Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D

Disclosures

Am J Health Syst Pharm. 2012;69(11):933-943. 

In This Article

Microbiology

Fidaxomicin, a narrow-spectrum antibiotic, has activity primarily against gram-positive aerobes and anaerobes and lacks activity against gram-negative organisms.[34–36] It has activity against gram-positive organisms, such as enterococci and staphylococci, but is considered bactericidal against C. difficile.[36] The minimum inhibitory concentration (MIC) for 90% of organisms (MIC90) for fidaxomicin against C. difficile ranged from 0.0078 to 2 μg/mL in in vitro studies.[35–39]Table 1 compares the in vitro activity of fidaxomicin, metronidazole, and vancomycin against C. difficile isolates. Overall, MIC50 and MIC90 ranges against C. difficile were lower for fidaxomicin compared with those for metronidazole and vancomycin.[35–39] Citron et al.[38] reported that the MIC90 for fidaxomicin was the same for either the NAP1/BI/027 or non-NAP1/BI/027 strain.

Fidaxomicin and its active metabolite, OP-1118, have been evaluated for activity against normal human gastrointestinal flora. The effects of fidaxomicin and vancomycin on normal flora were compared by analyzing the changes in Bacteroides species counts over a 10-day treatment period.[40] Irrespective of the daily dose (i.e., 100–400 mg/day), fidaxomicin did not significantly alter Bacteroides species counts. In contrast, vancomycin 125 mg administered four times daily orally significantly reduced the mean ± S.D. log10 colony-forming units of Bacteroides species per gram of stool (7.4 ± 2.7 on day 0 versus 3.6 ± 1.9 on day 10, p < 0.03). Another in vitro study compared the activity of fidaxomicin and OP-1118 against commensal intestinal flora and C. difficile.[41] OP-1118 was found to have an antibacterial spectrum similar to that of its parent compound, but MIC values were 4− to 16-fold greater with OP-1118 versus fidaxomicin (Table 2). The effect of fidaxomicin on the acquisition of vancomycin-resistant enterococci (VRE) has also been reported.[42] In subjects with stool cultures initially negative for VRE, there was a 33% (n = 160) acquisition of VRE in vancomycin-treated subjects versus 7% (n = 115) acquisition of VRE in the fidaxomicin-treated subjects (p = 0.001).

To assess the effect of protein binding on antimicrobial activity, a susceptibility method, microbroth dilution, was performed in the presence and absence of 5% fecal material.[41] MIC values against C. difficile increased from 1 to 4 μg/mL for OP-1118 and from 0.25 to 2 μg/mL for fidaxomicin when 5% fecal material was added. However, the fecal concentrations of both agents were well above MIC values against C. difficile, suggesting that protein binding is unlikely to affect antimicrobial activity.

Fidaxomicin was shown to have a postantibiotic effect (PAE) ranging from 5.5 to 12.5 hours.[43] The long PAE, in comparison with vancomycin (0–1.5 hours), likely contributes to fidaxomicin's efficacy. The antibacterial activity of fidaxomicin was evaluated in the presence of different cations, using variations in pH (6–8), varying innoculum densities, and different commercial lots of media.[43,44] There was no increase in fidaxomicin's MIC between pH 6.2 and 7, but an eightfold increase in fidaxomicin's MIC against C. difficile was noted at pH 7.9.[44]

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