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T2048 Rifaximin Salvage Therapy for Metronidazole-Resistant Clostridium difficile Infection—a Prospective Pilot Trial
AGA Abstracts
total mortality were registered through the official “Cancer registry” and “Statistics Norway”. RESULTS. Six-hundred and eighty-five individuals were found eligible for the screening examination, 445(65%) attended. Ceacal intubation rate was 81%, no sedation was used. The bowel cleansing was regarded satisfactory in 95%. Findings of adenomas were followed up according to Norwegian guidelines. For the period 1996 to 2007, representing 11 years of follow-up, with a total of 1369 person years, altogether 13 cases of CRC, three screening detected, were diagnosed in the screening group, compared to 19 cases in the control group(OR 0,68 (95% confidence interval: 0,34-1,37, p=0,15)). In the screening group and in the control group 173 (25%)and 182 (27%)individuals, respectively, had died during these years, p=0,54. CONLUSION. A once-only colonoscopy screening examination with a high attendance rate in this average risk population showed only a modest non-statistically significant reduction in CRC incidence.
patients were exposed to proton pump inhibitors in the last 3 months; all were CDI resistant to metronidazole (stools positive for toxins A and B after oral metronidazole 500 mg three times daily for 5 days). Oral rifaximin 400 mg three times daily for 14 days was given to all patients as salvage therapy after stopping metronidazole. Patients were followed for 56 days, and stool was tested for C difficile using PCR (Quest Diagnostics, Teterboro, NJ) to assess the effect of treatment. A negative PCR test was defined as favorable response to rifaximin. Exclusions included patients with sepsis; abdominal distention; leukocyte count >20,000/mm3; human immunodeficiency virus infection; multi-organ failure; renal failure; and recent (within the last 6 weeks) exposure to vancomycin or rifampicin and patients on ventilator support, those who were recent organ transplant recipients, and those receiving chemotherapy. Results: Sixteen of twenty-two (64%) patients who completed therapy eradicated the infection (negative CD PCR after 56 days). Three (12%) patients aborted therapy because of abdominal distention. In a per-protocol analysis, 72.7% of patients responded to rifaximin salvage therapy. Oral rifaximin was well tolerated. Conclusions: Rifaximin may be considered in patients in the treatment of mild-to-moderate metronidazole resistant CDI. Larger randomized trials might support these preliminary findings. T2049 The SeqA Protein of Vibrio Cholerae Is Essential for Viability and Its Production Is Growth Phase Regulated Djenann Saint-Dic, Keren Glinert, Troy T. Tweiten, Lyn Sue Kahng Vibrio cholerae is the cause of the epidemic diarrheal disease cholera, and Vibrio species are unique in containing bipartite genomes with a large and a small chromosome. We and others have shown that V. cholerae can contain multiple simultaneously active origins of replication at rapid growth rates. Coordinating the replication of these chromosomes is thus a critical process, particularly as the bacteria must respond to widely differing nutrient conditions in their host and environmental reservoirs. In E. coli, which has only one chromosome, the SeqA protein binds newly-synthesized DNA: this “sequestration” function is an important means of coordinating the timing of initiation of multiple origins within a single cell. The SeqA homolog also plays a critical role in the biology of V. cholerae. We previously demonstrated that V. cholerae DNA is similarly sequestered and that SeqA overexpression is lethal, leading to a DNA replication arrest from inhibition of initiation as well as a severe cell division defect. Our first aim was to determine whether V. cholerae seqA is also essential for viability. We found that in contrast to the E. coli seqA homolog, V. cholerae seqA could not be deleted unless an episomal copy of the gene was present, and is thus essential. Furthermore, a complemented strain with a low number of excess copies grew slowly, and its proliferation appeared to lag particularly at low culture densities. We hypothesized that the amount of SeqA in the cell is tightly controlled, and fine-tuning its abundance may be particularly important during growth transitions. Thus, our next aim was to determine the quantity of SeqA in V. cholerae as a function of bacterial growth. We found that SeqA abundance increased several-fold during exponential growth of cultures in both minimal and rich medium, and persisted at the highest level through stationary phase. Finally, to determine whether transcriptional regulation could account for this variance, we cloned the promoter region of seqA. Using a lacZ transcriptional reporter plasmid in a lacZ null strain background, we discovered that PseqA activity increased during exponential growth phase, remaining high during stationary phase; however, the promoter activity rapidly dropped to 16% of maximal activity as cells emerged from stationary phase. In contrast, the parent lacZ- strain and a control strain with the empty reporter plasmid both had low activity (<1% maximal activity) that did not vary with growth. Thus, V. cholerae SeqA protein is both essential for viability and detrimental if overexpressed, and its abundance is growth phase regulated at the transcriptional level.
Cases of CRC from 1996 to 2007 T2047 Risk of Colorectal Cancer in Patients with Barrett's Esophagus: A Dutch Population-Based Study P. J. de Jonge, Mark van Blankenstein, Caspar W. Looman, M. K. Casparie, Gerrit A. Meijer, Ernst J. Kuipers Background: The association between Barrett's esophagus (BE) and colorectal cancer (CRC) is disputed. Population-based studies on the risk of CRC in BE are scarce. Aim: To determine the risk of CRC in a nationwide cohort of BE patients in The Netherlands with long-term follow-up. Methods: Patients diagnosed with BE between 1991 and 2006 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of CRC observed in these patients was compared with that in the general Dutch population aged over 40 years. Relative risks and 95% confidence intervals (95% CI) were calculated by a Poisson model. To explore the presence of ascertainment bias, CRC risk was calculated for the first year of follow-up, between one year and five years of follow-up and after more than five years follow-up after initial BE diagnosis. Results: A total of 42,207 patients with a first diagnosis of BE were included. During a mean follow-up of 5.6 years (SD 4), 714 patients (1.7%) were diagnosed with CRC (overall rate 3.4/1000 person years at risk), at a mean age of 73.7 years (SD 10). Of those CRCs, 317 (44%) were detected within the first year after initial BE diagnosis, and 397 (54%) thereafter. In this same cohort of BE patients, 666 patients (1.6%) developed esophageal high-grade dysplasia (HGD) or adenocarcinoma (EAC) during follow-up. For all patients with BE, the relative risk of CRC was 1.70 (95% CI: 1.581.83), as compared to the general Dutch population aged over 40 years. However, the relative risk within the first year of follow-up after BE diagnosis (RR: 4.76 (95% CI: 4.265.31) was significantly higher as compared to one to five years of follow-up (RR: 0.99 (95% CI: 0.86-1.14) (p<0.001) or more than five years of follow-up (RR: 1.28 (95% CI: 1.111.47) (p<0.001). These effects were seen both in men and women. Conclusion: This population-based study on CRC incidence in patients with BE failed to establish a true association between these two conditions. Although the overall risk of CRC for BE patients appeared to be significantly higher as compared to the general Dutch population, this finding was most likely the effect of ascertainment bias, as CRC risk was especially high within the first year of follow-up. Our results indicate that efforts to search for common risk factors in BE and CRC patients are unlikely to be remunerative, and that a more extensive CRC screening strategy in BE patients than has currently been recommended for the general population is not indicated.
T2050 Interleukin-8 Promoter Polymorphism and Risk of Clostridium difficile Infection Kianoosh Katchar, Xinhua Chen, Sagar Garud, Mary Hu, Claribel Taylor, Hua Xu, Shailaja Jamma, Daniel A. Leffler, Ciaran P. Kelly Background & Aims: The chemokine interleukin 8 (IL-8) mediates the activation and migration of neutrophils from peripheral blood into tissue and thereby plays a pivotal role in acute inflammation. Recent studies have demonstrated that a -251A/T single nucleotide polymorphism (SNP) of the IL-8 promoter is involved in several human diseases and alters IL-8 production. In this study we aimed to establish the relationship of -251 IL-8 promoter polymorphisms and risk for and outcomes of C. difficile infection (CDI). Material and Methods: Demographic and clinical information as well as IL-8 -251 SNP genotype was determined in 48 subjects with one episode of CDI, 34 with recurrent CDI and 41 hospitalized antibiotic recipients without CDI. Results: In subjects with CDI, the -251/TT genotype (47.9%) was significantly more common than the other genotypes (AT 33.3% (p=0.11), AA 18.8%( p < 0.001). Among individuals with the TT and AA genotypes, single episode and recurrent CDI were equally common (single 51.3%, recurrent 48.7% p=0.873 for TT and single 47.1%, recurrent 52.9% p=0.808 for AA). However patients with the AT-genotype were significantly less likely to develop recurrent disease (single 76.9%, recurrent 23.1% p=0.006). In the control group, the frequency of TT-genotype was significantly lower compared to CDI subjects (26.8% versus 47.9% p <0.001). No significant difference was found between the CDI and control groups for the prevalence of the AT-genotype (48.8% controls versus 33.3% CDI, p = 0.096) or AA-genotype (24.4% controls 18.8% CDI p = 0.13), individually. However, in aggregate, the non TT-genotypes were more common in control versus CDI subjects p=0.025 (74.2% respectively 52.1%). The TT genotype was seen in 50% of both white non-Hispanic participants and white Hispanic participants but only 16.7% of African American participants (p < 0.05) who had a proportionally higher prevalence of the AA genotype (50% vs. 25.7%). Conclusion: Our study indicates that the IL-8 -251 homozygous TT genotype is highly associated with increased risk of CDI and that individuals heterozygous for the IL-8 -251 AT allele have a lower risk recurrent CDI. These data point toward a genetic predisposition for development of initial and recurrent CDI and the high prevalence of TT genotype in white subjects may help to explain the increased risk of CDI seen in this population.
T2048 Rifaximin Salvage Therapy for Metronidazole-Resistant Clostridium difficile Infection—a Prospective Pilot Trial P Patrick Basu, Amreen Dinani, Krishna Rayapudi, Tommy Pacana, Sindhu Ramamurthy Background/Introduction: C difficile infection (CDI) is a recent epidemic in the United States. These spore-bearing bacteria affect all age groups in the community, particularly in the hospital setting. Toxins A and B play a major role in CDI pathogenesis, along with a recently discovered toxin—binary toxin (actin-specific ADP-ribosyltransferase toxin), which cannot be detected in stool using commercial assays. Binary toxin causes toxic mega colon and significant mortality. Oral metronidazole has been standard therapy for CDI for over a decade. Resistance to metronidazole has become a clinical challenge that warrants the use of salvage therapy. We evaluated the efficacy of the nonabsorbed oral antibiotic rifaximin in metronidazole-resistant CDI in the community. Methods: Twenty five patients with CDI were recruited into the study. Patient characteristics were recorded: age range, 48-65 years; male, 13; female, 12; community-acquired CDI, 13; nursing home-acquired CDI, 12; mean white blood cell count, 14,000/mm3; mean creatinine, 0.9 mg/dL; all had mild-to-moderate CDI (5-10 bowel movements a day without sepsis); all were exposed to antibiotics within the last 3 months; 12 (48%) patients were hospitalized in the last 3 months; 18 (72%)
AGA Abstracts
A-628
total mortality were registered through the official “Cancer registry” and “Statistics Norway”. RESULTS. Six-hundred and eighty-five individuals were found eligible for the screening examination, 445(65%) attended. Ceacal intubation rate was 81%, no sedation was used. The bowel cleansing was regarded satisfactory in 95%. Findings of adenomas were followed up according to Norwegian guidelines. For the period 1996 to 2007, representing 11 years of follow-up, with a total of 1369 person years, altogether 13 cases of CRC, three screening detected, were diagnosed in the screening group, compared to 19 cases in the control group(OR 0,68 (95% confidence interval: 0,34-1,37, p=0,15)). In the screening group and in the control group 173 (25%)and 182 (27%)individuals, respectively, had died during these years, p=0,54. CONLUSION. A once-only colonoscopy screening examination with a high attendance rate in this average risk population showed only a modest non-statistically significant reduction in CRC incidence.
patients were exposed to proton pump inhibitors in the last 3 months; all were CDI resistant to metronidazole (stools positive for toxins A and B after oral metronidazole 500 mg three times daily for 5 days). Oral rifaximin 400 mg three times daily for 14 days was given to all patients as salvage therapy after stopping metronidazole. Patients were followed for 56 days, and stool was tested for C difficile using PCR (Quest Diagnostics, Teterboro, NJ) to assess the effect of treatment. A negative PCR test was defined as favorable response to rifaximin. Exclusions included patients with sepsis; abdominal distention; leukocyte count >20,000/mm3; human immunodeficiency virus infection; multi-organ failure; renal failure; and recent (within the last 6 weeks) exposure to vancomycin or rifampicin and patients on ventilator support, those who were recent organ transplant recipients, and those receiving chemotherapy. Results: Sixteen of twenty-two (64%) patients who completed therapy eradicated the infection (negative CD PCR after 56 days). Three (12%) patients aborted therapy because of abdominal distention. In a per-protocol analysis, 72.7% of patients responded to rifaximin salvage therapy. Oral rifaximin was well tolerated. Conclusions: Rifaximin may be considered in patients in the treatment of mild-to-moderate metronidazole resistant CDI. Larger randomized trials might support these preliminary findings. T2049 The SeqA Protein of Vibrio Cholerae Is Essential for Viability and Its Production Is Growth Phase Regulated Djenann Saint-Dic, Keren Glinert, Troy T. Tweiten, Lyn Sue Kahng Vibrio cholerae is the cause of the epidemic diarrheal disease cholera, and Vibrio species are unique in containing bipartite genomes with a large and a small chromosome. We and others have shown that V. cholerae can contain multiple simultaneously active origins of replication at rapid growth rates. Coordinating the replication of these chromosomes is thus a critical process, particularly as the bacteria must respond to widely differing nutrient conditions in their host and environmental reservoirs. In E. coli, which has only one chromosome, the SeqA protein binds newly-synthesized DNA: this “sequestration” function is an important means of coordinating the timing of initiation of multiple origins within a single cell. The SeqA homolog also plays a critical role in the biology of V. cholerae. We previously demonstrated that V. cholerae DNA is similarly sequestered and that SeqA overexpression is lethal, leading to a DNA replication arrest from inhibition of initiation as well as a severe cell division defect. Our first aim was to determine whether V. cholerae seqA is also essential for viability. We found that in contrast to the E. coli seqA homolog, V. cholerae seqA could not be deleted unless an episomal copy of the gene was present, and is thus essential. Furthermore, a complemented strain with a low number of excess copies grew slowly, and its proliferation appeared to lag particularly at low culture densities. We hypothesized that the amount of SeqA in the cell is tightly controlled, and fine-tuning its abundance may be particularly important during growth transitions. Thus, our next aim was to determine the quantity of SeqA in V. cholerae as a function of bacterial growth. We found that SeqA abundance increased several-fold during exponential growth of cultures in both minimal and rich medium, and persisted at the highest level through stationary phase. Finally, to determine whether transcriptional regulation could account for this variance, we cloned the promoter region of seqA. Using a lacZ transcriptional reporter plasmid in a lacZ null strain background, we discovered that PseqA activity increased during exponential growth phase, remaining high during stationary phase; however, the promoter activity rapidly dropped to 16% of maximal activity as cells emerged from stationary phase. In contrast, the parent lacZ- strain and a control strain with the empty reporter plasmid both had low activity (<1% maximal activity) that did not vary with growth. Thus, V. cholerae SeqA protein is both essential for viability and detrimental if overexpressed, and its abundance is growth phase regulated at the transcriptional level.
Cases of CRC from 1996 to 2007 T2047 Risk of Colorectal Cancer in Patients with Barrett's Esophagus: A Dutch Population-Based Study P. J. de Jonge, Mark van Blankenstein, Caspar W. Looman, M. K. Casparie, Gerrit A. Meijer, Ernst J. Kuipers Background: The association between Barrett's esophagus (BE) and colorectal cancer (CRC) is disputed. Population-based studies on the risk of CRC in BE are scarce. Aim: To determine the risk of CRC in a nationwide cohort of BE patients in The Netherlands with long-term follow-up. Methods: Patients diagnosed with BE between 1991 and 2006 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of CRC observed in these patients was compared with that in the general Dutch population aged over 40 years. Relative risks and 95% confidence intervals (95% CI) were calculated by a Poisson model. To explore the presence of ascertainment bias, CRC risk was calculated for the first year of follow-up, between one year and five years of follow-up and after more than five years follow-up after initial BE diagnosis. Results: A total of 42,207 patients with a first diagnosis of BE were included. During a mean follow-up of 5.6 years (SD 4), 714 patients (1.7%) were diagnosed with CRC (overall rate 3.4/1000 person years at risk), at a mean age of 73.7 years (SD 10). Of those CRCs, 317 (44%) were detected within the first year after initial BE diagnosis, and 397 (54%) thereafter. In this same cohort of BE patients, 666 patients (1.6%) developed esophageal high-grade dysplasia (HGD) or adenocarcinoma (EAC) during follow-up. For all patients with BE, the relative risk of CRC was 1.70 (95% CI: 1.581.83), as compared to the general Dutch population aged over 40 years. However, the relative risk within the first year of follow-up after BE diagnosis (RR: 4.76 (95% CI: 4.265.31) was significantly higher as compared to one to five years of follow-up (RR: 0.99 (95% CI: 0.86-1.14) (p<0.001) or more than five years of follow-up (RR: 1.28 (95% CI: 1.111.47) (p<0.001). These effects were seen both in men and women. Conclusion: This population-based study on CRC incidence in patients with BE failed to establish a true association between these two conditions. Although the overall risk of CRC for BE patients appeared to be significantly higher as compared to the general Dutch population, this finding was most likely the effect of ascertainment bias, as CRC risk was especially high within the first year of follow-up. Our results indicate that efforts to search for common risk factors in BE and CRC patients are unlikely to be remunerative, and that a more extensive CRC screening strategy in BE patients than has currently been recommended for the general population is not indicated.
T2050 Interleukin-8 Promoter Polymorphism and Risk of Clostridium difficile Infection Kianoosh Katchar, Xinhua Chen, Sagar Garud, Mary Hu, Claribel Taylor, Hua Xu, Shailaja Jamma, Daniel A. Leffler, Ciaran P. Kelly Background & Aims: The chemokine interleukin 8 (IL-8) mediates the activation and migration of neutrophils from peripheral blood into tissue and thereby plays a pivotal role in acute inflammation. Recent studies have demonstrated that a -251A/T single nucleotide polymorphism (SNP) of the IL-8 promoter is involved in several human diseases and alters IL-8 production. In this study we aimed to establish the relationship of -251 IL-8 promoter polymorphisms and risk for and outcomes of C. difficile infection (CDI). Material and Methods: Demographic and clinical information as well as IL-8 -251 SNP genotype was determined in 48 subjects with one episode of CDI, 34 with recurrent CDI and 41 hospitalized antibiotic recipients without CDI. Results: In subjects with CDI, the -251/TT genotype (47.9%) was significantly more common than the other genotypes (AT 33.3% (p=0.11), AA 18.8%( p < 0.001). Among individuals with the TT and AA genotypes, single episode and recurrent CDI were equally common (single 51.3%, recurrent 48.7% p=0.873 for TT and single 47.1%, recurrent 52.9% p=0.808 for AA). However patients with the AT-genotype were significantly less likely to develop recurrent disease (single 76.9%, recurrent 23.1% p=0.006). In the control group, the frequency of TT-genotype was significantly lower compared to CDI subjects (26.8% versus 47.9% p <0.001). No significant difference was found between the CDI and control groups for the prevalence of the AT-genotype (48.8% controls versus 33.3% CDI, p = 0.096) or AA-genotype (24.4% controls 18.8% CDI p = 0.13), individually. However, in aggregate, the non TT-genotypes were more common in control versus CDI subjects p=0.025 (74.2% respectively 52.1%). The TT genotype was seen in 50% of both white non-Hispanic participants and white Hispanic participants but only 16.7% of African American participants (p < 0.05) who had a proportionally higher prevalence of the AA genotype (50% vs. 25.7%). Conclusion: Our study indicates that the IL-8 -251 homozygous TT genotype is highly associated with increased risk of CDI and that individuals heterozygous for the IL-8 -251 AT allele have a lower risk recurrent CDI. These data point toward a genetic predisposition for development of initial and recurrent CDI and the high prevalence of TT genotype in white subjects may help to explain the increased risk of CDI seen in this population.
T2048 Rifaximin Salvage Therapy for Metronidazole-Resistant Clostridium difficile Infection—a Prospective Pilot Trial P Patrick Basu, Amreen Dinani, Krishna Rayapudi, Tommy Pacana, Sindhu Ramamurthy Background/Introduction: C difficile infection (CDI) is a recent epidemic in the United States. These spore-bearing bacteria affect all age groups in the community, particularly in the hospital setting. Toxins A and B play a major role in CDI pathogenesis, along with a recently discovered toxin—binary toxin (actin-specific ADP-ribosyltransferase toxin), which cannot be detected in stool using commercial assays. Binary toxin causes toxic mega colon and significant mortality. Oral metronidazole has been standard therapy for CDI for over a decade. Resistance to metronidazole has become a clinical challenge that warrants the use of salvage therapy. We evaluated the efficacy of the nonabsorbed oral antibiotic rifaximin in metronidazole-resistant CDI in the community. Methods: Twenty five patients with CDI were recruited into the study. Patient characteristics were recorded: age range, 48-65 years; male, 13; female, 12; community-acquired CDI, 13; nursing home-acquired CDI, 12; mean white blood cell count, 14,000/mm3; mean creatinine, 0.9 mg/dL; all had mild-to-moderate CDI (5-10 bowel movements a day without sepsis); all were exposed to antibiotics within the last 3 months; 12 (48%) patients were hospitalized in the last 3 months; 18 (72%)
AGA Abstracts
A-628