted a prospective, longitudinal study of 53 non-immunocompromised participants with primary CDI. Stool sample collection began pre-CDI antibiotic treatment at the time of diagnosis, and continued up to 8 weeks post-antibiotic treatment, with weekly or twice weekly collections. Samples were analyzed using (1) 16S rRNA amplicon sequencing, (2) liquid chromatography/mass-spectrometry metabolomics measuring 1387 annotated metabolites, and (3) short-chain fatty acid profiling. The amplicon sequencing data showed significantly delayed recovery of microbial diversity in recurrent participants, and depletion of key anaerobic taxa at multiple time-points, including Clostridium cluster XIVa and IV taxa. The metabolomic data also showed delayed recovery in recurrent participants, and moreover mapped to pathways suggesting distinct functional abnormalities in the microbiome or host, such as decreased microbial deconjugation activity, lowered levels of endocannabinoids, and elevated markers of host cell damage. Further, using predictive statistical/machine learning models, we demonstrated that the metabolomic data, but not the other data sources, can accurately predict future recurrence at 1 week (AUC 0.77 [0.71, 0.86; 95% interval]) and 2 weeks (AUC 0.77 [0.69, 0.85; 95% interval]) post-treatment for primary CDI.ConclusionsThe prospective, longitudinal, and multi-omic nature of our CDI recurrence study allowed us to uncover previously unrecognized dynamics in the microbiome and host presaging recurrence, and, in particular, to elucidate changes in the understudied gut metabolome. Moreover, we demonstrated that a small set of metabolites can accurately predict future recurrence. Our findings have implications for development of diagnostic tests and treatments that could ultimately short-circuit the cycle of CDI recurrence, by providing candidate metabolic biomarkers for diagnostics development, as well as offering insights into the complex microbial and metabolic alterations that are protective or permissive for recurrence. Video Abstract.

Project description:Clostridioides (Clostridium) difficile is an opportunistic pathogen known for its ability to colonize the human gut under conditions of dysbiosis. Several aspects of its carbon and amino acid metabolism have been investigated, but its cobamide (vitamin B12 and related cofactors) metabolism remains largely unexplored. C. difficile has seven predicted cobamide-dependent pathways encoded in its genome in addition to a nearly complete cobamide biosynthesis pathway and a cobamide uptake system. To address the importance of cobamides to C. difficile, we studied C. difficile 630 Δerm and mutant derivatives under cobamide-dependent conditions in vitro Our results show that C. difficile can use a surprisingly diverse array of cobamides for methionine and deoxyribonucleotide synthesis and can use alternative metabolites or enzymes, respectively, to bypass these cobamide-dependent processes. C. difficile 630 Δerm produces the cobamide pseudocobalamin when provided the early precursor 5-aminolevulinic acid or the late intermediate cobinamide (Cbi) and produces other cobamides if provided an alternative lower ligand. The ability of C. difficile 630 Δerm to take up cobamides and Cbi at micromolar or lower concentrations requires the transporter BtuFCD. Genomic analysis revealed genetic variations in the btuFCD loci of different C. difficile strains, which may result in differences in the ability to take up cobamides and Cbi. These results together demonstrate that, like other aspects of its physiology, cobamide metabolism in C. difficile is versatile.IMPORTANCE The ability of the opportunistic pathogen Clostridioides difficile to cause disease is closely linked to its propensity to adapt to conditions created by dysbiosis of the human gut microbiota. The cobamide (vitamin B12) metabolism of C. difficile has been underexplored, although it has seven metabolic pathways that are predicted to require cobamide-dependent enzymes. Here, we show that C. difficile cobamide metabolism is versatile, as it can use a surprisingly wide variety of cobamides and has alternative functions that can bypass some of its cobamide requirements. Furthermore, C. difficile does not synthesize cobamides de novo but produces them when given cobamide precursors. A better understanding of C. difficile cobamide metabolism may lead to new strategies to treat and prevent C. difficile-associated disease.

Dataset Information

Excess length of hospital stay, mortality and cost attributable to Clostridioides (Clostridium) difficile infection and recurrence: a nationwide analysis in Japan.

Publications

Excess length of hospital stay, mortality and cost attributable to <i>Clostridioides</i> (<i>Clostridium</i>) <i>difficile</i> infection and recurrence: a nationwide analysis in Japan.

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