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In vitro activity of new quinolones against Clostridium difficile

In vitro activity of new quinolones against Clostridium difficile Abstract We evaluated the in vitro activities of ofloxacin, levofloxacin, grepafloxacin, trovafloxacin and ciprofloxacin against Clostridium difficile. The MIC90 was 128 mg/L for ofloxacin and levofloxacin, 64 mg/L for ciprofloxacin, 16 mg/L for grepafloxacin and 8 mg/L for trovafloxacin. Thirty per cent of isolates were resistant to trovafloxacin, and rates of resistance to ofloxacin, levofloxacin, grepafloxacin and ciprofloxacin were considerably higher. None of the antimicrobials studied would be a reliable therapeutic option against C. difficile. Whether some of the new fluoroquinolones can induce C. difficile-associated diarrhoea remains to be answered. Introduction Clostridium difficile is the major cause of infectious diarrhoea and pseudomembranous colitis in patients after hospitalization in developed countries.1 Recently, C. difficile has also been described as an important cause of community-acquired diarrhoea.2 There is a temporal relationship between the onset of C. difficile-associated diarrhoea (CDAD) and prior or concurrent antimicrobial therapy. The antimicrobial agents most frequently associated with CDAD seem to be those with a broad antibacterial spectrum but low activity against C. difficile, such as clindamycin, co-amoxiclav and the cephalosporins. Metronidazole and vancomycin are the drugs of choice for the treatment of CDAD and, with some exceptions,3 are highly active against C. difficile strains in vitro. The in vitro activity of the older quinolones against anaerobic bacteria has been reported to be moderate or poor, so they have not been considered for use in treating CDAD. However, these antimicrobials have rarely been involved in the induction of the disease. A few reports have associated ciprofloxacin use with cases of CDAD,4 but the low frequency of cases reported suggests that their ability to induce CDAD is low. Recently, some new quinolones have become available. The spectrum of these new drugs has broadened, and some are active against anaerobes.5 Data on their in vitro activities specifically against C. difficile are limited to studies including a wide range of different anaerobe species in which C. difficile is often represented by only a few isolates.5–7 Our study examines the in vitro activities of new and established quinolones against C. difficile in order to assess their potential utility in the treatment of CDAD and their possible role as inducers of the disease. Materials and methods One hundred and thirteen clinical isolates of toxigenic C. difficile were collected from our routine diagnostic laboratory over a 6 month period (July–December 1998). Strains were identified according to standard biochemical methods and by a cytotoxicity assay. Antimicrobial agents were kindly provided by the following manufacturers: levofloxacin, Hoechst Marion Roussel (Kansas City, KS, USA); grepafloxacin, GlaxoWellcome (London, UK); trovafloxacin, Pfizer (New York, NY, USA); ciprofloxacin, Bayer (Leverkusen, Germany). Ofloxacin was purchased from Sigma Laboratories (St Louis, MO, USA). All agents were prepared and stored according to the manufacturers' instructions. Antimicrobial susceptibility testing was performed by the agar dilution method, on brucella blood agar, according to the National Committee for Clinical Laboratory Standards (NCCLS).8 Strains were tested with an inoculum of 105 cfu applied with a multipoint inoculator. Plates were incubated at 37°C for 48 h in anaerobic conditions (80% nitrogen, 10% hydrogen, 10% carbon dioxide). The MIC was defined as the lowest concentration of the agent that inhibited growth. The appearance of one or two colonies or a barely visible haze was disregarded. Reference strains were included as controls to monitor the antimicrobial susceptibility testing. The breakpoint for resistance (not clearly defined by the NCCLS for the antimicrobials and/or anaerobic bacteria assayed) was ≥2 mg/L for ciprofloxacin and ≥4 mg/L for the remaining agents. Results The in vitro activity of the quinolones against C. difficile is summarized in the Table. MICs ranged from 0.06 mg/L (trovafloxacin) to >128 mg/L (ofloxacin). MIC50s varied from 0.5 mg/L for trovafloxacin to 16 mg/L for ciprofloxacin and ofloxacin and MIC90s from 8 mg/L for trovafloxacin to 128 mg/L for ofloxacin and levofloxacin. With the breakpoints used in this study, all isolates tested were resistant to grepafloxacin. All isolates but one (99%) were resistant to ciprofloxacin or ofloxacin. One hundred and seven isolates (95%) were resistant to levofloxacin and 34 (30%) to trovafloxacin (Table). Discussion CDAD is a significant nosocomial concern, being associated with considerable morbidity and mortality, particularly for people with other underlying diseases. Metronidazole and oral vancomycin constitute the therapy of choice for CDAD. Metronidazole is probably the most widely used antimicrobial agent for this condition. Nevertheless, metronidazole-resistant C. difficile strains have been described recently (9% in our institution3). Treatment with vancomycin is expensive and can select vancomycin-resistant strains of some microorganisms belonging to the normal enteric flora, such as enterococci, with consequent epidemiological impact. Furthermore, ≤30% of relapses have been reported after standard treatments and multiple relapsing episodes are common events. In all these cases, new and efficient treatments would be welcome. So far, most established quinolones have shown low activity against anaerobes and specifically against C. difficile. New quinolones are now available with more promising activity against anaerobic bacteria.5 No clearly standardized breakpoints have been reported for susceptibility testing of anaerobes, especially when testing new drugs. In selecting breakpoints, we considered breakpoints for other microorganisms or those used by other authors in similar conditions.5,7 In our study, the MIC90 was ≥8 mg/L for all the antimicrobials tested. C. difficile showed very high rates of resistance to ciprofloxacin, ofloxacin, levofloxacin and grepafloxacin. Trovafloxacin was much more active against C. difficile than the other quinolones, but a third of the isolates tested were resistant to trovafloxacin. Although trovafloxacin has recently been banned in the European Union owing to potential hepatotoxicity, we included it in our study because some other countries are still using it or are planning to introduce it in the near future. It is not known whether C. difficile, which may, in small numbers, be part of the normal enteric flora, overgrows because of suppression of the susceptible flora by antimicrobials or whether it is acquired exogenously after the reduction of the indigenous flora which may, normally, act as a barrier to infection. To our knowledge, with one exception,9 there are no reports of CDAD being induced by the new quinolones, although it is possible that, because of their broader antibacterial spectrum and hence their potential reduction of the normal flora, they might be more likely to induce CDAD. As shown by our results, these new drugs do not have good anti-clostridial activity. A recent study indicates that trovafloxacin can suppress bowel flora without causing overgrowth of C. difficile after 17 days of follow-up.10 However, in the intensive care unit of our hospital, two patients who were given trovafloxacin 300 mg/day orally for 21 days to treat lower respiratory tract infection both had severe episodes of diarrhoea in which toxigenic C. difficile was isolated from stool samples (on day 6 in one patient and on day 15 in the other). In both cases, anti-clostridial therapy was introduced, with a favourable clinical outcome (unpublished data). In our opinion, none of the antimicrobials studied offers a reliable therapeutic option for CDAD. Their role as potential inducers of CDAD, resulting from both their lack of favourable activity against C. difficile and their wide spectrum of antimicrobial activity, which includes many anaerobic bacteria, remains unknown. Table. In vitro activities of quinolones against 113 clinical isolates of C. difficile . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 Open in new tab Table. In vitro activities of quinolones against 113 clinical isolates of C. difficile . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 Open in new tab * Corresponding author. Tel: +34-91-586-87-93; Fax: +34-91-504-49-06; E-mail: [email protected] We are grateful to Thomas O'Boyle for his corrections to our English in this manuscript. References 1 Gerding, D. N., Johnson, S., Peterson, L. R., Mulligan, M. E. & Silva, J. ( 1995 ). Clostridium difficile-associated diarrhoea and colitis. Infection Control and Hospital Epidemiology 16 , 459 –77. 2 Kyne, L., Merry, C., O'Connell, B., Keane, C. & O'Neill, D ( 1998 ). Community-acquired Clostridium difficile infection. Journal of Infection 36 , 287 –8. 3 Peláez, T., Alcalá, L., Martínez-Sánchez, L., Muñoz, P., García-Lechuz, J. M., Rodríguez-Creixems, M. et al. (1998). Metronidazole resistance in Clostridium difficile: a new emerging problem? In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract E-173, p. 219. American Society for Microbiology, Washington, DC. 4 Hillman, R. J., Rao, G. G., Harris, J. R. & Taylor-Robinson, D. ( 1990 ). Ciprofloxacin as a cause of Clostridium difficile-associated diarrhoea in an HIV antibody-positive patient. Journal of Infection 21 , 205 –7. 5 Nord, C. E. ( 1996 ). In vitro activity of quinolones and other antimicrobial agents against anaerobic bacteria. Clinical Infectious Diseases 23 , Suppl. 1, S15 –8. 6 Wexler, H. M., Molitoris, E., Reeves, D. & Finegold, S. M. ( 1994 ). In vitro activity of DU-6859a against anaerobic bacteria. Antimicrobial Agents and Chemotherapy 38 , 2504 –9. 7 Woodcock, J. M., Andrews, J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. ( 1997 ). In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 41 , 101 –6. 8 National Commitee for Clinical Laboratory Standards. (1997). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fourth Edition: Approved Standard M11-A4. NCCLS, Villanova, PA. 9 Inagaki, Y., Yamamoto, N., Chida, T., Okamura, N. & Tanaka, M. ( 1995 ). The effect of DU-6859a, a new potent fluoroquinolone, on faecal microflora in human volunteers. Japanese Journal of Antibiotics 48 , 368 –79. 10 van Nispen, C. H., Hoepelman, A. I., Rozenberg-Arska, M., Verhoef, J., Purkins, L. & Willavize, S. A. ( 1998 ). A double-blind, placebo-controlled, parallel group study of oral trovafloxacin on bowel microflora in healthy male volunteers. American Journal of Surgery 176 , 27S –31S. © 2001 The British Society for Antimicrobial Chemotherapy http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

In vitro activity of new quinolones against Clostridium difficile

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Oxford University Press
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© 2001 The British Society for Antimicrobial Chemotherapy
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0305-7453
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1460-2091
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10.1093/jac/47.2.195
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Abstract

Abstract We evaluated the in vitro activities of ofloxacin, levofloxacin, grepafloxacin, trovafloxacin and ciprofloxacin against Clostridium difficile. The MIC90 was 128 mg/L for ofloxacin and levofloxacin, 64 mg/L for ciprofloxacin, 16 mg/L for grepafloxacin and 8 mg/L for trovafloxacin. Thirty per cent of isolates were resistant to trovafloxacin, and rates of resistance to ofloxacin, levofloxacin, grepafloxacin and ciprofloxacin were considerably higher. None of the antimicrobials studied would be a reliable therapeutic option against C. difficile. Whether some of the new fluoroquinolones can induce C. difficile-associated diarrhoea remains to be answered. Introduction Clostridium difficile is the major cause of infectious diarrhoea and pseudomembranous colitis in patients after hospitalization in developed countries.1 Recently, C. difficile has also been described as an important cause of community-acquired diarrhoea.2 There is a temporal relationship between the onset of C. difficile-associated diarrhoea (CDAD) and prior or concurrent antimicrobial therapy. The antimicrobial agents most frequently associated with CDAD seem to be those with a broad antibacterial spectrum but low activity against C. difficile, such as clindamycin, co-amoxiclav and the cephalosporins. Metronidazole and vancomycin are the drugs of choice for the treatment of CDAD and, with some exceptions,3 are highly active against C. difficile strains in vitro. The in vitro activity of the older quinolones against anaerobic bacteria has been reported to be moderate or poor, so they have not been considered for use in treating CDAD. However, these antimicrobials have rarely been involved in the induction of the disease. A few reports have associated ciprofloxacin use with cases of CDAD,4 but the low frequency of cases reported suggests that their ability to induce CDAD is low. Recently, some new quinolones have become available. The spectrum of these new drugs has broadened, and some are active against anaerobes.5 Data on their in vitro activities specifically against C. difficile are limited to studies including a wide range of different anaerobe species in which C. difficile is often represented by only a few isolates.5–7 Our study examines the in vitro activities of new and established quinolones against C. difficile in order to assess their potential utility in the treatment of CDAD and their possible role as inducers of the disease. Materials and methods One hundred and thirteen clinical isolates of toxigenic C. difficile were collected from our routine diagnostic laboratory over a 6 month period (July–December 1998). Strains were identified according to standard biochemical methods and by a cytotoxicity assay. Antimicrobial agents were kindly provided by the following manufacturers: levofloxacin, Hoechst Marion Roussel (Kansas City, KS, USA); grepafloxacin, GlaxoWellcome (London, UK); trovafloxacin, Pfizer (New York, NY, USA); ciprofloxacin, Bayer (Leverkusen, Germany). Ofloxacin was purchased from Sigma Laboratories (St Louis, MO, USA). All agents were prepared and stored according to the manufacturers' instructions. Antimicrobial susceptibility testing was performed by the agar dilution method, on brucella blood agar, according to the National Committee for Clinical Laboratory Standards (NCCLS).8 Strains were tested with an inoculum of 105 cfu applied with a multipoint inoculator. Plates were incubated at 37°C for 48 h in anaerobic conditions (80% nitrogen, 10% hydrogen, 10% carbon dioxide). The MIC was defined as the lowest concentration of the agent that inhibited growth. The appearance of one or two colonies or a barely visible haze was disregarded. Reference strains were included as controls to monitor the antimicrobial susceptibility testing. The breakpoint for resistance (not clearly defined by the NCCLS for the antimicrobials and/or anaerobic bacteria assayed) was ≥2 mg/L for ciprofloxacin and ≥4 mg/L for the remaining agents. Results The in vitro activity of the quinolones against C. difficile is summarized in the Table. MICs ranged from 0.06 mg/L (trovafloxacin) to >128 mg/L (ofloxacin). MIC50s varied from 0.5 mg/L for trovafloxacin to 16 mg/L for ciprofloxacin and ofloxacin and MIC90s from 8 mg/L for trovafloxacin to 128 mg/L for ofloxacin and levofloxacin. With the breakpoints used in this study, all isolates tested were resistant to grepafloxacin. All isolates but one (99%) were resistant to ciprofloxacin or ofloxacin. One hundred and seven isolates (95%) were resistant to levofloxacin and 34 (30%) to trovafloxacin (Table). Discussion CDAD is a significant nosocomial concern, being associated with considerable morbidity and mortality, particularly for people with other underlying diseases. Metronidazole and oral vancomycin constitute the therapy of choice for CDAD. Metronidazole is probably the most widely used antimicrobial agent for this condition. Nevertheless, metronidazole-resistant C. difficile strains have been described recently (9% in our institution3). Treatment with vancomycin is expensive and can select vancomycin-resistant strains of some microorganisms belonging to the normal enteric flora, such as enterococci, with consequent epidemiological impact. Furthermore, ≤30% of relapses have been reported after standard treatments and multiple relapsing episodes are common events. In all these cases, new and efficient treatments would be welcome. So far, most established quinolones have shown low activity against anaerobes and specifically against C. difficile. New quinolones are now available with more promising activity against anaerobic bacteria.5 No clearly standardized breakpoints have been reported for susceptibility testing of anaerobes, especially when testing new drugs. In selecting breakpoints, we considered breakpoints for other microorganisms or those used by other authors in similar conditions.5,7 In our study, the MIC90 was ≥8 mg/L for all the antimicrobials tested. C. difficile showed very high rates of resistance to ciprofloxacin, ofloxacin, levofloxacin and grepafloxacin. Trovafloxacin was much more active against C. difficile than the other quinolones, but a third of the isolates tested were resistant to trovafloxacin. Although trovafloxacin has recently been banned in the European Union owing to potential hepatotoxicity, we included it in our study because some other countries are still using it or are planning to introduce it in the near future. It is not known whether C. difficile, which may, in small numbers, be part of the normal enteric flora, overgrows because of suppression of the susceptible flora by antimicrobials or whether it is acquired exogenously after the reduction of the indigenous flora which may, normally, act as a barrier to infection. To our knowledge, with one exception,9 there are no reports of CDAD being induced by the new quinolones, although it is possible that, because of their broader antibacterial spectrum and hence their potential reduction of the normal flora, they might be more likely to induce CDAD. As shown by our results, these new drugs do not have good anti-clostridial activity. A recent study indicates that trovafloxacin can suppress bowel flora without causing overgrowth of C. difficile after 17 days of follow-up.10 However, in the intensive care unit of our hospital, two patients who were given trovafloxacin 300 mg/day orally for 21 days to treat lower respiratory tract infection both had severe episodes of diarrhoea in which toxigenic C. difficile was isolated from stool samples (on day 6 in one patient and on day 15 in the other). In both cases, anti-clostridial therapy was introduced, with a favourable clinical outcome (unpublished data). In our opinion, none of the antimicrobials studied offers a reliable therapeutic option for CDAD. Their role as potential inducers of CDAD, resulting from both their lack of favourable activity against C. difficile and their wide spectrum of antimicrobial activity, which includes many anaerobic bacteria, remains unknown. Table. In vitro activities of quinolones against 113 clinical isolates of C. difficile . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 Open in new tab Table. In vitro activities of quinolones against 113 clinical isolates of C. difficile . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 . Number of isolates with indicated MICa . . . . Antimicrobial . 0.06 . 0.12 . 0.25 . 0.5 . 1 . 2 . 4 . 8 . 16 . 32 . 64 . 128 . >128 . MIC50a . MIC90a . % Resistant . a mg/L. Ciprofloxacin 0 0 1 0 0 0 8 45 24 22 13 0 0 16 64 99 Ofloxacin 0 0 0 0 0 1 24 24 11 9 20 16 8 16 128 99 Levofloxacin 0 0 0 0 0 6 52 0 0 12 14 29 0 4 128 95 Grepafloxacin 0 0 0 0 0 0 26 43 35 8 1 0 0 8 16 100 Trovafloxacin 2 7 18 29 14 9 10 24 0 0 0 0 0 0.5 8 30 Open in new tab * Corresponding author. Tel: +34-91-586-87-93; Fax: +34-91-504-49-06; E-mail: [email protected] We are grateful to Thomas O'Boyle for his corrections to our English in this manuscript. References 1 Gerding, D. N., Johnson, S., Peterson, L. R., Mulligan, M. E. & Silva, J. ( 1995 ). Clostridium difficile-associated diarrhoea and colitis. Infection Control and Hospital Epidemiology 16 , 459 –77. 2 Kyne, L., Merry, C., O'Connell, B., Keane, C. & O'Neill, D ( 1998 ). Community-acquired Clostridium difficile infection. Journal of Infection 36 , 287 –8. 3 Peláez, T., Alcalá, L., Martínez-Sánchez, L., Muñoz, P., García-Lechuz, J. M., Rodríguez-Creixems, M. et al. (1998). Metronidazole resistance in Clostridium difficile: a new emerging problem? In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract E-173, p. 219. American Society for Microbiology, Washington, DC. 4 Hillman, R. J., Rao, G. G., Harris, J. R. & Taylor-Robinson, D. ( 1990 ). Ciprofloxacin as a cause of Clostridium difficile-associated diarrhoea in an HIV antibody-positive patient. Journal of Infection 21 , 205 –7. 5 Nord, C. E. ( 1996 ). In vitro activity of quinolones and other antimicrobial agents against anaerobic bacteria. Clinical Infectious Diseases 23 , Suppl. 1, S15 –8. 6 Wexler, H. M., Molitoris, E., Reeves, D. & Finegold, S. M. ( 1994 ). In vitro activity of DU-6859a against anaerobic bacteria. Antimicrobial Agents and Chemotherapy 38 , 2504 –9. 7 Woodcock, J. M., Andrews, J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. ( 1997 ). In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 41 , 101 –6. 8 National Commitee for Clinical Laboratory Standards. (1997). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fourth Edition: Approved Standard M11-A4. NCCLS, Villanova, PA. 9 Inagaki, Y., Yamamoto, N., Chida, T., Okamura, N. & Tanaka, M. ( 1995 ). The effect of DU-6859a, a new potent fluoroquinolone, on faecal microflora in human volunteers. Japanese Journal of Antibiotics 48 , 368 –79. 10 van Nispen, C. H., Hoepelman, A. I., Rozenberg-Arska, M., Verhoef, J., Purkins, L. & Willavize, S. A. ( 1998 ). A double-blind, placebo-controlled, parallel group study of oral trovafloxacin on bowel microflora in healthy male volunteers. American Journal of Surgery 176 , 27S –31S. © 2001 The British Society for Antimicrobial Chemotherapy

Journal

Journal of Antimicrobial Chemotherapy – Oxford University Press

Published: Feb 1, 2001

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