PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
 
Antimicrob Agents Chemother. 2010 May; 54(5): 2273–2275.
Published online 2010 March 22. doi:  10.1128/AAC.00090-10
PMCID: PMC2863674

In Vitro Activity of Fidaxomicin (OPT-80) Tested against Contemporary Clinical Isolates of Staphylococcus spp. and Enterococcus spp. [down-pointing small open triangle]

Fidaxomicin (formerly OPT-80) is a narrow-spectrum investigational, nonabsorbed oral agent being developed for the treatment of Clostridium difficile infection (CDI), which is not uncommon among hospitalized patients, resulting in longer hospital stays and increased medical care costs and mortality (2, 6, 7, 9-13, 15, 16). Current CDI therapies are compromised by high recurrence rates and risk of selection for vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) colonization (1, 14). Fidaxomicin, similar to other RNA polymerase inhibitors (8), is active against gram-positive organisms while exhibiting little activity against gram-negative species (7). Furthermore, fidaxomicin clinical trials (phase 2 dose-ranging and phase 3 versus vancomycin for the treatment of CDI) have demonstrated a safety profile (15) similar to that of vancomycin but with a statistically and clinically significant reduction in relapse rate (P = 0.004) and improved clinical “global cure” (cure with no relapse; P = 0.006) rates compared to vancomycin (2, 9, 12, 13). While several in vitro studies have noted fidaxomicin to be highly active against gram-positive anaerobes, including C. difficile (2, 6, 7), data on its activity against gram-positive aerobic pathogens that can colonize the intestinal tract 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 (Tables (Tables11 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 collections (Network on Antimicrobial Resistance in Staphylococcus aureus). These strains were identified to the species level by at least two clinical microbiology laboratories, including a reference facility (JMI Laboratories, North Liberty, IA). Antimicrobial agents tested against these staphylococci and enterococci included fidaxomicin (Optimer Pharmaceuticals, San Diego, CA) and 16 comparison antimicrobials. The collection was processed and interpreted by the reference broth microdilution method performed according to the Clinical and Laboratory Standards Institute (CLSI) standards (4, 5), and interpretive criteria for comparator agents were those published in CLSI M100-S19 (5).

TABLE 1.
Fidaxomicin activity against 215 isolates of S. aureus, CoNS, E. faecalis, and E. faecium, including resistant subsets of each species group
TABLE 2.
Comparative activities of fidaxomicin and vancomycin against Staphylococcus and Enterococcus spp. (215 strains) tested by reference methodsd

All fidaxomicin MIC results for S. aureus were 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 had no effect on fidaxomicin MIC values (Table (Table1).1). Overall, S. aureus had 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; Tables Tables11 and and2).2). A wider range of fidaxomicin MIC values (≤0.5 to 8 μg/ml) was observed for coagulase-negative staphylococci (CoNS). As with S. aureus, methicillin resistance and mupirocin or linezolid nonsusceptibility (5) did not influence fidaxomicin MIC results for CoNS (Table (Table1).1). For enterococci, the fidaxomicin MIC distribution ranged from 1 to 8 μg/ml, with 97.5% of all isolates having MIC values of ≤4 μg/ml. Fidaxomicin was 2-fold more active against E. faecalis (MIC50/90, 2 μg/ml) when compared to E. faecium (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 used for these species). All E. faecalis isolates were inhibited by ≤4 μg/ml fidaxomicin, and vancomycin resistance had no significant effect on fidaxomicin potency. Fidaxomicin MIC values for E. faecium 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 S. aureus, CoNS, E. faecalis, and E. faecium (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 in vitro report has described fidaxomicin MIC values tested against a small number (40 strains) of clinically relevant staphylococci (mixed S. aureus and CoNS population) 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 μg/ml compared to MIC90 of 8 μg/ml, respectively) (7). Neither study observed a fidaxomicin MIC of >16 μg/ml.

Current antimicrobials used 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, 11-14). Both oral vancomycin and metronidazole have been shown to promote persistent 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 reported that C. difficile-infected patients who received fidaxomicin were less likely to be subsequently colonized with VRE compared to patients receiving vancomycin treatment (13). These authors and others (11) concluded that the difference in colonization rates between the treatment groups may be due to the fidaxomicin inhibitory activity against VRE strains (MIC90, 2 to 4 μg/ml; Table Table1)1) and the concurrent nondisruption of normal anaerobic bowel flora (11, 13). These data show that fidaxomicin has modest antimicrobial activity against staphylococci and enterococci, regardless of resistance phenotypes for other antimicrobial classes; but those MIC values were many fold below the reported gut luminal concentrations (15). Expanded, systematic clinical surveillance studies will be required to monitor changes in antimicrobial susceptibility rates among C. difficile, VRE, and normal bowel microflora in patients receiving fidaxomicin for CDI treatment.

Acknowledgments

This investigation was sponsored by an educational/research grant from Optimer Pharmaceuticals, Inc.

Footnotes

[down-pointing small open triangle]Published ahead of print on 22 March 2010.

REFERENCES

1. Al-Nassir, W. N., A. K. Sethi, Y. Li, M. J. Pultz, M. M. Riggs, and C. J. Donskey. 2008. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob. Agents Chemother. 52:2403-2406. [PMC free article] [PubMed]
2. Citron, D. M., F. Babakhani, E. J. Goldstein, K. Nagaro, S. Sambol, P. Sears, Y. K. Shue, and D. N. Gerding. 2009. Typing and susceptibility of bacterial isolates from the fidaxomicin (OPT-80) phase II study for C. difficile infection. Anaerobe 15:234-236. [PubMed]
3. Clinical and Laboratory Standards Institute. 1999. M26-A. Methods for determining bactericidal activity of antimicrobial agents; approved guideline. Clinical and Laboratory Standards Institute, Wayne, PA.
4. Clinical and Laboratory Standards Institute. 2009. M07-A8. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, eighth edition. Clinical and Laboratory Standards Institute, Wayne, PA.
5. Clinical and Laboratory Standards Institute. 2009. M100-S19. Performance standards for antimicrobial susceptibility testing; 19th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.
6. Credito, K. L., and P. C. Appelbaum. 2004. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob. Agents Chemother. 48:4430-4434. [PMC free article] [PubMed]
7. Finegold, S. M., D. Molitoris, M. L. Vaisanen, Y. Song, C. Liu, and M. Bolanos. 2004. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob. Agents Chemother. 48:4898-4902. [PMC free article] [PubMed]
8. Gualtieri, M., P. Villain-Guillot, J. Latouche, J. P. Leonetti, and L. Bastide. 2006. Mutation in the Bacillus subtilis RNA polymerase beta′ subunit confers resistance to lipiarmycin. Antimicrob. Agents Chemother. 50:401-402. [PMC free article] [PubMed]
9. Johnson, A. P. 2007. Drug evaluation: OPT-80, a narrow-spectrum macrocyclic antibiotic. Curr. Opin. Investig. Drugs 8:168-173. [PubMed]
10. Kyne, L., M. B. Hamel, R. Polavaram, and C. P. Kelly. 2002. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin. Infect. Dis. 34:346-353. [PubMed]
11. Louie, T., J. Emery, W. Krulicki, B. Byrne, and M. Mah. 2009. OPT-80 eliminates Clostridium difficile and is sparing of Bacteroides species during treatment of C. difficile infection. Antimicrob. Agents Chemother. 53:261-263. [PMC free article] [PubMed]
12. Louie, T., M. Miller, C. Donskey, K. Mullane, and E. J. Goldstein. 2009. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob. Agents Chemother. 53:223-228. [PMC free article] [PubMed]
13. Nerandzic, M. M., K. Mullane, M. Miller, F. Babakhani, and C. J. Donskey. 2009. Acquisition and overgrowth of vancomycin-resistant enterococci in patients treated with either fidaxomicin (FCX) or vancomycin (VAN) for Clostridium difficile infection, abstr. K-1915. Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother. (ICAAC). American Society for Microbiology, Washington, DC.
14. Sethi, A. K., W. N. Al-Nassir, M. M. Nerandzic, and C. J. Donskey. 2009. Skin and environmental contamination with vancomycin-resistant enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease. Infect. Control Hosp. Epidemiol. 30:13-17. [PubMed]
15. Shue, Y. K., P. S. Sears, S. Shangle, R. B. Walsh, C. Lee, S. L. Gorbach, F. Okumu, and R. A. Preston. 2008. Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob. Agents Chemother. 52:1391-1395. [PMC free article] [PubMed]
16. Wilcox, M. H., L. Mooney, R. Bendall, C. D. Settle, and W. N. Fawley. 2008. A case-control study of community-associated Clostridium difficile infection. J. Antimicrob. Chemother. 62:388-396. [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)