Fidaxomicin Inhibits Spore Production in Clostridium difficile.

Clin Infect Dis. 2012 Aug;55 Suppl 2:S162-9

Authors: Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL

Abstract

Fidaxomicin (FDX) is a novel antimicrobial agent with narrow-spectrum and potent bactericidal activity against Clostridium difficile. In recent clinical trials, FDX was superior to vancomycin in preventing recurrences of C. difficile infection. A possible mechanism of reducing recurrence may be through an inhibitory effect on sporulation. The effect of FDX and its major metabolite, OP-1118, on C. difficile growth and sporulation kinetics was compared with that of vancomycin, metronidazole, and rifaximin. Drugs at subminimum inhibitory concentrations (sub-MICs) were added to cells at an early stationary phase of growth; this was followed by collection of cells at various intervals for quantitation of total viable cell and heat-resistant spore counts on taurocholate-containing media. The effect of the drugs at 2-2.5Ã MIC on the expression of sporulation genes in C. difficile was also compared using quantitative reverse-transcriptase polymerase chain reaction. Both FDX and OP-1118 (1/4Ã MIC) inhibited sporulation when added to early-stationary-phase cells in C. difficile strains, including the epidemic NAP1/BI/027 strain. In contrast, vancomycin, metronidazole, and rifaximin (at similar sub-MICs) did not inhibit sporulation. The number of spores following treatment with comparator drugs increased to the same level as the no-drug control treatment. Expression of mother cell-specific (spoIIID) and forespore-specific (spoIIR) sporulation genes also was inhibited by FDX and OP-1118 but not significantly by vancomycin. Both FDX and OP-1118 (unlike vancomycin, rifaximin, and metronidazole) effectively inhibited sporulation by C. difficile. The inhibitory effect of FDX on C. difficile sporulation may contribute to its superior performance in sustaining clinical response and reducing recurrences and may also be beneficial in decreasing shedding and transmission of this pathogen.

PMID: 22752866 [PubMed - in process]

Relapse Versus Reinfection: Recurrent Clostridium difficile Infection Following Treatment With Fidaxomicin or Vancomycin.

Clin Infect Dis. 2012 Aug;55 Suppl 2:S104-9

Authors: Figueroa I, Johnson S, Sambol SP, Goldstein EJ, Citron DM, Gerding DN

Abstract

Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (±2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (±6.4) days for relapses and 14.7 (±6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates. Clinical Trials Registration. NCT00314951 and NCT00468728.

PMID: 22752857 [PubMed - in process]

Antimicrobial activities of fidaxomicin.

Clin Infect Dis. 2012 Aug;55 Suppl 2:S143-8

Authors: Goldstein EJ, Babakhani F, Citron DM

Abstract

Fidaxomicin is bactericidal against Clostridium difficile. The combined results of 8 in vitro studies of 1323 C. difficile isolates showed the minimum inhibitory concentration (MIC) range of fidaxomicin to be â¤0.001-1 μg/mL, with a maximum MIC for inhibition of 90% of organisms (MIC(90)) of 0.5 μg/mL. Isolates from 2 phase III clinical trials demonstrated that fidaxomicin MICs of baseline isolates did not predict clinical cure, failure, or recurrence of C. difficile infections. No resistance to fidaxomicin developed during treatment in either study, although a single strain recovered from a cured patient had an elevated MIC of 16 µg/mL at the time of recurrence. For 135 strains, OP-1118, a major metabolite, had an MIC for inhibition of 50% of organisms of 4 μg/mL and an MIC(90) of 8 μg/mL. Changes in inoculum size (10(2)-10(5) colony-forming units/spot) or cation concentrations of calcium or magnesium appeared to have no effect on fidaxomicin MICs. Fidaxomicin has little or no activity against gram-negative aerobes and anaerobes or yeast.

PMID: 22752863 [PubMed - in process]