Letters
Figure. Age-Specific Prevalence of the Metabolic Syndrome by Sex and Race/Ethnicity, 2003-2012 Ages 20-39 y 60
Ages 40-59 y
Sex
Ages ≥60 y
60
60
Females Race/ethnicity
40
Non-Hispanic white Black
30
Hispanic Other
20
10
Prevalence of Metabolic Syndrome, %
50
Prevalence of Metabolic Syndrome, %
Prevalence of Metabolic Syndrome, %
Males 50
40
30
20
10
0
0
Overall
Sex
Race/Ethnicity
50
40
30
20
10
0
Overall
Sex
Race/Ethnicity
Overall
Sex
Race/Ethnicity
Error bars indicate 95% confidence intervals. Comparisons of prevalence estimates were performed using χ2 tests; patients aged 20-39 years in each group were used as the reference. All comparisons yielded P < .001.
bolic syndrome was 18.3% among those aged 20 to 39 years and increased to 46.7% among those aged 60 years or older. Among patients aged 60 years or older, more than 50% of women and Hispanics had the metabolic syndrome (Figure). Discussion | Nearly 35% of all adults and 50% of those aged 60 years or older were estimated to have the metabolic syndrome, a concerning observation given the aging US population. Previous analyses of NHANES through 2006 demonstrated increasing rates of the metabolic syndrome, whereas our study suggests that the prevalence has remained stable overall since 2007 and declined in women.5 Greater awareness of the metabolic syndrome and its health consequences may have contributed to improvements in optimizing treatment of risk factors such as hypertension and diabetes. Furthermore, recent NHANES data demonstrate that obesity prevalence in the United States also appears to have stabilized, which also may contribute to the stabilizing prevalence of the metabolic syndrome.6 Limitations of our study include potential misclassification of individuals taking diabetes or hypertension medications for other reasons. In addition, our study did not evaluate differences in the prevalence of individual components of the metabolic syndrome. Even though we used concurrent use of hypertension or diabetes medication as satisfying those components of the metabolic syndrome, only data for cholesterol medication in general were available for analyses and not specifically for treatment of triglycerides or HDL cholesterol. We did not include these to avoid overestimation of metabolic syndrome prevalence. Maria Aguilar, MD Taft Bhuket, MD Sharon Torres, PA Benny Liu, MD Robert J. Wong, MD, MS 1974
Author Affiliations: Department of Medicine, Alameda Health System-Highland Hospital, Oakland, California (Aguilar); Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, California (Bhuket, Torres, Liu, Wong). Corresponding Author: Robert J. Wong, MD, MS, Endoscopy Unit, Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital Campus, 1411 E 31st St, Oakland, CA 94602 ([email protected]). Author Contributions: Dr Wong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bhuket, Wong. Acquisition, analysis, or interpretation of data: Aguilar, Torres, Liu, Wong. Drafting of the manuscript: Liu, Wong. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Torres, Wong. Administrative, technical, or material support: Bhuket, Liu, Wong. Study supervision: Wong. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359. 2. Ford ES, Li C. Metabolic syndrome and health-related quality of life among US adults. Ann Epidemiol. 2008;18(3):165-171. 3. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24(4):683-689. 4. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59(10):1410-1415. 5. Mozumdar A, Liguori G. Persistent increase of prevalence of metabolic syndrome among US adults: NHANES III to NHANES 1999-2006. Diabetes Care. 2011;34(1):216-219. 6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-814.
COMMENT & RESPONSE
Treatment for Clostridium difficile Infection in Adults To the Editor Clostridium difficile infection is a common, serious diarrheal illness, and strains such as the virulent
JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Letters
North American pulsed-field gel electrophoresis type 1 make treatment challenging. The meta-analysis1 summarizing the available treatment options for incident C difficile infection in adults recommended vancomycin with or without adjunctive therapy as the treatment of choice for severe, complicated infections and metronidazole for milder disease. Emerging therapies are promising but have some limitations. Fidaxomicin is an option for the treatment of C difficile infection and may have a role in the prevention of recurrence for non–North American pulsed-field gel electrophoresis type 1 disease; however, due to significant cost, it is not yet available on all formularies. Fecal microbiota transplantation has been shown to improve symptoms and establish clinical cure in recurrent C difficile infection, but its role in primary C difficile infection remains to be established. Access to this modality continues to be limited and investigational in many areas. Therefore, the armamentarium for decreasing recurrence remains underdeveloped. Treatment algorithms recommend an evaluation of the ongoing need for the precipitating antibiotic. We further propose that existing treatment algorithms for C difficile infection could be strengthened by addressing the use of proton pump inhibitors (PPI), which is a common and potentially modifiable risk factor for recurrence. In observational studies, PPI use has been associated with both incident2 and recurrent C difficile infection.3,4 The use of PPI in patients with C difficile is common (40%3-60%4) with up to half being prescribed without an evidence-based indication.4 Notwithstanding the limitations of observational studies, we suggest that the cessation of unnecessary PPI use is potentially an overlooked means of reducing recurrence risk. In the same way that an evaluation for the cessation of the precipitating antibiotic is recommended,1 we propose that reassessment of ongoing PPI use be included in the management algorithm for both primary and recurrent disease. Emily G. McDonald, MD Todd C. Lee, MD, MPH Author Affiliations: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. Corresponding Author: Todd C. Lee, MD, MPH, Royal Victoria Hospital, 687 Pine Ave W, Montreal, QC H3A 1A1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313(4):398-408. 2. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365(18):16931703. 3. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170 (9):772-778. 4. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection [published online March 2, 2015]. JAMA Intern Med. doi:10.1001 /jamainternmed.2015.42.
jama.com
To the Editor Although we agree that the majority of the systematic review1 of best practices for the diagnosis and treatment of C difficile infection in adults was supported by evidence, we have concerns that the conclusions about fidaxomicin may not fully reflect the available clinical data. First, Bagdasarian and colleagues stated that fidaxomicin demonstrated noninferiority to vancomycin for clinical cure. Although clinical response was similar, phase 3 trials established, and the US Food and Drug Administration accepted, that fidaxomicin was statistically superior to vancomycin for sustained clinical response (ie, cure without recurrence or death) based on an analysis of the full set of patients.2,3 Second, the review mentioned that fidaxomicin is not considered first-line therapy for mild or uncomplicated disease and no data support use of fidaxomicin in complicated or fulminant disease. However, this statement did not take into account the 37% of patients in the phase 3 trials who had severe disease defined by a white blood cell count of 15 000 cells/mm3 or higher and/or 10 or greater unformed bowel movements per day. Patients with life-threatening C difficile infection such as toxic megacolon were excluded because of the threat of death within 48 hours. Third, an important issue is the development of resistance to fidaxomicin because of an elevated minimal inhibitory concentration of 16 μg/mL found in a single strain from a patient at the time of recurrence. The clinical significance of this finding is unclear, but this minimal inhibitory concentration is still orders of magnitude less than the concentration of fidaxomicin in the gut (>1000 μg/g of colonic contents). Although we recognize the importance of resistance in a new antibiotic, and for this reason have established an ongoing nationwide surveillance system, we think the significance of a single strain with somewhat reduced susceptibility should not be emphasized. Fourth, we think that sufficient evidence is available about fidaxomicin because the published data from the phase 3 trials included 1105 patients in the modified intent-to-treat populations and represent the largest prospective interventional studies of this disease to date.2,3 Since the introduction of fidaxomicin nearly 5 years ago, more than 100 scientific articles about this drug have been published. We believe that fidaxomicin is an effective and appropriate treatment for C difficile infection. Cong Dai, MD, PhD Min Jiang, MD, PhD Ming-Jun Sun, MD, PhD Author Affiliations: Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, China. Corresponding Author: Ming-Jun Sun, MD, PhD, Department of Gastroenterology, First Affiliated Hospital, China Medical University, 92 Beier Rd, Shenyang City, Liaoning Province, China 110001 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313(4):398-408.
(Reprinted) JAMA May 19, 2015 Volume 313, Number 19
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
1975
Letters
2. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289. 3. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
In Reply We agree with Drs McDonald and Lee that PPI use has been associated with incident and recurrent C difficile infection. Even though we mentioned this association in the text, tables, and figures of our review, we chose not to include PPI or other modifiable risk factors (other than concurrent use of non–C difficile infection antibiotics), in the treatment algorithm. There are numerous reports highlighting an association with acquisition and recurrence of C difficile infection; however, to date, no one has prospectively studied whether discontinuation of PPI therapy improves outcomes from C difficile infection. Despite this, we believe discontinuation of PPI therapy is a reasonable consideration, particularly because many patients receive it unnecessarily.1 Dr Dai and colleagues argue for the superiority of fidaxomicin. In a meta-analysis of clinical trials by Crook et al,2 fidaxomicin was not superior to vancomycin for clinical cure (resolution of diarrhea [defined as ≤3 unformed stools for 2 consecutive days] maintained for the subsequent duration of therapy with no further requirement for C difficile infection therapy assessed 2 days after the end of the 10-day blinded treatment course) in either the per-protocol analysis or the modified intention-to-treat analysis, but was superior for recurrence and global cure (clinical cure without recurrence [defined as reappearance of >3 unformed stools during any 24-hour period with positive testing for C difficile infection and a need for retreatment]). Thus, the primary driver of superiority in global cure was recurrence; in our review, we pointed out that fidaxomicin was superior to vancomycin for recurrence. Despite cost, use of fidaxomicin may be appropriate for patients at high risk of recurrence; however, there is insufficient evidence to claim that the superiority extends to clinical cure. Our recommendations reflected this interpretation of the data. We agree with Dai and colleagues that 37% of patients in the clinical trials for fidaxomicin had severe disease, and we included fidaxomicin as an option for severe C difficile infection in our treatment algorithm. We did not include fidaxomicin as an option for complicated C difficile infection because, as these authors point out, patients with complicated C difficile infection were excluded from the trials. We also agree that a single strain of C difficile with an elevated minimum inhibitory concentration for fidaxomicin is not cause for alarm. In our review, the discussion of resistance was limited to rifaximin, which we stated should not be used as monotherapy due to the propensity for developing resistance. In addition, Dai and colleagues did not mention the issue of cost in their letter. Although we agree that data support the use of fidaxomicin, especially for recurrent C difficile infection, the economic cost in many instances is prohibitive. Cost-effectiveness analyses have reached contradictory 1976
conclusions,3,4 and this was a factor in formulating our suggested treatment protocol. Krishna Rao, MD Natasha Bagdasarian, MD, MPH Preeti N. Malani, MD, MSJ Author Affiliations: Department of Internal Medicine, University of Michigan Health System, Ann Arbor (Rao, Malani); Department of Internal Medicine, Wayne State University, Detroit, Michigan (Bagdasarian); Associate Editor, JAMA (Malani). Corresponding Author: Preeti N. Malani, MD, MSJ, 3119 Taubman Center, Ann Arbor, MI 48109 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rao reported receiving grants from the Claude D. Pepper Older Americans Independence Center and the Michigan Institute for Clinical and Health Research. No other disclosures were reported. 1. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012;5 (4):219-232. 2. Crook DW, Walker AS, Kean Y, et al; Study 003/004 Teams. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103. 3. Bartsch SM, Umscheid CA, Fishman N, Lee BY. Is fidaxomicin worth the cost? an economic analysis. Clin Infect Dis. 2013;57(4):555-561. 4. Nathwani D, Cornely OA, Van Engen AK, Odufowora-Sita O, Retsa P, Odeyemi IAO. Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection. J Antimicrob Chemother. 2014;69(11):2901-2912.
Government Regulations on Physician Self-referral To the Editor The Viewpoint from Drs Adashi and Kocher1 called for repealing the IOASE to the Stark law. The Viewpoint is problematic because it paints all clinicians with the same brush of overusing self-referral for ancillary testing for financial gain and sets a tone of guilt by designation. This perspective dismisses the fact that the vast majority of practitioners are committed to providing patients the best care possible, in the right place, at the right time, and for the right reason. Successful and transparent application of the IOASE allows clinicians to provide important, patientcentered services in a coordinated and convenient fashion. Elimination of the IOASE may increase inefficiencies, present barriers to appropriate screenings and treatments, and make health care less accessible and less affordable. Patients may be forced to obtain ancillary services in new, unfamiliar, or geographically distant settings, often on days separate from those they have already set aside to see their physician. Patients from rural and underserved areas would be the hardest hit because they often live far from the nearest hospital or other free-standing diagnostic testing center. In addition, it is inconvenient and often impractical for Medicare beneficiaries to travel to a separate location for diagnostic testing. Practices that rely on this exception already meet complex billing, supervision, and location requirements. The medical profession already has taken steps to ensure that only medically necessary and appropriate ancillary services are performed. These steps include the development and implementation of evidence-based guidelines, appropriate use criteria, decision support tools, and training requirements.
JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
jama.com
Figure. Age-Specific Prevalence of the Metabolic Syndrome by Sex and Race/Ethnicity, 2003-2012 Ages 20-39 y 60
Ages 40-59 y
Sex
Ages ≥60 y
60
60
Females Race/ethnicity
40
Non-Hispanic white Black
30
Hispanic Other
20
10
Prevalence of Metabolic Syndrome, %
50
Prevalence of Metabolic Syndrome, %
Prevalence of Metabolic Syndrome, %
Males 50
40
30
20
10
0
0
Overall
Sex
Race/Ethnicity
50
40
30
20
10
0
Overall
Sex
Race/Ethnicity
Overall
Sex
Race/Ethnicity
Error bars indicate 95% confidence intervals. Comparisons of prevalence estimates were performed using χ2 tests; patients aged 20-39 years in each group were used as the reference. All comparisons yielded P < .001.
bolic syndrome was 18.3% among those aged 20 to 39 years and increased to 46.7% among those aged 60 years or older. Among patients aged 60 years or older, more than 50% of women and Hispanics had the metabolic syndrome (Figure). Discussion | Nearly 35% of all adults and 50% of those aged 60 years or older were estimated to have the metabolic syndrome, a concerning observation given the aging US population. Previous analyses of NHANES through 2006 demonstrated increasing rates of the metabolic syndrome, whereas our study suggests that the prevalence has remained stable overall since 2007 and declined in women.5 Greater awareness of the metabolic syndrome and its health consequences may have contributed to improvements in optimizing treatment of risk factors such as hypertension and diabetes. Furthermore, recent NHANES data demonstrate that obesity prevalence in the United States also appears to have stabilized, which also may contribute to the stabilizing prevalence of the metabolic syndrome.6 Limitations of our study include potential misclassification of individuals taking diabetes or hypertension medications for other reasons. In addition, our study did not evaluate differences in the prevalence of individual components of the metabolic syndrome. Even though we used concurrent use of hypertension or diabetes medication as satisfying those components of the metabolic syndrome, only data for cholesterol medication in general were available for analyses and not specifically for treatment of triglycerides or HDL cholesterol. We did not include these to avoid overestimation of metabolic syndrome prevalence. Maria Aguilar, MD Taft Bhuket, MD Sharon Torres, PA Benny Liu, MD Robert J. Wong, MD, MS 1974
Author Affiliations: Department of Medicine, Alameda Health System-Highland Hospital, Oakland, California (Aguilar); Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, California (Bhuket, Torres, Liu, Wong). Corresponding Author: Robert J. Wong, MD, MS, Endoscopy Unit, Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital Campus, 1411 E 31st St, Oakland, CA 94602 ([email protected]). Author Contributions: Dr Wong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bhuket, Wong. Acquisition, analysis, or interpretation of data: Aguilar, Torres, Liu, Wong. Drafting of the manuscript: Liu, Wong. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Torres, Wong. Administrative, technical, or material support: Bhuket, Liu, Wong. Study supervision: Wong. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359. 2. Ford ES, Li C. Metabolic syndrome and health-related quality of life among US adults. Ann Epidemiol. 2008;18(3):165-171. 3. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24(4):683-689. 4. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59(10):1410-1415. 5. Mozumdar A, Liguori G. Persistent increase of prevalence of metabolic syndrome among US adults: NHANES III to NHANES 1999-2006. Diabetes Care. 2011;34(1):216-219. 6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-814.
COMMENT & RESPONSE
Treatment for Clostridium difficile Infection in Adults To the Editor Clostridium difficile infection is a common, serious diarrheal illness, and strains such as the virulent
JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
jama.com
Letters
North American pulsed-field gel electrophoresis type 1 make treatment challenging. The meta-analysis1 summarizing the available treatment options for incident C difficile infection in adults recommended vancomycin with or without adjunctive therapy as the treatment of choice for severe, complicated infections and metronidazole for milder disease. Emerging therapies are promising but have some limitations. Fidaxomicin is an option for the treatment of C difficile infection and may have a role in the prevention of recurrence for non–North American pulsed-field gel electrophoresis type 1 disease; however, due to significant cost, it is not yet available on all formularies. Fecal microbiota transplantation has been shown to improve symptoms and establish clinical cure in recurrent C difficile infection, but its role in primary C difficile infection remains to be established. Access to this modality continues to be limited and investigational in many areas. Therefore, the armamentarium for decreasing recurrence remains underdeveloped. Treatment algorithms recommend an evaluation of the ongoing need for the precipitating antibiotic. We further propose that existing treatment algorithms for C difficile infection could be strengthened by addressing the use of proton pump inhibitors (PPI), which is a common and potentially modifiable risk factor for recurrence. In observational studies, PPI use has been associated with both incident2 and recurrent C difficile infection.3,4 The use of PPI in patients with C difficile is common (40%3-60%4) with up to half being prescribed without an evidence-based indication.4 Notwithstanding the limitations of observational studies, we suggest that the cessation of unnecessary PPI use is potentially an overlooked means of reducing recurrence risk. In the same way that an evaluation for the cessation of the precipitating antibiotic is recommended,1 we propose that reassessment of ongoing PPI use be included in the management algorithm for both primary and recurrent disease. Emily G. McDonald, MD Todd C. Lee, MD, MPH Author Affiliations: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. Corresponding Author: Todd C. Lee, MD, MPH, Royal Victoria Hospital, 687 Pine Ave W, Montreal, QC H3A 1A1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313(4):398-408. 2. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365(18):16931703. 3. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170 (9):772-778. 4. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection [published online March 2, 2015]. JAMA Intern Med. doi:10.1001 /jamainternmed.2015.42.
jama.com
To the Editor Although we agree that the majority of the systematic review1 of best practices for the diagnosis and treatment of C difficile infection in adults was supported by evidence, we have concerns that the conclusions about fidaxomicin may not fully reflect the available clinical data. First, Bagdasarian and colleagues stated that fidaxomicin demonstrated noninferiority to vancomycin for clinical cure. Although clinical response was similar, phase 3 trials established, and the US Food and Drug Administration accepted, that fidaxomicin was statistically superior to vancomycin for sustained clinical response (ie, cure without recurrence or death) based on an analysis of the full set of patients.2,3 Second, the review mentioned that fidaxomicin is not considered first-line therapy for mild or uncomplicated disease and no data support use of fidaxomicin in complicated or fulminant disease. However, this statement did not take into account the 37% of patients in the phase 3 trials who had severe disease defined by a white blood cell count of 15 000 cells/mm3 or higher and/or 10 or greater unformed bowel movements per day. Patients with life-threatening C difficile infection such as toxic megacolon were excluded because of the threat of death within 48 hours. Third, an important issue is the development of resistance to fidaxomicin because of an elevated minimal inhibitory concentration of 16 μg/mL found in a single strain from a patient at the time of recurrence. The clinical significance of this finding is unclear, but this minimal inhibitory concentration is still orders of magnitude less than the concentration of fidaxomicin in the gut (>1000 μg/g of colonic contents). Although we recognize the importance of resistance in a new antibiotic, and for this reason have established an ongoing nationwide surveillance system, we think the significance of a single strain with somewhat reduced susceptibility should not be emphasized. Fourth, we think that sufficient evidence is available about fidaxomicin because the published data from the phase 3 trials included 1105 patients in the modified intent-to-treat populations and represent the largest prospective interventional studies of this disease to date.2,3 Since the introduction of fidaxomicin nearly 5 years ago, more than 100 scientific articles about this drug have been published. We believe that fidaxomicin is an effective and appropriate treatment for C difficile infection. Cong Dai, MD, PhD Min Jiang, MD, PhD Ming-Jun Sun, MD, PhD Author Affiliations: Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, China. Corresponding Author: Ming-Jun Sun, MD, PhD, Department of Gastroenterology, First Affiliated Hospital, China Medical University, 92 Beier Rd, Shenyang City, Liaoning Province, China 110001 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313(4):398-408.
(Reprinted) JAMA May 19, 2015 Volume 313, Number 19
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Georgetown University Medical Center User on 05/22/2015
1975
Letters
2. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289. 3. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
In Reply We agree with Drs McDonald and Lee that PPI use has been associated with incident and recurrent C difficile infection. Even though we mentioned this association in the text, tables, and figures of our review, we chose not to include PPI or other modifiable risk factors (other than concurrent use of non–C difficile infection antibiotics), in the treatment algorithm. There are numerous reports highlighting an association with acquisition and recurrence of C difficile infection; however, to date, no one has prospectively studied whether discontinuation of PPI therapy improves outcomes from C difficile infection. Despite this, we believe discontinuation of PPI therapy is a reasonable consideration, particularly because many patients receive it unnecessarily.1 Dr Dai and colleagues argue for the superiority of fidaxomicin. In a meta-analysis of clinical trials by Crook et al,2 fidaxomicin was not superior to vancomycin for clinical cure (resolution of diarrhea [defined as ≤3 unformed stools for 2 consecutive days] maintained for the subsequent duration of therapy with no further requirement for C difficile infection therapy assessed 2 days after the end of the 10-day blinded treatment course) in either the per-protocol analysis or the modified intention-to-treat analysis, but was superior for recurrence and global cure (clinical cure without recurrence [defined as reappearance of >3 unformed stools during any 24-hour period with positive testing for C difficile infection and a need for retreatment]). Thus, the primary driver of superiority in global cure was recurrence; in our review, we pointed out that fidaxomicin was superior to vancomycin for recurrence. Despite cost, use of fidaxomicin may be appropriate for patients at high risk of recurrence; however, there is insufficient evidence to claim that the superiority extends to clinical cure. Our recommendations reflected this interpretation of the data. We agree with Dai and colleagues that 37% of patients in the clinical trials for fidaxomicin had severe disease, and we included fidaxomicin as an option for severe C difficile infection in our treatment algorithm. We did not include fidaxomicin as an option for complicated C difficile infection because, as these authors point out, patients with complicated C difficile infection were excluded from the trials. We also agree that a single strain of C difficile with an elevated minimum inhibitory concentration for fidaxomicin is not cause for alarm. In our review, the discussion of resistance was limited to rifaximin, which we stated should not be used as monotherapy due to the propensity for developing resistance. In addition, Dai and colleagues did not mention the issue of cost in their letter. Although we agree that data support the use of fidaxomicin, especially for recurrent C difficile infection, the economic cost in many instances is prohibitive. Cost-effectiveness analyses have reached contradictory 1976
conclusions,3,4 and this was a factor in formulating our suggested treatment protocol. Krishna Rao, MD Natasha Bagdasarian, MD, MPH Preeti N. Malani, MD, MSJ Author Affiliations: Department of Internal Medicine, University of Michigan Health System, Ann Arbor (Rao, Malani); Department of Internal Medicine, Wayne State University, Detroit, Michigan (Bagdasarian); Associate Editor, JAMA (Malani). Corresponding Author: Preeti N. Malani, MD, MSJ, 3119 Taubman Center, Ann Arbor, MI 48109 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rao reported receiving grants from the Claude D. Pepper Older Americans Independence Center and the Michigan Institute for Clinical and Health Research. No other disclosures were reported. 1. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012;5 (4):219-232. 2. Crook DW, Walker AS, Kean Y, et al; Study 003/004 Teams. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103. 3. Bartsch SM, Umscheid CA, Fishman N, Lee BY. Is fidaxomicin worth the cost? an economic analysis. Clin Infect Dis. 2013;57(4):555-561. 4. Nathwani D, Cornely OA, Van Engen AK, Odufowora-Sita O, Retsa P, Odeyemi IAO. Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection. J Antimicrob Chemother. 2014;69(11):2901-2912.
Government Regulations on Physician Self-referral To the Editor The Viewpoint from Drs Adashi and Kocher1 called for repealing the IOASE to the Stark law. The Viewpoint is problematic because it paints all clinicians with the same brush of overusing self-referral for ancillary testing for financial gain and sets a tone of guilt by designation. This perspective dismisses the fact that the vast majority of practitioners are committed to providing patients the best care possible, in the right place, at the right time, and for the right reason. Successful and transparent application of the IOASE allows clinicians to provide important, patientcentered services in a coordinated and convenient fashion. Elimination of the IOASE may increase inefficiencies, present barriers to appropriate screenings and treatments, and make health care less accessible and less affordable. Patients may be forced to obtain ancillary services in new, unfamiliar, or geographically distant settings, often on days separate from those they have already set aside to see their physician. Patients from rural and underserved areas would be the hardest hit because they often live far from the nearest hospital or other free-standing diagnostic testing center. In addition, it is inconvenient and often impractical for Medicare beneficiaries to travel to a separate location for diagnostic testing. Practices that rely on this exception already meet complex billing, supervision, and location requirements. The medical profession already has taken steps to ensure that only medically necessary and appropriate ancillary services are performed. These steps include the development and implementation of evidence-based guidelines, appropriate use criteria, decision support tools, and training requirements.
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