Effect of Antibiotic Treatment on Growth of and Toxin Production by
            <i>Clostridium difficile</i>
            in the Cecal Contents of Mice

Pultz, Nicole J.; Donskey, Curtis J.

doi:10.1128/aac.49.8.3529-3532.2005

Cited by 67 publications

(85 citation statements)

References 20 publications

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“…This is consistent with the clinical observation that the risk of subsequent CDI differs with different antibiotics 33 and in vitro and animal studies that also differentiate antibiotics on the basis of their ability to overcome colonization resistance against C. difficile. 31,34,35 Taken together these results suggest that this murine infection model accurately represents competition between two Enterococcus. 41 However, in our animals we did not find a direct relationship between changes in RegIIIγ expression following antibiotic treatment and colonization resistance to C. difficile (data not shown).…”

Section: Discussionmentioning

confidence: 56%

“…15 In rare cases where normal individuals are colonized by C. difficile without overt clinical disease, it is further hypothesized that the normal indigenous microbiota can at least limit the production of toxin, perhaps by directly interfering with toxin production or limiting the population size of C. difficile and preventing significant amounts of toxin from accumulating in the gut. 15,31 Accordingly, disruption of the indigenous microbiota by antibiotics leads to a loss of colonization resistance, making the gut vulnerable to colonization by exogenous C. difficile spores or, in previously colonized patients, expansion and toxin production. In support of this concept, Wilson and colleagues provided evidence for the ability of the normal gut microbiota to inhibit C. difficile by demonstrating that administration of normal cecal homogenates would decrease the number of viable C. difficile and prevent colitis in antibioticchallenged hamsters.…”

Section: Discussionmentioning

confidence: 99%

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The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

et al. 2011

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

et al. 2011

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“…Using a mouse model, we previously demonstrated that antibiotics that disrupt the anaerobic microflora (e.g., clindamycin and ceftriaxone) promoted in vitro growth of (Ն2-log increase in density after inoculation of 4 log 10 CFU/ml) and toxin production by nonepidemic C. difficile isolates in cecal contents, whereas antibiotics that cause minimal disruption of the anaerobic microflora, including levofloxacin, did not (Ն1-log decrease in density) (12). Piperacillin-tazobactam, an agent with inhibitory activity against many C. difficile isolates, suppressed the organism during treatment, but overgrowth and toxin production were promoted if exposure occurred after treatment during the period of recovery of the indigenous microflora (12).…”

mentioning

confidence: 99%

Effect of Fluoroquinolone Treatment on Growth of and Toxin Production by Epidemic and Nonepidemic Clostridium difficile Strains in the Cecal Contents of Mice

Adams

Riggs

Donskey

2007

Antimicrob Agents Chemother

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Several recent outbreaks of Clostridium difficile-associated disease (CDAD) have been attributed to the emergence of an epidemic strain with increased resistance to fluoroquinolone antibiotics. Some clinical studies have suggested that fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) may have a greater propensity to induce CDAD than ciprofloxacin and levofloxacin do. We examined the effects of subcutaneous fluoroquinolone treatment on in vitro growth of and toxin production by epidemic and nonepidemic C. difficile isolates in cecal contents of mice and evaluated the potential for these agents to inhibit fluoroquinolone-susceptible isolates during treatment. When C. difficile isolates were inoculated into cecal contents collected 2 days after the final antibiotic dose, gatifloxacin and moxifloxacin promoted significantly more growth and toxin production than ciprofloxacin and levofloxacin did. During treatment, gatifloxacin and moxifloxacin inhibited growth of fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates. Ciprofloxacin and levofloxacin promoted growth of C. difficile when administered at higher doses (i.e., 20 times the human dose in mg/kg of body weight), and levofloxacin inhibited growth of fluoroquinolone-susceptible, but not fluoroquinolone-resistant, C. difficile isolates when administered in combination with ceftriaxone. Thus, fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) promoted C. difficile growth to a greater extent than did ciprofloxacin and levofloxacin in this model. However, our findings suggest that fluoroquinolones may exert selective pressure favoring the emergence of epidemic fluoroquinolone-resistant C. difficile strains by inhibiting fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates during treatment and that agents such as levofloxacin or ciprofloxacin can exert such selective pressure when administered in combination with antibiotics that disrupt the anaerobic microflora.

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“…One possible explanation is the variation of C. difficile counts in vivo, as these correlated with fecal toxin levels in mice (31) and were on average 100-fold higher in CDAD patients than in asymptomatic C. difficile carriers (24). However, although broth cultures of individual isolates generated similar and reproducible optical densities and bacterial counts, we could not reliably determine C. difficile counts in feces using the selective medium TCCFA.…”

mentioning

confidence: 99%

“…CDAD is associated mainly with the use of antibiotics that reduce the protective microflora, which allows for overgrowth and toxin production by C. difficile (21), and chemostat and animal studies have verified that certain antibiotics induce C. difficile growth, toxin production, and toxin release (11,29,31). Furthermore, the age of the patient, underlying diseases, and levels of toxin-neutralizing antibodies are factors that affect attack rate, severity of disease, and the risk of relapse of CDAD (17,18,21,38).…”

mentioning

confidence: 99%

Correlation of Disease Severity with Fecal Toxin Levels in Patients with Clostridium difficile -Associated Diarrhea and Distribution of PCR Ribotypes and Toxin Yields In Vitro of Corresponding Isolates

Svenungsson²,

et al. 2006

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We investigated in vivo and in vitro yields of toxins A and B from and PCR ribotypes of Clostridium difficile isolates from 164 patients with differing severities of C. difficile-associated diarrhea (CDAD) (patients were grouped as follows: <3 loose stools per day, n ‫؍‬ 45; 3 to 10 per day, n ‫؍‬ 97; >10 per day, n ‫؍‬ 22). The median fecal toxin levels in each group were 0.5, 6.8, and 149 U/g feces (P < 0.001), respectively. Patients with severe diarrhea also had more-frequent occurrence of blood in stool and vomiting, but there was no association with fecal toxin levels per se. There was no correlation between fecal toxin level and toxin yield in vitro for the corresponding C. difficile isolate or between its PCR ribotype and disease severity. A broad range of toxin yields among isolates belonging to major PCR ribotypes indicated a presence of many subtypes. We hypothesize that bacterial and host factors that affect C. difficile toxin levels in feces are important determinants of symptoms in CDAD patients. An inverse correlation between toxin yield and spore count (r ‫؍‬ 0.66) in stationary-phase cultures supported the notion that toxin production and sporulation represent opposite alternative survival strategies for C. difficile cells facing nutrient shortage.Most strains of Clostridium difficile produce two toxins, A and B, that cause C. difficile-associated diarrhea (CDAD) with symptoms ranging from mild diarrhea to pseudomembranous colitis. CDAD is associated mainly with the use of antibiotics that reduce the protective microflora, which allows for overgrowth and toxin production by C. difficile (21), and chemostat and animal studies have verified that certain antibiotics induce C. difficile growth, toxin production, and toxin release (11,29,31). Furthermore, the age of the patient, underlying diseases, and levels of toxin-neutralizing antibodies are factors that affect attack rate, severity of disease, and the risk of relapse of CDAD (17,18,21,38). In addition, factors that differ between toxin-producing C. difficile strains, e.g., the amount of toxin produced, the serogroup, and the surface layer protein composition, may affect symptoms (12,14,20,25,32,33). For example, strains of C. difficile belonging to specific serogroups are highly virulent in animal models (3,8), but whether C. difficile strain types differ in terms of virulence in humans is less clear.The epidemiology and disease pattern of C. difficile strains have been studied by several methods, e.g., serotyping, toxinotyping, and PCR ribotyping (4). A cohort study showed no difference in the distributions of C. difficile immunoblot types between asymptomatic carriers and CDAD patients, suggesting that patient factors or bacterial numbers contribute to disease more than the properties of specific C. difficile strain types (24). In addition, for a total of 62 C. difficile strains isolated from 17 patients with CDAD and 11 carriers and typed by PCR ribotyping and by use of randomly amplified polymorphic DNA, no significant correlation between ge...

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Effect of Antibiotic Treatment on Growth of and Toxin Production by Clostridium difficile in the Cecal Contents of Mice

Cited by 67 publications

References 20 publications

The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

The interplay between microbiome dynamics and pathogen dynamics in a murine model ofClostridium difficileInfection

Effect of Fluoroquinolone Treatment on Growth of and Toxin Production by Epidemic and Nonepidemic Clostridium difficile Strains in the Cecal Contents of Mice

Correlation of Disease Severity with Fecal Toxin Levels in Patients with Clostridium difficile -Associated Diarrhea and Distribution of PCR Ribotypes and Toxin Yields In Vitro of Corresponding Isolates

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