Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile infection in an in vitro human gut model.

BACKGROUND: Fidaxomicin treatment reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. Extending duration of fidaxomicin therapy may further reduce recurrence. We compared the efficacy of four extended fidaxomicin regimens in an in vitro model of CDI. METHODS: Four gut models were primed with human faeces, spiked with C. difficile spores (PCR ribotype 027) and clindamycin instilled (33.9 mg/L, four-times daily, 7 days) to induce simulated CDI. Four extended fidaxomicin treatment regimens were evaluated: model 1, 20 days, 200 mg/L twice daily; model 2, 5 days 200 mg/L twice daily, 5 days rest, 5 days 200 mg/L twice daily; model 3, 5 days 200 mg/L twice daily, 5 days rest, 10 days 200 mg/L once daily; and model 4, 5 days 200 mg/L twice daily, 20 days 200 mg/L once every other day. C. difficile populations, toxin, gut microbiota and antimicrobial levels were monitored daily. RESULTS: All fidaxomicin regimens successfully resolved simulated CDI without recurrence. Five days of fidaxomicin instillation was barely sufficient to resolve CDI (models 2-4). A second pulse or tapered dosing further reduced C. difficile and toxin detection. All regimens were sparing of microbiota, affecting only enterococci and bifidobacteria. Pulsed or tapered regimens allowed greater bifidobacteria recovery than the extended (20 day) regimen. Bioactive fidaxomicin persisted throughout the experiment in all models at concentrations inhibitory to C. difficile. CONCLUSIONS: Pulsed or tapered fidaxomicin regimens may enhance suppression of C. difficile whilst allowing microbiota recovery; clinical studies are required to ascertain the potential of this approach in further reducing recurrent CDI.

Efficacy of surotomycin in an in vitro gut model of Clostridium difficile infection.

OBJECTIVES: We investigated the efficacy of the cyclic lipopeptide surotomycin in treating clindamycin-induced Clostridium difficile infection (CDI) using an in vitro gut model. METHODS: Two three-stage chemostat gut models were inoculated with human faeces, spiked with C. difficile spores (∼10(7) cfu/mL, PCR ribotype 027 or 001). Clindamycin (33.9 mg/L, four times daily for 7 days) was dosed to induce CDI. Following high-level toxin production, surotomycin (250 mg/L, twice daily for 7 days) was instilled. Microflora populations, C. difficile vegetative cells and spores, cytotoxin titres and antimicrobial levels (LC-MS/MS and bioassay) were determined. The emergence of C. difficile and enterococci with reduced susceptibility to surotomycin was monitored on breakpoint agar (4 × MIC). RESULTS: Counts of viable C. difficile were reduced to near the limit of detection on Days 1 and 3 of surotomycin instillation, and cytotoxin was undetectable on Days 3 and 4 of surotomycin instillation in the 027 and 001 models, respectively. Recurrence of vegetative growth and toxin production occurred 11 days (001 model) and 15 days (027 model) after surotomycin instillation had ceased, and remained for the duration of the experiment. Surotomycin instillation decreased populations of bifidobacteria, clostridia, enterococci and lactobacilli, but was sparing of Bacteroides fragilis group populations. All enumerated organisms had recovered to steady-state levels by 3 weeks post-surotomycin instillation. No evidence of the emergence of reduced susceptibility to surotomycin was observed. CONCLUSIONS: Surotomycin successfully reduced C. difficile vegetative cell counts and toxin levels in the gut model and was sparing of B. fragilis group populations. There was no evidence of decreased susceptibility to surotomycin during exposure or post-exposure.

Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure.

OBJECTIVES: Fidaxomicin reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. We investigated fidaxomicin primary or secondary treatment efficacy using a gut model. METHODS: Four triple-stage chemostat gut models were inoculated with faeces. After clindamycin induction of CDI, fidaxomicin (200 mg/L twice daily), vancomycin (125 mg/L four times daily) or metronidazole (9.3 mg/L three times daily) was administered for 7 days. Following failure/CDI recurrence, fidaxomicin (200 mg/L twice daily, 7 days) was instilled. C. difficile (CD) total viable counts (TVC), spore counts (SP), toxin titres (CYT), gut bacteria counts and antimicrobial concentrations were measured throughout. RESULTS: Fidaxomicin instillation reduced CD TVC/SP and CYT below the limit of detection (LOD) after 2 and 4 days, respectively, with no CDI recurrence. Metronidazole instillation failed to decrease CD TVC or CYT. Vancomycin instillation reduced CD TVC and CYT to LOD by day 4, but SP persisted. Recurrence occurred 13 days after vancomycin instillation; subsequent fidaxomicin instillation reduced CD TVC/SP/CYT below the LOD from day 2. CD was isolated sporadically, with no evidence of spore recrudescence or toxin production. Fidaxomicin had a minimal effect on the microflora, except for bifidobacteria. Fidaxomicin was detected for at least 21 days post-instillation, whereas other antimicrobials were undetectable beyond ∼4 days. CONCLUSIONS: Fidaxomicin successfully treated simulated primary and recurrent CDI. Fidaxomicin was superior to metronidazole in reducing CD TVC and SP, and superior to vancomycin in reducing SP without recurrence of vegetative cell growth. Fidaxomicin, but not vancomycin or metronidazole, persisted in the gut model for >20 days after instillation.

In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection.

OBJECTIVES: We investigated the in vitro activity of cadazolid against 100 Clostridium difficile isolates and its efficacy in a simulated human gut model of C. difficile infection (CDI). METHODS: MICs of cadazolid, metronidazole, vancomycin, moxifloxacin and linezolid were determined using agar incorporation for 100 C. difficile isolates, including 30 epidemic strains (ribotypes 027, 106 and 001) with reduced metronidazole susceptibility, 2 linezolid-resistant isolates and 2 moxifloxacin-resistant isolates. We evaluated the efficacy of two cadazolid dosing regimens (250 versus 750 mg/L twice daily for 7 days) to treat simulated CDI. Microflora populations, C. difficile total viable counts and spores, cytotoxin titres, possible emergence of cadazolid, linezolid or quinolone resistance, and antimicrobial concentrations were monitored throughout. RESULTS: Cadazolid was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The cadazolid geometric mean MIC was 152-fold, 16-fold, 9-fold and 7-fold lower than those of moxifloxacin, linezolid, metronidazole and vancomycin, respectively. Both cadazolid dosing regimens rapidly reduced C. difficile viable counts and cytotoxin with no evidence of recurrence. Cadazolid levels persisted at 50-100-fold supra-MIC for 14 days post-dosing. Cadazolid inhibition of enumerated gut microflora was limited, with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus spp. counts were unaffected. There was no evidence for selection of strains resistant to cadazolid, quinolones or linezolid. CONCLUSIONS: Cadazolid activity was greater than other tested antimicrobials against 100 C. difficile strains. Cadazolid effectively treated simulated CDI in a gut model, with limited impact on the enumerated gut microflora and no signs of recurrence or emergence of resistance within the experimental timeframe.

Effectiveness of a short (4 day) course of oritavancin in the treatment of simulated Clostridium difficile infection using a human gut model.

OBJECTIVES: We previously demonstrated that 7 days of oritavancin instillation effectively treats Clostridium difficile infection (CDI) in a human gut model. Oritavancin may be more effective than vancomycin due to apparently increased activity against spores. We compared the efficacy of shortened dosing duration (4 days) of oritavancin and vancomycin for CDI treatment using the gut model. METHODS: Clindamycin induced CDI in two triple-stage chemostat gut models primed with pooled human faeces and C. difficile ribotype 027 spores. Oritavancin (64 mg/L twice daily) or vancomycin (125 mg/L four times daily) was instilled for 4 days and the effects on C. difficile proliferation and toxin production, and gut microflora were determined. RESULTS: Both oritavancin and vancomycin reduced toxin to undetectable levels. Recurrent C. difficile germination occurred 20 days after vancomycin instillation, with high-level toxin production. Oritavancin reduced C. difficile counts to around the detection limit for the remainder of the experiment, with spores undetectable from day 1 of instillation. Toxin production was reduced to below detectable levels, but was sporadically seen later, despite no evidence of germination. Both oritavancin and vancomycin instillation led to only modest effects on gut microflora. CONCLUSIONS: Shortened courses of oritavancin and vancomycin effectively treated CDI in a human gut model, but evidence of recurrence was observed following vancomycin instillation. Oritavancin exposure inhibited the recovery of C. difficile spores, as previously described. Shortened antibiotic exposure minimizes disruption to the gut microflora. These data indicate the possible value of a 4 day oritavancin dosing regimen for CDI treatment.

Readability of out-patient letters copied to patients: can patients understand what is written about them?

UNLABELLED: The National Health Service Plan of 2000 proposed that patients should receive a copy of all correspondence regarding their care. There is concern that the readability of patients' letters may not be appropriate for many patients. MATERIALS AND METHODS: This study determined readability scores for sequential letters written to general practitioners and copied to patients, following ENT consultations at the Royal United Hospital in Bath. Intervention involved educating clinicians in techniques to improve readability. RESULTS AND ANALYSIS: A total of 295 letters from eight clinicians were assessed in the pre-intervention phase. The mean Flesch reading ease score was 61.8 (standard deviation 8.7) and the mean Flesch-Kincaid reading grade was 9.0 (standard deviation 1.7). Re-audit analysed a further 301 letters. There was no significant change in the readability of the letters post-intervention. DISCUSSION: It may not be feasible to present medical information intended for general practitioners in a way that is readable to most of the UK adult population.