(formerly OPT-80) is a narrow-spectrum investigational nonabsorbed oral agent being developed for the treatment of infection (CDI) which is not uncommon among hospitalized patients resulting in longer hospital stays and increased medical care costs and mortality (2 6 7 9 15 16 Current CDI therapies are compromised by high recurrence rates and risk of selection for vancomycin-resistant enterococci (VRE) and methicillin-resistant (MRSA) colonization (1 14 Fidaxomicin much like other RNA polymerase inhibitors (8) is active against gram-positive organisms while exhibiting little activity against gram-negative species (7). reduction KW-2478 in relapse rate (= 0.004) and improved clinical “global remedy” (remedy with no relapse; = 0.006) rates compared to vancomycin KW-2478 (2 9 12 13 While several studies have noted fidaxomicin to be highly active against gram-positive anaerobes including (2 6 7 data on its activity against gram-positive aerobic pathogens that can colonize the intestinal tract KW-2478 remain limited. In this study we evaluated the potency and activity spectrum of fidaxomicin tested against an international collection of common gram-positive isolates recovered from hospitalized patients including VRE and MRSA. All organisms tested (215 strains) originated from clinical sources (Furniture ?(Furniture11 and ?and2) 2 primarily skin and skin structure infections and bacteremia and were collected from 2004 to 2006 by the SENTRY Antimicrobial Surveillance Program based in 65 medical centers located in Europe (13 countries) Latin America (4 countries) and North America (the United States) or from special stock selections (Network on Antimicrobial Resistance in and spp. (215 strains) tested by reference methodswere within 4 doubling dilutions that ranged from 2 to 16 μg/ml and the presence of resistance mechanisms directed against oxacillin mupirocin linezolid or vancomycin experienced no effect on fidaxomicin MIC values (Table ?(Table1).1). Overall experienced fidaxomicin MIC50 (MIC for 50% of the strains tested) and MIC90 values of 4 and 8 μg/ml respectively with 97.3% of the strains inhibited at ≤8 μg/ml. The fidaxomicin modal and median MIC values for MRSA were 2-fold lower (MIC90 8 μg/ml) compared to those for methicillin-susceptible strains (MIC90 8 μg/ml; Furniture ?Furniture11 and ?and2).2). A wider range of fidaxomicin MIC values (≤0.5 KW-2478 to 8 μg/ml) was observed for coagulase-negative staphylococci (CoNS). As with (MIC50/90 2 μg/ml) when compared to (MIC50/90 4 μg/ml). Among the MRSA isolates tested antimicrobial resistance to erythromycin clindamycin levofloxacin and rifampin was 87.5 43.8 56.3 and 18.8% respectively while the comparative resistance rates among methicillin-susceptible strains were much lower at 16.3 2.3 9.3 and 2.3% respectively (data not shown). Daptomycin inhibited all tested staphylococcal and enterococcal isolates (100.0% susceptible) at the CLSI susceptibility breakpoint concentration (5). While tigecycline breakpoints have not been established by the CLSI for this species group all isolates were inhibited by ≤0.5 μg/ml (U.S. Food and Drug Administration susceptibility breakpoint utilized for these species). All isolates were inhibited by ≤4 μg/ml fidaxomicin and vancomycin resistance experienced no significant effect on fidaxomicin potency. Fidaxomicin MIC values for varied from 1 to 8 μg/ml (MIC50 and MIC90 4 μg/ml) regardless of ampicillin or vancomycin susceptibility patterns (Table ?(Table22). Fidaxomicin displayed limited bactericidal activity (3) against (five representative strains from each species or group) with minimal bactericidal concentration/MIC ratios for all but one strain at ≥16 (95.0%; data not shown). However these experiments did not test fidaxomicin at documented fecal levels (333 to 610 μg/g of stool at 150- to 450-mg dosing) (15). The control agent (vancomycin) did demonstrate some bactericidal activity for 8 of 10 staphylococcal strains but with none observed against the enterococci. Only one other report has explained fidaxomicin MIC values tested against a small number (40 strains) of clinically relevant staphylococci (mixed and CoNS Rabbit Polyclonal to ENDOGL1. populace) and enterococci (7). In that publication fidaxomicin MIC values against staphylococci (MIC90 2 μg/ml) were noted to be more potent when compared to the combined staphylococcal results reported here (MIC90 8 μg/ml). Conversely MIC results for enterococci were 2- to 4-fold lower in our study versus the earlier publication (MIC90 of 4 KW-2478 KW-2478 μg/ml compared to MIC90 of 8 μg/ml respectively) (7). Neither study observed a fidaxomicin MIC of >16 μg/ml. Current antimicrobials utilized for the primary treatment of CDI result in high recurrence rates and may lead to the selection of resistant bacterial subpopulations within the intestinal tract (1 11 Both oral vancomycin and metronidazole have been shown to promote prolonged overgrowth of VRE during CDI therapy (1) as well as increased environmental VRE contamination after resolution of the diarrhea (14). In contrast a recent presentation.