Abstract
Rifaximin, ampicillin-sulbactam, neomycin, nitazoxanide, teicoplanin, and vancomycin were tested against 536 strains of anaerobic bacteria. The overall MIC of rifaximin at which 50% of strains were inhibited was 0.25 μg/ml. Ninety percent of the strains tested were inhibited by 256 μg/ml of rifaximin or less, an activity equivalent to those of teicoplanin and vancomycin but less than those of nitazoxanide and ampicillin-sulbactam.
Intestinal microorganisms play an important role in a variety of human conditions and diseases. In addition to well-characterized diseases of the intestinal tract and infections in other body sites caused by bowel flora, both indigenous and colonizers, members of the gut flora may play a role in ostensibly noninfectious disease processes such as some autoimmune diseases. The increasing virulence and degree of resistance of anaerobic organisms such as Clostridium difficile further highlight the importance of finding and developing antimicrobial agents with selective activity in the gut.
Rifaximin (4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo-[5,4-c]-rifamycin SV) is a synthetic antimicrobial derived from rifamycin that acts by inhibiting bacterial RNA synthesis. It has activity against both gram-positive and gram-negative aerobic and anaerobic organisms. Levels as high as 8,000 μg of rifaximin/g of stool have been found following 3 days of treatment (800 mg daily), and there is negligible absorption of the drug from the gut (3, 5). Few adverse side effects have been reported (12), but development of resistance has been documented during therapy for Clostridium difficile (6, 9) and Bifidobacterium spp. and, to a lesser extent, for Bacteroides spp. and lactobacilli (2).
Orally administered drugs that are very poorly absorbed from the gut, such as rifaximin, may be useful not only for the treatment of intestinal infections but also for certain other situations in which intestinal bacteria may play a role. Rifaximin has been reported to be useful in a variety of infections, including traveler's diarrhea, irritable bowel syndrome, small bowel bacterial overgrowth, ulcerative colitis, mild to moderate Crohn's disease, pouchitis, and hepatic encephalopathy (1, 4).
In this study, the activity of rifaximin was tested against 536 strains of anaerobic bacteria that are found in the human intestinal tract. The results were compared with those obtained for ampicillin-sulbactam, neomycin, nitazoxanide, teicoplanin, and vancomycin.
The bacteria included in this study were recently isolated from patients at the Greater Los Angeles Veterans Administration Healthcare Center and are representative of the indigenous human bowel flora. Bacteria were identified according to established procedures (7), supplemented, when needed (for approximately half of the isolates), by 16S rRNA sequence analysis (10). MICs were determined by the NCCLS (now CLSI)-approved Wadsworth agar dilution technique (8). A test medium supplemented with 1% pyruvic acid was used for the growth of Bilophila wadsworthia. Triphenyltetrazolium chloride was used as an aid in interpreting the growth end points of Bilophila wadsworthia (11).
The antimicrobial agents tested were obtained as powders from the following companies: ampicillin and neomycin from Sigma (St. Louis, MO), nitazoxanide from Romark Pharmaceuticals (Tampa, FL), sulbactam from Pfizer (Groton, CT), teicoplanin from Haorui PharmaChem Inc. (Edison, NJ), rifaximin from Salix Pharmaceuticals (Raleigh, NC), and vancomycin from Voigt Global Distribution (Kansas City, MO).
The MIC ranges and the MICs at which 50% and 90% of isolates were inhibited (MIC50 and MIC90, respectively) are presented in Table 1. Rifaximin demonstrated activity against a wide variety of gram-negative and gram-positive anaerobes, inhibiting 403 of 536 strains (75%) at ≤1 μg/ml. Teicoplanin and vancomycin, as expected, were active mainly against gram-positive organisms. Neomycin had lower activity against all organisms tested. Ampicillin-sulbactam and nitazoxanide had the best activity overall, on a weight basis.
TABLE 1.
In vitro activities of rifaximin and comparator agents against intestinal anaerobes
| Anaerobe (no. of strains tested) and antimicrobial agent | MIC (μg/ml)
|
||
|---|---|---|---|
| 50% | 90% | Range | |
| Bacteroides fragilis (20) | |||
| Ampicillin-sulbactam | 1 | 16 | 0.5-16 |
| Neomycin | >1,024 | >1,024 | >1,024->1,024 |
| Nitazoxanide | 4 | 4 | 2-8 |
| Rifaximin | 0.25 | >1,024 | 0.25->1,024 |
| Teicoplanin | 64 | 128 | 32-128 |
| Vancomycin | 64 | 128 | 16-128 |
| Parabacteroides distasonis/merdae/goldsteinii groupa (17) | |||
| Ampicillin-sulbactam | 16 | 32 | 4-32 |
| Neomycin | 1,024 | >1,024 | 512->1,024 |
| Nitazoxanide | 4 | 4 | 2-4 |
| Rifaximin | 0.25 | 1 | 0.25-1 |
| Teicoplanin | 32 | 256 | 32-512 |
| Vancomycin | 128 | 128 | 32-128 |
| Bacteroides ovatus (11) | |||
| Ampicillin-sulbactam | 8 | 32 | 1-32 |
| Neomycin | >1,024 | >1,024 | 1,024->1,024 |
| Nitazoxanide | 2 | 4 | 1-4 |
| Rifaximin | 1 | 1 | 0.25->1,024 |
| Teicoplanin | 64 | 128 | 32-128 |
| Vancomycin | 128 | 128 | 32-256 |
| Bacteroides thetaiotaomicron (10) | |||
| Ampicillin-sulbactam | 4 | 16 | 2-16 |
| Neomycin | >1,024 | >1,024 | >1,024->1,024 |
| Nitazoxanide | 2 | 8 | 1-8 |
| Rifaximin | 1 | >1,024 | 0.25->1,024 |
| Teicoplanin | 128 | 256 | 32-256 |
| Vancomycin | 128 | 256 | 64-256 |
| Bacteroides vulgatus (11) | |||
| Ampicillin-sulbactam | 16 | 32 | 2-32 |
| Neomycin | >1,024 | >1,024 | >1,024->1,024 |
| Nitazoxanide | 2 | 4 | 0.5-4 |
| Rifaximin | 0.25 | 0.5 | 0.25-4 |
| Teicoplanin | 64 | 64 | 32-128 |
| Vancomycin | 32 | 64 | 16-128 |
| Other Bacteroides fragilis group organismsb (18) | |||
| Ampicillin-sulbactam | 2 | 16 | 0.25-32 |
| Neomycin | >1,024 | >1,024 | 1,024->1,024 |
| Nitazoxanide | 4 | 4 | 1-4 |
| Rifaximin | 0.25 | 0.5 | 0.25-0.5 |
| Teicoplanin | 64 | 128 | 16-128 |
| Vancomycin | 64 | 128 | 64-128 |
| All Bacteroides fragilis group organisms (87) | |||
| Ampicillin-sulbactam | 4 | 32 | 0.25-32 |
| Neomycin | >1,024 | >1,024 | 512->1,024 |
| Nitazoxanide | 2 | 4 | 0.5-8 |
| Rifaximin | 0.25 | 1 | 0.25->1,024 |
| Teicoplanin | 64 | 128 | 16-512 |
| Vancomycin | 64 | 128 | 16-256 |
| Bilophila wadsworthia (13) | |||
| Ampicillin-sulbactam | 8 | 8 | 4-16 |
| Neomycin | >1,024 | >1,024 | 1,024->1,024 |
| Nitazoxanide | 4 | 4 | 2-4 |
| Rifaximin | 32 | 64 | 32-64 |
| Teicoplanin | 512 | 512 | 256-512 |
| Vancomycin | >1,024 | >1,024 | 1,024->1,024 |
| Desulfovibrio speciesc (17) | |||
| Ampicillin-sulbactam | 4 | 32 | 1-32 |
| Neomycin | 256 | 1,024 | 32->1,024 |
| Nitazoxanide | 1 | 4 | 0.25-16 |
| Rifaximin | 16 | 32 | 0.25-64 |
| Teicoplanin | >1,024 | >1,024 | 64->1,024 |
| Vancomycin | >1,024 | >1,024 | 64->1,024 |
| Fusobacterium nucleatum (10) | |||
| Ampicillin-sulbactam | 0.25 | 0.25 | 0.25-0.25 |
| Neomycin | 1,024 | 1,024 | 128-1,024 |
| Nitazoxanide | 0.25 | 0.5 | 0.25-0.5 |
| Rifaximin | 2 | 8 | 0.5-8 |
| Teicoplanin | 256 | 512 | 64-512 |
| Vancomycin | 256 | 512 | 64-512 |
| Other Fusobacterium speciesd (24) | |||
| Ampicillin-sulbactam | 1 | 4 | 0.25-8 |
| Neomycin | 512 | >1,024 | 2->1,024 |
| Nitazoxanide | 1 | 8 | 0.25-8 |
| Rifaximin | 16 | >1,024 | 0.25->1,024 |
| Teicoplanin | 256 | >1,024 | 0.25->1,024 |
| Vancomycin | 256 | >1,024 | 16->1,024 |
| All Fusobacterium species (34) | |||
| Ampicillin-sulbactam | 0.25 | 4 | 0.25-8 |
| Neomycin | 512 | 1,024 | 2->1,024 |
| Nitazoxanide | 0.5 | 8 | 0.25-8 |
| Rifaximin | 8 | >1,024 | 0.25->1,024 |
| Teicoplanin | 256 | >1,024 | 0.25->1,024 |
| Vancomycin | 256 | >1,024 | 16->1,024 |
| Porphyromonas speciese (16) | |||
| Ampicillin-sulbactam | 0.25 | 0.5 | 0.25-1 |
| Neomycin | 512 | >1,024 | 256->1,024 |
| Nitazoxanide | 0.5 | 1 | 0.25-1 |
| Rifaximin | 0.25 | 0.5 | 0.25-1 |
| Teicoplanin | 0.5 | 8 | 0.25-8 |
| Vancomycin | 4 | 8 | 1-16 |
| Prevotella speciesf (31) | |||
| Ampicillin-sulbactam | 0.5 | 4 | 0.25-4 |
| Neomycin | 512 | 1,024 | 8-1,024 |
| Nitazoxanide | 4 | 8 | 0.25-16 |
| Rifaximin | 0.25 | 0.5 | 0.25-1 |
| Teicoplanin | 2 | 4 | 0.25-8 |
| Vancomycin | 128 | 256 | 16-1,024 |
| Total for all gram-negative species (198) | |||
| Ampicillin-sulbactam | 2 | 16 | 0.25-32 |
| Neomycin | 1,024 | >1,024 | 2->1,024 |
| Nitazoxanide | 2 | 4 | 0.25-16 |
| Rifaximin | 0.5 | 64 | 0.25->1,024 |
| Teicoplanin | 64 | >1,024 | 0.25->1,024 |
| Vancomycin | 128 | >1,024 | 1->1,024 |
| Clostridium clostridioforme (11) | |||
| Ampicillin-sulbactam | 1 | 16 | 1-32 |
| Neomycin | 128 | 128 | 32-128 |
| Nitazoxanide | 0.25 | 0.25 | 0.25-0.25 |
| Rifaximin | 0.25 | 0.25 | 0.25-0.25 |
| Teicoplanin | 8 | 16 | 2-16 |
| Vancomycin | 2 | 2 | 1-2 |
| Clostridium difficile (10) | |||
| Ampicillin-sulbactam | 2 | 4 | 1-4 |
| Neomycin | 256 | 512 | 128->1,024 |
| Nitazoxanide | 0.25 | 0.5 | 0.25-0.5 |
| Rifaximin | 0.25 | 0.25 | 0.25-0.25 |
| Teicoplanin | 0.5 | 0.5 | 0.25-0.5 |
| Vancomycin | 1 | 2 | 1-2 |
| Clostridium hathewayi (10) | |||
| Ampicillin-sulbactam | 2 | 2 | 0.5-2 |
| Neomycin | 64 | 512 | 4->1,024 |
| Nitazoxanide | 0.5 | 0.5 | 0.25-0.5 |
| Rifaximin | 0.25 | 0.25 | 0.25-0.25 |
| Teicoplanin | 4 | 8 | 2-8 |
| Vancomycin | 1 | 1 | 0.5-1 |
| Clostridium innocuum (10) | |||
| Ampicillin-sulbactam | 0.25 | 0.5 | 0.25-0.5 |
| Neomycin | >1,024 | >1,024 | 1,024->1,024 |
| Nitazoxanide | 1 | 4 | 0.5-4 |
| Rifaximin | >1,024 | >1,024 | >1,024->1,024 |
| Teicoplanin | 1 | 1 | 0.5-1 |
| Vancomycin | 16 | 256 | 16-256 |
| Clostridium orbiscindens (10) | |||
| Ampicillin-sulbactam | 2 | 4 | 2-4 |
| Neomycin | 256 | 512 | 128-512 |
| Nitazoxanide | 0.25 | 0.5 | 0.25-0.5 |
| Rifaximin | >1,024 | >1,024 | 1,024->1,024 |
| Teicoplanin | 1 | 2 | 1-2 |
| Vancomycin | 8 | 8 | 8-8 |
| Clostridium perfringens (12) | |||
| Ampicillin-sulbactam | 0.25 | 0.25 | 0.25-0.25 |
| Neomycin | 1,024 | >1,024 | 1,024->1,024 |
| Nitazoxanide | 2 | 4 | 0.25-4 |
| Rifaximin | 0.25 | 0.25 | 0.25-0.25 |
| Teicoplanin | 0.25 | 0.25 | 0.25-0.25 |
| Vancomycin | 1 | 1 | 1-1 |
| Other Clostridium speciesg (106) | |||
| Ampicillin-sulbactam | 0.25 | 1 | 0.25-128 |
| Neomycin | 256 | 1,024 | 1->1,024 |
| Nitazoxanide | 0.5 | 4 | 0.25-32 |
| Rifaximin | 0.25 | >1,024 | 0.25->1,024 |
| Teicoplanin | 0.25 | 4 | 0.25->1,024 |
| Vancomycin | 1 | 4 | 0.5->1,024 |
| Total for all Clostridium species (169) | |||
| Ampicillin-sulbactam | 0.5 | 2 | 0.25-128 |
| Neomycin | 256 | >1,024 | 1->1,024 |
| Nitazoxanide | 0.5 | 4 | 0.25-32 |
| Rifaximin | 0.25 | >1,024 | 0.25->1,024 |
| Teicoplanin | 0.5 | 8 | 0.25->1,024 |
| Vancomycin | 1 | 8 | 0.5->1,024 |
| Gram-positive non-spore-forming rodsh (107) | |||
| Ampicillin-sulbactam | 0.25 | 2 | 0.25-4 |
| Neomycin | 128 | 1,024 | 2->1,024 |
| Nitazoxanide | 2 | 32 | 0.25-128 |
| Rifaximin | 0.5 | >1,024 | 0.25->1,024 |
| Teicoplanin | 0.5 | 8 | 0.25->1,024 |
| Vancomycin | 1 | 64 | 0.25->1,024 |
| Anaerobic gram-positive coccii (62) | |||
| Ampicillin-sulbactam | 0.25 | 2 | 0.25-16 |
| Neomycin | 128 | 512 | 2->1,024 |
| Nitazoxanide | 0.5 | 1 | 0.25-2 |
| Rifaximin | 0.25 | 4 | 0.25-16 |
| Teicoplanin | 0.25 | 0.5 | 0.25-4 |
| Vancomycin | 0.5 | 1 | 0.25-8 |
| Total for all gram-positive strains (338) | |||
| Ampicillin-sulbactam | 0.25 | 2 | 0.25-128 |
| Neomycin | 128 | >1,024 | 1->1,024 |
| Nitazoxanide | 1 | 16 | 0.25-128 |
| Rifaximin | 0.25 | >1,024 | 0.25->1,024 |
| Teicoplanin | 0.5 | 4 | 0.25->1,024 |
| Vancomycin | 1 | 8 | 0.25->1,024 |
| Total for all strains (536) | |||
| Ampicillin-sulbactam | 0.5 | 8 | 0.25-128 |
| Neomycin | 512 | >1,024 | 1->1,024 |
| Nitazoxanide | 1 | 8 | 0.25-128 |
| Rifaximin | 0.25 | 256 | 0.25->1,024 |
| Teicoplanin | 1 | 256 | 0.25->1,024 |
| Vancomycin | 4 | 256 | 0.25->1,024 |
Parabacteroides distasonis/merdae (12 strains) and Parabacteroides goldsteinii (5).
Bacteroides caccae (4 strains), Bacteroides nordii (4), Bacteroides stercoris (5), and Bacteroides uniformis (5).
Desulfovibrio desulfuricans (3 strains), Desulfovibrio fairfieldensis (3), Desulfovibrio piger (5), Desulfovibrio vulgaris (2), and Desulfovibrio species (4).
Fusobacterium mortiferum (6 strains), Fusobacterium necrophorum (11), Fusobacterium varium (5), and Fusobacterium species (2).
Porphyromonas asaccharolytica (5 strains), Porphyromonas somerae (6), and Porphyromonas uenonis (5).
Prevotella bivia (5 strains), Prevotella corporis (4), Prevotella disiens (6), Prevotella intermedia/intermedia-nigrescens (5), Prevotella loescheii (5), and Prevotella melaninogenica (6).
Clostridium acetobutylicum (1 strain), Clostridium aminobutyricum (1), Clostridium bartlettii (6), Clostridium beijerinckii (2), Clostridium bifermentans (7), Clostridium bolteae (7), Clostridium butyricum (5), Clostridium cadaveris (3), Clostridium cocleatum (1), Clostridium disporicum (8), Clostridium fallax (1), Clostridium glycolicum (9), Clostridium hastiforme (2), Clostridium lactifermentum (1), Clostridium leptum (1), Clostridium nexile (1), Clostridium paraputrificum (8), Clostridium ramosum (8), Clostridium rectum (1), Clostridium scindens (2), Clostridium septicum (1), Clostridium sordellii (5), Clostridium species (2), Clostridium spiroforme (2), Clostridium sporogenes (5), Clostridium subterminale (8), Clostridium symbiosum (3), and Clostridium tertium (5).
Actinomyces meyeri (3 strains), Actinomyces odontolyticus (4), Actinomyces viscosus (3), Atopobium minutum (3), Bifidobacterium adolescentis (6), Bifidobacterium bifidum (3), Bifidobacterium breve (5), Bifidobacterium dentium (1), Bifidobacterium infantis (2), Bifidobacterium longum (6), Bifidobacterium pseudocatenulatum (5), Bifidobacterium pseudolongum (2), Catenibacterium mitsuokai (2), Collinsella aerofaciens (5), Coprobacillus catenaforme (6), Eggerthella lenta (6), Eubacterium alactolyticum (4), Eubacterium biforme (2), Eubacterium callanderi (1), Eubacterium cylindroides (1), Eubacterium limosum (5), Eubacterium rectale (1), Eubacterium saburreum (3), Holdemania filiformis (2), Lactobacillus acidophilus (2), Lactobacillus catenaforme (3), Lactobacillus fermentum (1), Lactobacillus jensenii (3), Lactobacillus plantarum (3), Lactobacillus reuteri (1), Lactobacillus rhamnosus (3), Lactobacillus species (1), Propionibacterium acnes (4), Propionibacterium avidum (2), and Propionibacterium propionicus (3).
Anaerococcus prevotii (5 strains), Anaerococcus tetradius (5), Finegoldia magna (8), Peptoniphilus asaccharolyticus (5), Peptoniphilus harei (6), Peptostreptococcus anaerobius (6), Peptostreptococcus micros (6), Ruminococcus flavescens (1), Ruminococcus gnavus (8), Ruminococcus lactaris (1), Ruminococcus luti (3), Ruminococcus obeum (4), Ruminococcus productus (3), and Ruminococcus torques (1).
Of note, rifaximin (but not the other drugs) showed a low MIC50 and a very high MIC90 for a number of bacteria (Bacteroides fragilis, Bacteroides thetaiotaomicron, “other Fusobacterium species,” “other Clostridium species,” and gram-positive anaerobic, non-spore-forming rods), suggesting a possible preexisting resistance mechanism for these organisms. MICs were >1,024 μg/ml for 2/20 B. fragilis strains and 1 strain each of Bacteroides ovatus and B. thetaiotaomicron. Among the “other Fusobacterium species,” MICs were >1,024 μg/ml for four of six Fusobacterium mortiferum strains and two of five F. varium strains. With regard to clostridial species, MICs were >1,024 μg/ml for all 10 strains of both Clostridium innocuum and C. orbiscindens, all 8 strains of C. ramosum, both strains of C. spiroforme, and the 1 strain each of C. rectum and C. nexile that were tested. Finally, among the gram-positive non-spore-forming rods, all six strains of Coprobacillus cateniformis, all three strains of Lactobacillus catenaformis, and the one strain of Lactobacillus reuteri were resistant to 1,024 μg/ml of rifaximin, while one of the five Collinsella aerofaciens strains and one of two strains (each) of Eubacterium biforme and Lactobacillus acidophilus were similarly resistant. Thus, certain species, as well as some strains of other species, may be resistant.
In this study we determined the MICs of six antimicrobial agents against 536 anaerobic organisms that are representative of the indigenous bowel flora. Resistance to rifaximin may develop during therapy (2, 6, 9). Administered as an oral agent, rifaximin is virtually nonabsorbed and can achieve high levels in the intestinal tract that, for the most part, exceed the MICs observed in vitro against a wide range of pathogenic organisms. Because of the high levels that agents such as rifaximin, teicoplanin, and vancomycin achieve in the gut, the extent of their activity against broad categories of microorganisms is often underestimated. They have been mistakenly regarded as narrow-spectrum agents because their activity is considered in terms of the CLSI breakpoints, which relate to levels achievable in serum and tissue rather than to levels achieved in the gut (there are no CLSI breakpoints for use against gut organisms). Clostridium difficile-associated colitis has generally responded well to therapy with vancomycin, teicoplanin, metronidazole, or bacitracin, all administered orally; the current data indicate that it may respond well to oral rifaximin as well, but clinical studies are still limited and resistance has been encountered (6, 9). Drugs with broad activity against bowel anaerobes may interfere with colonization resistance and predispose to colonization with vancomycin-resistant enterococci. Other factors that would help determine the relative utility of these various agents would include the usefulness of the compounds for therapy of serious systemic infections, bactericidal activity, drug allergy, cross-resistance with other compounds (particularly those that are used systemically), the frequency of the dosage required, patient tolerance of the medication over prolonged periods, palatability, ease of administration to young children (liquid preparation preferred), and cost.
Acknowledgments
This study was supported in part by a grant from Salix Pharmaceuticals, Inc., Morrisville, NC.
We thank C. M. Warner for technical assistance.
Other than the grant received by S. M. Finegold from Salix Pharmaceuticals, Inc., there is no potential conflict of interest for any of the authors.
Footnotes
Published ahead of print on 27 October 2008.
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