Fidaxomicin reduces early toxin A and B production and sporulation in Clostridium difficile
            in vitro

Aldape, Michael J.; Packham, Aaron E.; Heeney, Dustin; Rice, Savannah Nicole; Bryant, Amy E.; Stevens, Dennis L.

doi:10.1099/jmm.0.000580

Cited by 10 publications

(12 citation statements)

References 18 publications

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“…For this experiment, we employed fidaxomicin (MIC = 0.125 μg/mL; Table 1 ) as a positive control and subsequently noted a substantial reduction in TcdA levels at all sub-MICs ( Figure 2 b), which is consistent with its reported toxin-suppressing activity. 36 , 37 Additionally, we were curious to see if vancomycin (MIC = 1 μg/mL; Table 1 )—a CDI therapeutic that is not expected to modulate toxin production—would have any effect on TcdA levels in our assay. Treating vancomycin as a type of negative control, we repeated the experiment and were surprised to see a partial reduction in toxin levels at 1 μg/mL ( Figure 2 c).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Derivatives of (+)-Puupehenone against Clostridioides difficile and Other Gram-Positive Bacteria

Johnstone

Landgraf

et al. 2022

ACS Omega

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Patients receiving healthcare are at higher risk of acquiring healthcare-associated infections, which cause a significant number of illnesses and deaths. Most pathogens responsible for these infections are highly resistant to multiple antibiotics, prompting the need for discovery of new therapeutics to combat these evolved threats. We synthesized structural derivatives of (+)-puupehenone, a marine natural product, and observed growth inhibition of several clinically relevant Gram-positive bacteria, particularly Clostridioides difficile . The most potent compounds—(+)-puupehenone, 1 , 15 , 19 , and 20 —all inhibited C. difficile in the range of 2.0–4.0 μg/mL. Additionally, when present in the range of 1–8 μg/mL, a subset of active compounds—(+)-puupehenone, 1 , 6 , 15 , and 20 —greatly reduced the ability of C. difficile to produce exotoxins, which are required for disease in infected hosts. Our findings showcase a promising class of compounds for potential drug development against Gram-positive pathogens, such as C. difficile .

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Section: Resultsmentioning

confidence: 99%

Evaluation of Derivatives of (+)-Puupehenone against Clostridioides difficile and Other Gram-Positive Bacteria

Johnstone

Landgraf

et al. 2022

ACS Omega

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“…Regarding other particular characteristics, fidaxomicin and its metabolite OP-1118, differently from vancomycin, are able to inhibit sporulation (spore formation) of C. difficile , a fact which is thought to contribute to the observed increased rates of sustained response and reduced risk of recurrence in comparisons with other treatments (see the following section), since spores may persist after completion of a successful treatment course and subsequently germinate and proliferate, leading to a novel CDI episode [ 54 , 55 , 56 ]. After spores are formed, fidaxomicin, like vancomycin, is unable to inhibit germination, but both agents are able to counteract the outgrowth of vegetative cells from germinating spores [ 57 ].…”

Section: Characteristics Mechanism Of Action and Antimicrobial Activi...mentioning

confidence: 99%

“…However, fidaxomicin, but not vancomycin, has been demonstrated to persist on C. difficile spores after washing in saline and fecal filtrate, with consequent higher inhibitory effect on the outgrowth of vegetative cells and toxin production [ 58 , 59 ]. A substantial direct inhibitory effect of fidaxomicin and OP-1118 on toxin production may also explain the less frequent detection of post-treatment toxin production in fidaxomicin-treated patients than in vancomycin-treated patients [ 56 , 60 , 61 ]. A reduction in toxin A- and toxin B-mediated inflammatory responses and colonic tissue damage has also been described following exposure to fidaxomicin [ 62 , 63 ].…”

Section: Characteristics Mechanism Of Action and Antimicrobial Activi...mentioning

confidence: 99%

Fidaxomicin for the Treatment of Clostridioides difficile Infection in Adult Patients: An Update on Results from Randomized Controlled Trials

et al. 2022

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In recently updated international guidelines, fidaxomicin is preferentially recommended as first-line treatment over vancomycin both for the first episode of CDI and for rCDI, based on the results of different randomized controlled trials (RCTs). Although noninferiority was the rule in phase-3 RCTs with regard to the primary endpoint of clinical cure, for shaping these recommendations, particular attention was devoted to the improved global cure and reduced risk of recurrent CDI (rCDI) observed with fidaxomicin compared to vancomycin in RCTs. Overall, while the major driver of choice should remain the global benefit for the patient, consideration of available resources should be necessarily weighed in the balance, since fidaxomicin still remains more costly than vancomycin. Against this background, precisely stratifying risk groups for rCDI will represent a crucial research trajectory of future real-life studies on the treatment of first CDI episodes. In the current narrative review, we discuss the updated evidence from RCTs on the efficacy of fidaxomicin for the treatment of either the first CDI episode or rCDI, which eventually supports its positioning within current treatment algorithms and guidelines.

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“…In fact, analysis of a subset of 89 patients from the phase 3 trial108 showed that major components of the microbiome persisted after fidaxomicin administration, whereas vancomycin was associated with a further 2-4 log 10 reduction in colony forming units of Bacteroidetes/Prevotella group organisms 109. Among the other potential mechanisms, a reduction in toxin A and B production could also be involved 110. Finally, fidaxomicin was also shown to improve control of environmental contamination with C difficile.…”

Section: Treatmentmentioning

confidence: 99%

Clostridioides difficile: diagnosis and treatments

Guery

Galpérine

Barbut

2019

BMJ

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Clostridioides difficile (formerly Clostridium) is a major cause of healthcare associated diarrhea, and is increasingly present in the community. Historically, C difficile infection was considered easy to diagnose and treat. Over the past two decades, however, diagnostic techniques have changed in line with a greater understanding of the physiopathology of C difficile infection and the use of new therapeutic molecules. The evolution of diagnosis showed there was an important under- and misdiagnosis of C difficile infection, emphasizing the importance of algorithms recommended by European and North American infectious diseases societies to obtain a reliable diagnosis. Previously, metronidazole was considered the reference drug to treat C difficile infection, but more recently vancomycin and other newer drugs are shown to have higher cure rates. Recurrence of infection represents a key parameter in the evaluation of new drugs, and the challenge is to target the right population with the adapted therapeutic molecule. In multiple recurrences, fecal microbiota transplantation is recommended. New approaches, including antibodies, vaccines, and new molecules are already available or in the pipeline, but more data are needed to support the inclusion of these in practice guidelines. This review aims to provide a baseline for clinicians to understand and stratify their choice in the diagnosis and treatment of C difficile infection based on the most recent data available.

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Fidaxomicin reduces early toxin A and B production and sporulation in Clostridium difficile in vitro

Abstract: The ability of fidaxomicin to suppress early exotoxin production and endospore formation by historical and epidemic strains of C. difficile may explain its clinical success in treating severe and recurrent cases of CDI disease.

Cited by 10 publications

References 18 publications

Evaluation of Derivatives of (+)-Puupehenone against Clostridioides difficile and Other Gram-Positive Bacteria

Evaluation of Derivatives of (+)-Puupehenone against Clostridioides difficile and Other Gram-Positive Bacteria

Fidaxomicin for the Treatment of Clostridioides difficile Infection in Adult Patients: An Update on Results from Randomized Controlled Trials

Clostridioides difficile: diagnosis and treatments

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