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Clostridioides difficile infection: are the three currently used antibiotic treatment options equal from pharmacological and microbiological points of view?

  • Marcela Krutova
    Correspondence
    Corresponding author: Krutova Marcela, Department of Medical Microbiology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06 Prague 5, Czech Republic, Tel: +420 732 532 499.
    Affiliations
    Department of Medical Microbiology, 2nd Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic

    European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study group for Clostridioides difficile (ESGCD), Basel, Switzerland
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  • Mark Wilcox
    Affiliations
    European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study group for Clostridioides difficile (ESGCD), Basel, Switzerland

    Healthcare Associated Infection Research Group, Leeds Teaching Hospitals National Health Service (NHS) Trust & University of Leeds, Leeds, United Kingdom
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  • Ed Kuijper
    Affiliations
    European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study group for Clostridioides difficile (ESGCD), Basel, Switzerland

    Department of Medical Microbiology and National Expertise Centre for Clostridioides difficile infection, Leiden University Medical Centre and National Institute for Public Health and the Environment, Leiden, Netherlands

    European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study group for Host and Microbiota Interaction (ESGHAMI), Basel, Switzerland
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Open AccessPublished:September 22, 2022DOI:https://doi.org/10.1016/j.ijid.2022.09.013

      Highlights

      • Oral administration of metronidazole results in low concentration in stool.
      • A low concentration of metronidazole prolongs Clostridioides difficile shedding.
      • Oral vancomycin and fidaxomicin reach very high concentrations in the stool.
      • A high concentration of vancomycin also suppresses gram-negative anaerobes.
      • Fidaxomicin has a narrow spectrum of antimicrobial activity and persists on spores.

      Abstract

      Recently, the recommendations for the treatment of Clostridioides difficile infection (CDI) have been updated. However, in addition to the clinical efficacy data, the drug of choice should ideally represent optimal antimicrobial stewardship, with an emphasis on rapid restoration of the gut microbiota to minimize the risk of infection relapses. Oral administration of metronidazole results in low concentration in stool, and interaction with fecal microbiota reduces its antimicrobial bioactivity. Reported elevated minimum inhibitory concentrations of metronidazole in epidemic C. difficile ribotypes and the emergence of plasmid-mediated resistance to metronidazole represent additional potential risks for clinical failure. If metronidazole is the only CDI treatment option, antimicrobial susceptibility testing on agar containing heme should be performed in C. difficile isolate. Compared with metronidazole, oral vancomycin and fidaxomicin reach very high concentrations in the stool, and therefore can quickly reduce C. difficile shedding. Health care facilities with higher CDI incidence and/or occurrence of epidemic ribotypes should not use metronidazole because prolonged C. difficile shedding can increase the risk for further C. difficile transmission. Only fidaxomicin has a narrow spectrum of antimicrobial activity, which might be, together with persistence on spores, the main contributing factor to reduce the recurrent CDI rates.

      Graphical abstract

      Keywords

      1. Introduction

      Clostridioides difficile is the leading cause of health care–associated diarrhea and a frequent cause of infective diarrhea in the community. C. difficile infection (CDI) increases in-hospital mortality and excess health care costs and has a long-lasting effect on the quality of life of the patients (
      • Barbut F
      • Day N
      • Bouée S
      • Youssouf A
      • Grandvoinnet L
      • Lalande V
      • et al.
      Toxigenic Clostridium difficile carriage in general practice: results of a laboratory-based cohort study.
      ;
      • Hensgens MPM
      • Dekkers OM
      • Demeulemeester A
      • Buiting AGM
      • Bloembergen P
      • van Benthem BHB
      • et al.
      Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study.
      ;
      • Marra AR
      • Perencevich EN
      • Nelson RE
      • Samore M
      • Khader K
      • Chiang HY
      • et al.
      Incidence and outcomes associated with Clostridium difficile infections: a systematic review and meta-analysis.
      ;
      • Vent-Schmidt J
      • Attara GP
      • Lisko D
      • Steiner TS.
      Patient experiences with Clostridioides difficile infection: results of a Canada-wide survey.
      ).
      Since 2017, various international organizations have updated their guidance documents and recommendations for CDI treatment (
      • Johnson S
      • Lavergne V
      • Skinner AM
      • Gonzales-Luna AJ
      • Garey KW
      • Kelly CP
      • Wilcox MH.
      Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults.
      ;
      • Kelly CR
      • Fischer M
      • Allegretti JR
      • LaPlante K
      • Stewart DB
      • Limketkai BN
      • Stollman NH.
      ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections.
      ;
      • Krutova M
      • de Meij TGJ
      • Fitzpatrick F
      • Drew DJ
      • Wilcox MH
      • Kuijper EJ.
      How to: Clostridioides difficile infection in children.
      ;
      • McDonald LC
      • Gerding DN
      • Johnson S
      • Bakken JS
      • Carroll KC
      • Coffin SE
      • Dubberke ER
      • Garey KW
      • Gould CV
      • Kelly C
      • Loo V
      • Shaklee Sammons J
      • Sandora TJ
      • Wilcox MH
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ;
      • van Prehn J
      • Reigadas E
      • Vogelzang EH
      • Bouza E
      • Hristea A
      • Guery B
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
      ). Due to a significant reduction in recurrent rates, fidaxomicin is the preferred option in initial nonsevere CDI and the first CDI recurrence (
      • Johnson S
      • Lavergne V
      • Skinner AM
      • Gonzales-Luna AJ
      • Garey KW
      • Kelly CP
      • Wilcox MH.
      Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults.
      ;
      • Krutova M
      • de Meij TGJ
      • Fitzpatrick F
      • Drew DJ
      • Wilcox MH
      • Kuijper EJ.
      How to: Clostridioides difficile infection in children.
      ;
      • van Prehn J
      • Reigadas E
      • Vogelzang EH
      • Bouza E
      • Hristea A
      • Guery B
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
      ). Fidaxomicin is an equal option in severe CDI compared with vancomycin (
      • Johnson S
      • Lavergne V
      • Skinner AM
      • Gonzales-Luna AJ
      • Garey KW
      • Kelly CP
      • Wilcox MH.
      Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults.
      ;
      • Kelly CR
      • Fischer M
      • Allegretti JR
      • LaPlante K
      • Stewart DB
      • Limketkai BN
      • Stollman NH.
      ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections.
      ;
      • Krutova M
      • de Meij TGJ
      • Fitzpatrick F
      • Drew DJ
      • Wilcox MH
      • Kuijper EJ.
      How to: Clostridioides difficile infection in children.
      ;
      • McDonald LC
      • Gerding DN
      • Johnson S
      • Bakken JS
      • Carroll KC
      • Coffin SE
      • Dubberke ER
      • Garey KW
      • Gould CV
      • Kelly C
      • Loo V
      • Shaklee Sammons J
      • Sandora TJ
      • Wilcox MH
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ;
      • van Prehn J
      • Reigadas E
      • Vogelzang EH
      • Bouza E
      • Hristea A
      • Guery B
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
      ). All guidance documents except for one do not recommend oral metronidazole as the first-line drug for the treatment of initial nonsevere CDI and consider metronidazole use only when fidaxomicin or vancomycin is not available (
      • Johnson S
      • Lavergne V
      • Skinner AM
      • Gonzales-Luna AJ
      • Garey KW
      • Kelly CP
      • Wilcox MH.
      Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults.
      ;
      • Kelly CR
      • Fischer M
      • Allegretti JR
      • LaPlante K
      • Stewart DB
      • Limketkai BN
      • Stollman NH.
      ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections.
      ;
      • Krutova M
      • de Meij TGJ
      • Fitzpatrick F
      • Drew DJ
      • Wilcox MH
      • Kuijper EJ.
      How to: Clostridioides difficile infection in children.
      ;
      • McDonald LC
      • Gerding DN
      • Johnson S
      • Bakken JS
      • Carroll KC
      • Coffin SE
      • Dubberke ER
      • Garey KW
      • Gould CV
      • Kelly C
      • Loo V
      • Shaklee Sammons J
      • Sandora TJ
      • Wilcox MH
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
      ;
      • van Prehn J
      • Reigadas E
      • Vogelzang EH
      • Bouza E
      • Hristea A
      • Guery B
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
      ). The American College of Gastroenterology still supports the use of metronidazole for initial nonsevere CDI in low-risk patients, such as younger outpatients with minimal comorbidities (
      • Kelly CR
      • Fischer M
      • Allegretti JR
      • LaPlante K
      • Stewart DB
      • Limketkai BN
      • Stollman NH.
      ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections.
      ). Revised practice guidelines have had a significant impact on CDI treatment with an increase in vancomycin and fidaxomicin prescription. Although the prescription of metronidazole decreased after the publishing of recommendations, it is still one of the most frequently used antimicrobials in patients with CDI (
      • Clancy CJ
      • Buehrle D
      • Vu M
      • Wagener MM
      • Nguyen MH.
      Impact of revised Infectious Diseases Society of America and Society for Healthcare Epidemiology of America clinical practice guidelines on the treatment of Clostridium difficile infections in the United States.
      ).
      Undoubtedly, antibiotic treatment of CDI already has very limited options, and these have been further reduced. In addition to clinical efficacy data, the drug of choice should be in line with good antimicrobial stewardship practice, with an emphasis on rapid restoration of the depleted gut microbiota to reduce the risk of infection relapses. The aim of this narrative review was to augment the CDI treatment recommendations by summarizing the pharmacological and microbiological properties of fidaxomicin, vancomycin, and metronidazole.

      2. Literature search

      The literature for this narrative review was drawn from a search of PubMed until March 2022. Index search terms were Clostridium difficile, Clostridiodes difficile, metronidazole, vancomycin, fidaxomicin, gut microbiota, resistance, shedding, and stool concentration. Only original studies written in English were included. The references of articles were also screened and added, if appropriate.
      An overview of pharmacodynamic, pharmacokinetic, and microbiological properties for oral administration of metronidazole, vancomycin, and fidaxomicin is shown in Figure.

      3. Pharmacological properties

      Oral metronidazole is absorbed almost completely (90%) in the upper gastrointestinal tract and enters the large intestine primarily through secretion across the gut mucosa; the intraluminal concentrations of metronidazole are proportional to the extent of inflammation (
      • Bolton RP
      • Culshaw MA.
      Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile.
      ;
      • Lamp KC
      • Freeman CD
      • Klutman NE
      • Lacy MK.
      Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.
      ). Metronidazole therapy (six CDI episodes with 400 mg every 8 hours orally, three CDI episodes with 500 mg every 8 hours intravenously, and one CDI episode with only 200 mg every 8 hours orally) resulted in mean levels (± SD) in watery feces of 9.3 ± 7.5 μg/g wet weight (range 0.8-24.2) decreasing to 3.3 ± 3.6 μg/g wet weight (range 0.5-10.4) in semiformed stool samples and have been found to be very low or zero (1.23 ± 2.8 μg/g; range 0-10.2) in formed stool samples (
      • Bolton RP
      • Culshaw MA.
      Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile.
      ). Notably, the dosage in the majority of patients in this study was about 20% lower than that in CDI treatment recommendations, and it is unknown whether stool concentration would increase noticeably when the dosage of 500 mg every 8 hours is administered.
      In contrast to metronidazole, fecal concentrations of vancomycin with a dosage of 125 mg every 6 hours ranged from 175-6299 μg/g; for fidaxomicin, for a dosage of 200 mg every 12 hours, concentrations were 1396 ± 1019 µg/g, with 834 ± 617 µg/g for OP-1118, which is an active metabolite of fidaxomicin (
      • Sears P
      • Crook DW
      • Louie TJ
      • Miller MA
      • Weiss K.
      Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with Clostridium difficile infection.
      ;
      • Thabit AK
      • Nicolau DP.
      Impact of vancomycin faecal concentrations on clinical and microbiological outcomes in Clostridium difficile infection.
      ).
      Unlike metronidazole, systemic absorption is minimal after oral administration of either vancomycin or fidaxomicin (
      • Sears P
      • Crook DW
      • Louie TJ
      • Miller MA
      • Weiss K.
      Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with Clostridium difficile infection.
      ;
      • Thabit AK
      • Nicolau DP.
      Impact of vancomycin faecal concentrations on clinical and microbiological outcomes in Clostridium difficile infection.
      ). However, in severe inflammation of the intestinal mucosa with concomitant renal impairment, systemic absorption of orally administered vancomycin can be enhanced (

      European Medicines Agency, Vancomycin Article-31 referral - Annex III. https://www.ema.europa.eu/en/documents/referral/vancomycin-article-31-referral-annex-iii_en.pdf, 2017 (accessed 3 March 2022).

      ), especially with higher dosages (250-500 mg per 6 hours) (
      • Pogue JM
      • DePestel DD
      • Kaul DR
      • Khaled Y
      • Frame DG.
      Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft-versus-host disease of the gastrointestinal tract.
      ;
      • Yamazaki S
      • Suzuki T
      • Suzuki T
      • Takatsuka H
      • Ishikawa M
      • Hattori N
      • et al.
      An extremely high bioavailability of orally administered vancomycin in a patient with severe colitis and renal insufficiency.
      ). The increased systemic absorption due to severe inflammation can also hypothetically be expected with fidaxomicin; however, the nonclinical pharmacology and safety pharmacology of fidaxomicin has not revealed any unexpected effects overall (

      European Medicines Agency, Dificlir: EPAR - Porduct Information, 2022, https://www.ema.europa.eu/en/documents/product-information/dificlir-epar-product-information_en.pdf, (accessed 3 March 2022).

      ).

      4. In vitro activity

      4.1 Vegetative Clostridium difficile cells

      Metronidazole is a nitroimidazole that inhibits DNA synthesis, with bactericidal activity against anaerobic bacteria and protozoa. Metronidazole is a prodrug that enters the cell by passive diffusion and is activated when its nitro group is reduced. Reduced metronidazole can interact with DNA causing strand breakage and helix destabilization, which leads to cell death (
      • Odenholt I
      • Walder M
      • Wullt M.
      Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.
      ;
      • O'Grady K
      • Knight DR
      • Riley TV.
      Antimicrobial resistance in Clostridioides difficile.
      ). Vancomycin is a glycopeptide antimicrobial with bacteriostatic activity that inhibits peptidoglycan biosynthesis in the cell wall in gram-positive bacteria (
      • Odenholt I
      • Walder M
      • Wullt M.
      Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.
      ;
      • O'Grady K
      • Knight DR
      • Riley TV.
      Antimicrobial resistance in Clostridioides difficile.
      ). In higher concentrations of vancomycin (8 and 16 mg/l), a bactericidal effect was observed (
      • Odenholt I
      • Walder M
      • Wullt M.
      Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.
      ). Fidaxomicin is a narrow-spectrum macrocyclic antibiotic that targets bacterial RNA polymerase, with a bactericidal activity against Clostridia belonging to clusters I and XI and gram-positive nonspore-forming rods and anaerobic gram-positive cocci (
      • Babakhani F
      • Gomez A
      • Robert N
      • Sears P.
      Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile.
      ;
      • Finegold SM
      • Molitoris D
      • Vaisanen ML
      • Song Y
      • Liu C
      • Bolaños M.
      In vitro activities of OPT-80 and comparator drugs against intestinal bacteria.
      ). When the killing kinetics is compared, metronidazole exerted a very rapid bactericidal effect (<4 log10 colony-forming unit [CFU] after 3 hours) but in concentrations of 8 x minimum inhibitory concentration (MIC) (4 mg/l) and above (
      • Odenholt I
      • Walder M
      • Wullt M.
      Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.
      ). Overall, vancomycin gave less kill than metronidazole (
      • Odenholt I
      • Walder M
      • Wullt M.
      Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.
      ), and slower killing kinetics were also found in vancomycin than fidaxomicin. The bacterial count of C. difficile cells treated with vancomycin (4 × MIC) dropped slightly over two logs in 48 hours, whereas in the fidaxomicin experiment, the bacterial counts dropped below the detection limit (100 CFU ml-1) by 48 hours (
      • Babakhani F
      • Gomez A
      • Robert N
      • Sears P.
      Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile.
      ).
      Antimicrobial susceptibility testing (AST) recommendations differ between the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI); however, both bodies do not recommend using the broth microdilution method due to the difference in MICs compared with those yielded by agar dilution (
      Clinical and Laboratory Standards Institute
      Performance Standards for antimicrobial Susceptibility testing. M100.
      ;

      European committee on antimicrobial susceptibility testing (EUCAST), Clinical breakpoints - breakpoints and guidance, 2022, http://www.eucast.org/clinical_breakpoints. (accessed 3 March 2022).

      ;
      • Hastey CJ
      • Dale SE
      • Nary J
      • Citron D
      • Law JH
      • Roe-Carpenter DE
      • Chesnel L.
      Comparison of Clostridium difficile minimum inhibitory concentrations obtained using agar dilution vs broth microdilution methods.
      ). EUCAST recommends “fastidious anaerobe agar” for the AST of anaerobes, and the break points for C. difficile are based on epidemiological cutoff values; >2mg/l for metronidazole and vancomycin resistance. CLSI recommends “Brucella blood agar” supplemented with 5% sheep blood, hemin, and vitamin K1 for AST of anaerobes, with MIC break points for C. difficile of ≥32 mg/l and ≥4 mg/l for metronidazole and vancomycin, respectively. For metronidazole, it is important to note that very recent data shows that the consistent detection of metronidazole resistance is dependent on the presence of heme in agar media and its protection from light (
      • Boekhoud IM
      • Sidorov I
      • Nooij S
      • Harmanus C
      • Bos-Sanders IMJG
      • Viprey V
      • et al.
      Haem is crucial for medium-dependent metronidazole resistance in clinical isolates of Clostridioides difficile.
      ;
      • Wu X
      • Shen WJ
      • Deshpande A
      • Olaitan AO
      • Palmer KL
      • Garey KW
      • Hurdle JG.
      The integrity of heme is essential for reproducible detection of metronidazole-resistant Clostridioides difficile by agar dilution susceptibility tests.
      ). Both agars recommended by EUCAST and CLSI contain heme but in unknown quantities because of supplementation by blood. For fidaxomicin, there is still no official MIC break point available; 0.25 mg/l was suggested based on the MICs from European isolates (
      • Freeman J
      • Vernon J
      • Morris K
      • Nicholson S
      • Todhunter S
      • Longshaw C
      • Pan-European Wilcox MH.
      ).
      Antimicrobial resistance in human C. difficile isolates showed equal-weighted pooled resistance for metronidazole and vancomycin of 1.0% (95% CI 0-3% and 0-2%, respectively) with a break point of >2 mg/l in a recent meta-analysis, including data for 5900 C. difficile isolates tested for metronidazole susceptibility and 11,188 C. difficile isolates tested for susceptibility to vancomycin (
      • Sholeh M
      • Krutova M
      • Forouzesh M
      • Mironov S
      • Sadeghifard N
      • Molaeipour L
      • et al.
      Antimicrobial resistance in Clostridioides (Clostridium) difficile derived from humans: a systematic review and meta-analysis.
      ). When also analyzing C. difficile isolates from nonhuman sources, the weighted pooled resistance increased to 1.9% (95% CI 0.5-3.6%) for metronidazole and to 2.1% (95% CI 0-5.1%) for vancomycin (
      • Saha S
      • Kapoor S
      • Tariq R
      • Schuetz AN
      • Tosh PK
      • Pardi DS
      • Khanna S.
      Increasing antibiotic resistance in Clostridioides difficile: a systematic review and meta-analysis.
      ). For fidaxomicin, a few isolates with MICs from 1-64 mg/l were found recently in several studies investigating a large number of isolates (
      • Freeman J
      • Vernon J
      • Pilling S
      • Morris K
      • Nicolson S
      • Shearman S
      • et al.
      Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study.
      ;
      • Goldstein EJ
      • Citron DM
      • Sears P
      • Babakhani F
      • Sambol SP
      • Gerding DN.
      Comparative susceptibilities to fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two phase III trials of fidaxomicin against Clostridium difficile infection.
      ;
      • Karlowsky JA
      • Adam HJ
      • Baxter MR
      • Dutka CW
      • Nichol KA
      • Laing NM
      • et al.
      Antimicrobial susceptibility of Clostridioides difficile isolated from diarrhoeal stool specimens of Canadian patients: summary of results from the Canadian Clostridioides difficile (CAN-DIFF) surveillance study from 2013 to 2017.
      ;
      • Peng Z
      • Addisu A
      • Alrabaa S
      • Sun X.
      Antibiotic resistance and toxin production of Clostridium difficile isolates from the hospitalized patients in a Large Hospital in Florida.
      ;
      • Schwanbeck J
      • Riedel T
      • Laukien F
      • Schober I
      • Oehmig I
      • Zimmermann O
      • et al.
      Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB.
      ); however, it should be noted that no commercial E-test for fidaxomicin is available in the market, so routine antimicrobial susceptibility data are limited.
      MICs can differ according to C. difficile ribotype (RT). Elevated geometric mean MICs relative to other RTs were found in RTs 001, 027, 106, and 356 for metronidazole and in RTs 018 and 356 for vancomycin. These RTs belonged to epidemic types occurring in several European countries, except for RT356, which is probably genetically related to RT018 based on 94% similarity of polymerase chain reaction ribotyping banding profile, and was found only in Italy (
      • Freeman J
      • Vernon J
      • Morris K
      • Nicholson S
      • Todhunter S
      • Longshaw C
      • Pan-European Wilcox MH.
      ).
      The clinical importance of MICs of metronidazole was highlighted in the study of Gonzales-Luna and colleagues. In the study cohort of 356 patients, increased MICs (≥1 µg/ml) have been identified as an independent predictor for clinical failure in patients with CDI treated with metronidazole (odds ratio 2.27; 95% CI 1.18-4.34); the majority of strains with a metronidazole MIC ≥1 µg/ml were RT027 (n = 45/65 [69%]) (
      • Gonzales-Luna AJ
      • Olaitan AO
      • Shen WJ
      • Deshpande A
      • Carlson TJ
      • Dotson KM
      • et al.
      Reduced susceptibility to metronidazole is associated with initial clinical failure in Clostridioides difficile infection.
      ).
      The molecular mechanisms of resistance to metronidazole and vancomycin in C. difficile remain poorly understood. It is hypothesized that resistance to metronidazole is likely due to multifactorial processes involving alterations to metabolism with nitroreductases, iron uptake, active efflux, drug inactivation, DNA repair, or biofilm formation (
      • O'Grady K
      • Knight DR
      • Riley TV.
      Antimicrobial resistance in Clostridioides difficile.
      ). Vancomycin resistance mediated by van genes is very well described in Enterococcus sp. However, these gene clusters are also present in C. difficile but without corresponding vancomycin resistance phenotypes (
      • O'Grady K
      • Knight DR
      • Riley TV.
      Antimicrobial resistance in Clostridioides difficile.
      ). Recently, the presence of plasmid pCD-METRO and its international dissemination has been reported in both toxigenic and nontoxigenic C. difficile strains, with reduced susceptibility to metronidazole (
      • Boekhoud IM
      • Sidorov I
      • Nooij S
      • Harmanus C
      • Bos-Sanders IMJG
      • Viprey V
      • et al.
      Haem is crucial for medium-dependent metronidazole resistance in clinical isolates of Clostridioides difficile.
      ). Recently, plasmid-mediated resistance to vancomycin was also described in C. difficile isolate from a patient with CDI nonresponding to vancomycin treatment (
      • Pu M
      • Cho JM
      • Cunningham SA
      • Behera GK
      • Becker S
      • Amjad T
      • et al.
      Plasmid acquisition alters vancomycin susceptibility in Clostridioides difficile.
      ). For fidaxomicin, several different mutations have been reported in laboratory-generated mutants, leading to alteration of fidaxomicin susceptibility (
      • O'Grady K
      • Knight DR
      • Riley TV.
      Antimicrobial resistance in Clostridioides difficile.
      ). An amino acid substitution V1143D in the RpoB was identified in clinical C. difficile isolate with MIC of >64 mg/l. This genetic change was also associated with reduced toxin A/B production and moderately reduced spore formation (
      • Schwanbeck J
      • Riedel T
      • Laukien F
      • Schober I
      • Oehmig I
      • Zimmermann O
      • et al.
      Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB.
      ).
      It should be noted that fecal concentrations of vancomycin and fidaxomicin are many times greater than MICs detected in resistant C. difficile isolates than metronidazole with low stool concentration (
      • Bolton RP
      • Culshaw MA.
      Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile.
      ;
      • Sears P
      • Crook DW
      • Louie TJ
      • Miller MA
      • Weiss K.
      Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with Clostridium difficile infection.
      ;
      • Thabit AK
      • Nicolau DP.
      Impact of vancomycin faecal concentrations on clinical and microbiological outcomes in Clostridium difficile infection.
      ).

      4.2 Clostridium difficile spores

      Sporulation allows C. difficile to persist in the host and disseminate through environmental contamination. The persistence of C. difficile spores in the gut can play a role in the recurrence (relapse) of CDI (
      • Chilton CH
      • Crowther GS
      • Ashwin H
      • Longshaw CM
      • Wilcox MH.
      Association of fidaxomicin with C. difficile spores: effects of persistence on subsequent spore recovery, outgrowth and toxin production.
      ). Significant inhibition of C. difficile sporulation in vitro was not observed with either metronidazole or vancomycin, but both fidaxomicin and OP-1118 inhibited sporulation, including for the epidemic NAP1/BI/027 strain (
      • Babakhani F
      • Bouillaut L
      • Gomez A
      • Sears P
      • Nguyen L
      • Sonenshein AL.
      Fidaxomicin inhibits spore production in Clostridium difficile.
      ;
      • Garneau JR
      • Valiquette L
      • Fortier LC.
      Prevention of Clostridium difficile spore formation by sub-inhibitory concentrations of tigecycline and piperacillin/tazobactam.
      ). Antimicrobial activity on C. difficile spores was detected in fidaxomicin-exposed spores but was absent in the vancomycin-exposed spores after washing in phosphate-buffered saline or in the more in vivo reflective fecal filtrate. The retention of antimicrobial activity prevented the recovery of spores on selective agar (
      • Chilton CH
      • Crowther GS
      • Ashwin H
      • Longshaw CM
      • Wilcox MH.
      Association of fidaxomicin with C. difficile spores: effects of persistence on subsequent spore recovery, outgrowth and toxin production.
      ).

      Effect of the gut microbiota on the activity of anti-C. difficile infection agents

      It is unknown if the measured activities of antibiotics in vitro in a very well-defined environment against pure cultures of C. difficile represent what occurs in vivo in the intestinal tract with the presence of various other bacterial species and metabolites, which vary across individuals. Using in vitro models with bacterial communities, the activity spectrum of antibiotics, in general, is more complicated than testing in vitro with one species and one agent (
      • Maier L
      • Goemans CV
      • Wirbel J
      • Kuhn M
      • Eberl C
      • Pruteanu M
      • et al.
      Unravelling the collateral damage of antibiotics on gut bacteria.
      ). A further consideration is the effect of feces on the bioactivity of antibiotics used to treat CDI. The inactivation of metronidazole in the presence of gut contents was shown in the study of Rafii and colleagues, suggesting nitroreductase-producing enterococci as the possible cause (
      • Rafii F
      • Wynne R
      • Heinze TM
      • Paine DD.
      Mechanism of metronidazole-resistance by isolates of nitroreductase-producing Enterococcus gallinarum and Enterococcus casseliflavus from the human intestinal tract.
      ). Importantly, a recent study using feces samples collected from 18 healthy individuals observed reduced antibiotic bioactivity of all three anti-CDI antimicrobials at 24 hours; however, the observed mean decreases for fidaxomicin (2.8-fold) or for vancomycin (1.5-fold) are unlikely to impact treatment efficacy due to the high fecal concentrations achieved. In contrast to vancomycin and fidaxomicin, a 727-fold reduction of bioactivity for metronidazole was seen and, considering the suboptimal stool concentration of this antibiotic, could be expected to have an impact on treatment outcome (personal communication with Mark Wilcox).

      6. “Collateral damage” to the gut microbiota

      Metronidazole, vancomycin, and fidaxomicin are bactericidal antibiotics with different mechanisms of action (Figure). The target site of antibiotics is one factor that determines the narrowness of the antibacterial spectrum. Fidaxomicin has very little effect or no activity against gram-negative aerobic and anaerobic bacteria, which likely contributes to the rapid recovery of the markedly disrupted microbiota found in patients with CDI (
      • Louie TJ
      • Cannon K
      • Byrne B
      • Emery J
      • Ward L
      • Eyben M
      • Krulicki W.
      Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI.
      ). Metronidazole affects the gut microbiome to a larger extent than vancomycin because it is active against anaerobic bacteria, including gram-negative anaerobes, primarily Bacteroides, Fusobacterium, and Prevotella spp., and also gram-positive anaerobes, such as Peptostreptococcus and Clostridium spp. Vancomycin inhibits various aerobic and anaerobic gram-positive bacteria, including other Clostridium spp. (
      • Louie TJ
      • Cannon K
      • Byrne B
      • Emery J
      • Ward L
      • Eyben M
      • Krulicki W.
      Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI.
      ). Although vancomycin is not normally active against gram-negative bacteria, vancomycin's very high intestinal concentrations can suppress the Bacteroides/Prevotella group bacteria (
      • Louie TJ
      • Cannon K
      • Byrne B
      • Emery J
      • Ward L
      • Eyben M
      • Krulicki W.
      Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI.
      ;
      • Newton DF
      • Macfarlane S
      • Macfarlane GT.
      Effects of antibiotics on bacterial species composition and metabolic activities in chemostats containing defined populations of human gut microorganisms.
      ). Bacteroides play an important role in colonization resistance due to their numerous presences on the mucosal surface and interference with intestinal pathogens (
      • Eckburg PB
      • Bik EM
      • Bernstein CN
      • Purdom E
      • Dethlefsen L
      • Sargent M
      • et al.
      Diversity of the human intestinal microbial flora.
      ). In addition, vancomycin decreased fecal secondary bile acids, which inhibit the growth of the vegetative form of C. difficile (
      • Vrieze A
      • Out C
      • Fuentes S
      • Jonker L
      • Reuling I
      • Kootte RS
      • et al.
      Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.
      ). Importantly, the changes in the gut microbiota and their metabolites (metabolomics) by vancomycin and metronidazole may persist for a considerable time period and affect various host functions, including immune regulation and metabolic activities (
      • Soto M
      • Herzog C
      • Pacheco JA
      • Fujisaka S
      • Bullock K
      • Clish CB
      • Kahn CR.
      Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism.
      ;
      • Vrieze A
      • Out C
      • Fuentes S
      • Jonker L
      • Reuling I
      • Kootte RS
      • et al.
      Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.
      ).

      7. Acquisition and overgrowth of vancomycin-resistant Enterococci

      The changes in the recommendations for the treatment of CDI toward the use of vancomycin led to concerns of increased selective pressure for vancomycin-resistant enterococci (VRE). No increased risk for VRE acquisition has been identified in patients treated with metronidazole or vancomycin (
      • Stevens VW
      • Khader K
      • Echevarria K
      • Nelson RE
      • Zhang Y
      • Jones M
      • et al.
      Use of oral vancomycin for Clostridioides difficile infection and the risk of vancomycin-resistant enterococci.
      ). Interestingly, a reduced acquisition of VRE (7% vs 31%, respectively; P <0.001) and Candida species (19% vs 29%, respectively; P-value = 0.03) was observed in patients who were treated with fidaxomicin versus those treated with vancomycin (
      • Nerandzic MM
      • Mullane K
      • Miller MA
      • Babakhani F
      • Donskey CJ.
      Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection.
      ).
      In addition, in patients with pre-existing VRE, a significant decrease in the mean concentration in stool was detected in the fidaxomicin group (5.9 vs 3.8 log10 VRE/g stool; P-value = 0.01) but not in the vancomycin group (5.3 vs 4.2 log10 VRE/g stool; P-value = 0.20), (
      • Nerandzic MM
      • Mullane K
      • Miller MA
      • Babakhani F
      • Donskey CJ.
      Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection.
      ). In contrast, no significant difference in the density of VRE was observed after the onset of CDI therapy (during therapy or up to 2 weeks after completion of therapy, P >0.35) comparing vancomycin and metronidazole CDI treatment groups (
      • Al-Nassir WN
      • Sethi AK
      • Li Y
      • Pultz MJ
      • Riggs MM
      • Donskey CJ.
      Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease.
      ).

      8. C. difficile shedding

      The treatment selection affects the clinical outcome of the patient but may also have an impact on the C. difficile shedding and environmental contamination and thus play a role in reducing health care-associated C. difficile transmission. Two prospective observational studies found fidaxomicin to be associated with lower rates of C. difficile contamination of the hospital environment than metronidazole and/or vancomycin. The study of Biswas and colleagues showed that patients treated with fidaxomicin (25/68, 36.8%) were less likely to contaminate their environment than patients treated with metronidazole and/or vancomycin (38/66 [57.6%], P-value = 0.02) (
      • Biswas JS
      • Patel A
      • Otter JA
      • Wade P
      • Newsholme W
      • van Kleef E
      • Goldenberg SD.
      Reduction in Clostridium difficile environmental contamination by hospitalized patients treated with fidaxomicin.
      ). In the study of Davies and colleagues, observed rates of environmental contamination were 30% versus 50%, P-value = 0.04, on days 4-5 and 22% versus 49%, P-value = 0.005, on days 9-12 in five-room sites sampled of fidaxomicin or vancomycin/metronidazole recipients, respectively (
      • Davies K
      • Mawer D
      • Walker AS
      • Berry C
      • Planche T
      • Stanley P
      • et al.
      An analysis of Clostridium difficile environmental contamination during and after treatment for C difficile infection.
      ). These data were further supported by the results of a prospective, unblinded, randomized, controlled trial, where contrary to observational studies, the metronidazole, vancomycin, and fidaxomicin treatment arms were evaluated separately (
      • Turner NA
      • Warren BG
      • Gergen-Teague MF
      • Addison RM
      • Addison B
      • Rutala WA
      • et al.
      Impact of oral metronidazole, vancomycin, and fidaxomicin on host shedding and environmental contamination with Clostridioides difficile.
      ). Fidaxomicin and vancomycin were associated with a more rapid decline in C. difficile stool shedding than metronidazole (-0.36 log10 CFUs/d, -0.17 log10 CFUs/d, and -0.01 log10 CFUs/d, respectively. Both vancomycin and fidaxomicin (6.3% vs 13.1%) were associated with lower rates of environmental contamination than metronidazole (21.4%), respectively. With specific modeling of within-subject change over time, fidaxomicin was associated with a more rapid decline in environmental contamination than vancomycin or metronidazole (adjusted odds ratio, 0.83, 95% CI 0.70-0.99; P-value = 0.04), (
      • Turner NA
      • Warren BG
      • Gergen-Teague MF
      • Addison RM
      • Addison B
      • Rutala WA
      • et al.
      Impact of oral metronidazole, vancomycin, and fidaxomicin on host shedding and environmental contamination with Clostridioides difficile.
      ).

      9. Conclusion

      The microbiological and pharmacological data support the CDI treatment recommendation of leaving metronidazole as the third alternative option only when fidaxomicin or vancomycin is not available or feasible. Oral vancomycin and fidaxomicin reach very high concentrations in the stool, but only fidaxomicin has a minimal effect on gut microbiota, inhibits sporulation, and shows antimicrobial activity on spores.

      Funding

      This study was supported by the project National Institute of Virology and Bacteriology (Programme EXCELES, ID Project No. LX22NPO5103), funded by the European Union, NextGenerationEU.

      Ethical approval

      No ethical approval was necessary for this type of study.

      Author contributions

      M.K. conducted the literature search for this narrative review and wrote the original draft. E.J.K. and M.H.W. reviewed and commented on subsequent versions. All authors read and approved the submitted version.

      Declaration of Competing Interest

      M.K. and E.J.K. have no competing interests to declare. M.H.W. received lecture fees from Merck, Pfizer, and Seres and consultation fees from AiCuris, Bayer, Crestone, Da Volterra, Deinove, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, and Vaxxilon/Idorsia.

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