The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Dalbavancin or Oritavancin for Skin Infections To the Editor: Boucher et al. (June 5 issue)1 report the results of DISCOVER 1 and DISCOVER 2, and in the same issue Corey et al.2 report the results of SOLO I. These randomized trials investigated the efficacy of oritavancin and dalbavancin in acute bacterial skin and skin-structure infections. We are concerned that the design of these studies and that of other pivotal studies are not consistent with clinical management of acute bacterial skin and skin-structure infections and that their results are thus not useful for clinical decisions in real life — at least in Europe and some other areas of the world. First, vancomycin may not be an adequate comparison drug. Betalactam antibiotics remain the mainstay drugs for the treatment for methicillin-susceptible Staphylococcus aureus and streptococci, which are the main causes of these infections in most areas, as shown in a recent observational study in Europe.3 Second, most patients with these complicated this week’s letters 1160 Dalbavancin or Oritavancin for Skin Infections 1163 Tofacitinib versus Methotrexate in Rheumatoid Arthritis 1165 Antiretroviral Therapy after Cryptococcal Meningitis 1167 Antidepressant Use in Pregnancy and the Risk of Cardiac Defects 1169 Diagnostic Clinical Genome and Exome Sequencing 1170 Resistance to Therapy in Acute Promyelocytic Leukemia
1160
acute bacterial skin and skin-structure infections are not admitted to the hospital but rather are treated at home with oral antibiotics after surgical drainage of the infected area. In fact, it is difficult for most hospitals in western European countries to include patients in trials with these inclusion criteria. Maria Núñez-Núñez, Pharm.D. Hospital Universitario Virgen Macarena Seville, Spain
Jesús Rodríguez-Baño, M.D., Ph.D. University of Seville Seville, Spain No potential conflict of interest relevant to this letter was reported. 1. Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF,
Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014;370:2169-79. 2. Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014;370:2180-90. 3. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F. Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010-2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 2013;19(9):E377-E385. DOI: 10.1056/NEJMc1407925
To the Editor: In their studies based on intentionto-treat analyses, Boucher et al. and Corey et al. concluded that the new treatments were not inferior to the conventional treatment. Although these are reasonable conclusions, problems such as high dropout rates, which are detrimental to a superiority trial, can be advantageous in a noninferiority study.1 This is because an intention-totreat analysis is more likely to narrow the difference between the treatment groups and yield a
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
noninferior result, potentially leading to a type I the etiologic organisms are susceptible to penierror. Because of this inherent risk in noninferior- cillins. ity studies, Piaggio et al.2 and Le Henanff et al.3 Martin Cormican, M.D. state that both the intention-to-treat analysis and National University of Ireland, Galway the per-protocol analysis are of equal impor- Galway, Ireland tance, and they advise that the two should be [email protected] presented together to enable readers to assess No potential conflict of interest relevant to this letter was rethe validity of the study results. For this reason, ported. we ask the authors to present the per-protocol 1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guideanalysis with the intention-to-treat analysis, lines for the diagnosis and management of skin and soft-tissue which we believe will add confidence to their infections. Clin Infect Dis 2005;41:1373-406. [Errata, Clin Infect Dis 2005;41:1830, 2006;42:1219.] data set. 2. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guideJihoon Baang, M.D. Susan Fisher, Ph.D. Temple University School of Medicine Philadelphia, PA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Guidance for Industry: non-inferiority clinical trials. Silver
Spring, MD: Food and Drug Administration, 2010 (http://www .fda.gov/downloads/Drugs/Guidances/UCM202140.pdf). 2. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006;295:115260. [Erratum, JAMA 2006;296:1842.] 3. Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:1147-51. DOI: 10.1056/NEJMc1407925
To the Editor: If, in the course of hospital rounds focusing on antimicrobial stewardship, I saw a patient who had been prescribed parenteral vancomycin for a minimum of 3 days followed by linezolid for a total of 10 to 14 days for a nonpurulent skin infection, I would point to this course of treatment as an example of unusual prescribing.1,2 If this treatment was continued after methicillin-susceptible S. aureus or Streptococcus pyogenes had been isolated, I would find it hard to justify as being rational in terms of prudent prescribing principles, toxicity, and cost. Yet, in the DISCOVER 1 and DISCOVER 2 studies of dalbavancin, this regimen is presented as conventional therapy for 651 patients with skin infection, including 127 patients with laboratory-confirmed methicillin-susceptible S. aureus and 13 patients with Strep. pyogenes. It would be unhelpful if this article promotes the idea that this is conventional prescribing for skin infection, especially after the microbiologic characteristics indicate that
lines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):e18-e55. [Erratum, Clin Infect Dis 2011;53:319.] DOI: 10.1056/NEJMc1407925
Dr. Boucher and Colleagues Reply: NúñezNúñez and Rodríguez-Baño and Cormican raise questions about our study design and the location of treatment. The DISCOVER studies were designed in accordance with published treatment guidelines and regulatory guidance.1,2 Vancomycin remains the “reference standard” empirical therapy for serious methicillin-resistant S. aureus (MRSA) infections globally.1 As the incidence of MRSA skin infections increases, empirical therapy with anti-MRSA agents such as vancomycin is recommended. Our patients were seriously ill: 85% had fever, the size of the area of the skin infection was large (median, >300 cm2), more than half the patients had the systemic inflammatory response syndrome, and MRSA was frequently identified. Accordingly, these patients received initial parenteral and subsequent oral anti-MRSA therapy. Since these were global trials, the choice of oral step-down therapy in the group of patients who received the comparison drug had to be an agent approved in many countries. Linezolid meets this criterion, is active against streptococci and MRSA, and has an oral formulation. In the United States, rates of MRSA can be greater than 50%, and vancomycin followed by linezolid is among the most common regimens used. Regarding hospitalization, the demographic characteristics of our study population are consistent with those of hospitalized patients with skin infections in Europe. The nearly 2000 European patients in the REACH (Current Management of Patients Hospitalized with Com-
n engl j med 371;12 nejm.org september 18, 2014
1161
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
plicated Skin and Soft Tissue Infections across Europe [2010-2011]) study received intravenous antibiotics for a mean of 9.7 days and they were hospitalized for a median of 18.5 days; 10.2% of these patients had MRSA infection.3 Baang and Fisher request an analysis of treatment success in the per-protocol population. Our studies were the first to use the “new” early end point of success at 48 to 72 hours after the first dose of an antibiotic. The primary efficacy analysis was performed in the intentionto-treat population, since this is most relevant for an end point measured at an early time point. Excluding patients from the intention-totreat population could lead to bias, particularly if post-baseline factors are considered. Per-protocol analyses were conducted on the later end points (see Table 2 of the article and Table S3 in the Supplementary Appendix, available with the full text of the article at NEJM.org). In addition, a per-protocol analysis at the early time point was conducted, and treatment success was seen in 486 of 606 patients who received dalbavancin (80.2%) and 481 of 581 patients who received vancomycin–linezolid (82.8%) (absolute difference, −2.5 percentage points; 95% confidence interval, −7.0 to 1.9). However, the use of a perprotocol population only leads to a better estimate of the drug effect if the intention-to-treat population includes a large number of patients who would not benefit from the antibiotic (i.e., those who did not have the disease under study). In DISCOVER 1 and DISCOVER 2, a total of 2% of patients in each treatment group did not meet the protocol requirements for inclusion or exclusion. Thus, as anticipated for these studies, the per-protocol analysis of the early, primary end point resulted in a conclusion similar to that in the intention-to-treat population. Helen W. Boucher, M.D. Tufts Medical Center Boston, MA [email protected]
George H. Talbot, M.D. Talbot Advisors Anna Maria, FL
Michael W. Dunne, M.D. Durata Therapeutics Branford, CT Since publication of their article, the authors report no further potential conflict of interest.
1162
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m e dic i n e
1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guide-
lines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59(2):e10-e52. 2. Guidance for Industry: acute bacterial skin and skin structure infections — developing drugs for treatment. Silver Spring, MD: Food and Drug Administration, 2010 (http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071185.pdf). 3. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F. Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010-2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 2013;19(9):E377-E385. DOI: 10.1056/NEJMc1407925
Dr. Corey and Colleagues Reply: In response to Núñez-Núñez and Rodríguez-Baño: vancomycin was an appropriate comparison drug in the SOLO I study because MRSA remains prevalent in most geographic areas, including Europe. In 2012, a total of 17.8% of 37,495 surveillance isolates of S. aureus from 30 European countries were resistant to methicillin1; 10 countries (including Spain) reported MRSA rates between 20% and 50% and 2 reported rates above 50%. Hence, empirical beta-lactam therapy is predicted to be unreliable in treating serious skin infections in Europe. This prediction was confirmed in the study by Garau et al. on management of skin infections in 1995 patients from 10 European countries.2 Among the 402 patients in whom the initial beta-lactam–containing regimen was modified, nearly half (186 patients [46.3%]) had regimens that were modified because of an insufficient therapeutic response. In that study, the mean duration of treatment was 14.6 days and the mean length of hospital stay was 18.5 days (28.9 days for patients with MRSA). Hence, there remains a need for antibiotics that can reduce the length of hospital stay or prevent hospital admission altogether. The infection types in patients in the SOLO I study are representative of those seen in current clinical practice and closely match those in the study by Garau et al. The wide geographic distribution of SOLO I study sites required that the comparison drug be active against MRSA. Our study results were therefore broadly applicable to current management of acute bacterial skin and skin-structure infections in many regions, including Europe.
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
In response to Baang and Fisher: results in G. Ralph Corey, M.D. patients who could be evaluated clinically were Duke University Medical Center consistent with those in the modified inten- Durham, NC [email protected] tion-to-treat population. The population of patients who could be evaluated clinically in our Hai Jiang, Ph.D. study is synonymous with the per-protocol Greg Moeck, Ph.D. population, since it consisted of all patients in The Medicines Company Parsippany, NJ the modified intention-to-treat population who Since publication of their article, the authors report no furmet the criteria for study inclusion, received the ther potential conflict of interest. full-course of study treatment, and underwent 1. European Centre for Disease Prevention and Control (ECDC). an assessment for clinical cure at the post- Antimicrobial resistance surveillance in Europe 2012: annual therapy evaluation by the site investigator, as report of the European Antimicrobial Resistance Surveillance stated in the legend to Figure 1 of our article. Network (EARS-Net). Stockholm: ECDC, 2013. 2. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi In addition, Figure 2 of our article and Tables F. Current management of patients hospitalized with compliS4, S7, and S11 in the Supplementary Appendix, cated skin and soft tissue infections across Europe (2010-2011): available at NEJM.org, are all based on the assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect population of patients who could be evaluated 2013;19(9):E377-E385. clinically. DOI: 10.1056/NEJMc1407925
Tofacitinib versus Methotrexate in Rheumatoid Arthritis To the Editor: In the article by Lee et al. (June 19 issue),1 the reported elevation in levels of serum creatinine and low-density lipoprotein (LDL) cholesterol in a proportion of patients in the tofacitinib group may be a cause for concern, given the prevalence of adverse renal and cardiovascular outcomes among patients with rheumatoid arthritis.2,3 Preliminary data suggest that the half-life of tofacitinib is prolonged in patients with impaired renal function, and if this drug simultaneously reduces renal function, it could create a self-perpetuating cycle prolonging its action.4 Apprehension regarding renal function is counterbalanced by the findings of a phase 2b study of tofacitinib involving patients undergoing renal transplantation. This study reported superior allograft function and efficacy that was similar to cyclosporine in preventing rejection of renal allografts.5 Tofacitinib also may suppress renal tubular secretion of creatinine, thus increasing serum levels without truly affecting renal function. Given the coincident increase in serum LDL cholesterol levels in these patients, one might be concerned about the possibility that tofacitinib induced or exacerbated proteinuria. Are data on urinary protein excretion available to
more fully characterize the renal implications of tofacitinib use? Donal Sexton, M.D. National University of Ireland, Galway Galway, Ireland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus
methotrexate in rheumatoid arthritis. N Engl J Med 2014;370: 2377-86. 2. Karstila K, Korpela M, Sihvonen S, Mustonen J. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: follow-up of a populationbased study. Clin Rheumatol 2007;26:2089-95. 3. del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-45. 4. Krishnaswami S, Chow V, Boy M, Wang C, Chan G. Pharmacokinetics of tofacitinib, a Janus kinase inhibitor, in patients with impaired renal function and end-stage renal disease. J Clin Pharmacol 2014;54:46-52. 5. Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446-56. DOI: 10.1056/NEJMc1408607
To the Editor: We have major concerns about the safety of tofacitinib, which was developed as
n engl j med 371;12 nejm.org september 18, 2014
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The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Dalbavancin or Oritavancin for Skin Infections To the Editor: Boucher et al. (June 5 issue)1 report the results of DISCOVER 1 and DISCOVER 2, and in the same issue Corey et al.2 report the results of SOLO I. These randomized trials investigated the efficacy of oritavancin and dalbavancin in acute bacterial skin and skin-structure infections. We are concerned that the design of these studies and that of other pivotal studies are not consistent with clinical management of acute bacterial skin and skin-structure infections and that their results are thus not useful for clinical decisions in real life — at least in Europe and some other areas of the world. First, vancomycin may not be an adequate comparison drug. Betalactam antibiotics remain the mainstay drugs for the treatment for methicillin-susceptible Staphylococcus aureus and streptococci, which are the main causes of these infections in most areas, as shown in a recent observational study in Europe.3 Second, most patients with these complicated this week’s letters 1160 Dalbavancin or Oritavancin for Skin Infections 1163 Tofacitinib versus Methotrexate in Rheumatoid Arthritis 1165 Antiretroviral Therapy after Cryptococcal Meningitis 1167 Antidepressant Use in Pregnancy and the Risk of Cardiac Defects 1169 Diagnostic Clinical Genome and Exome Sequencing 1170 Resistance to Therapy in Acute Promyelocytic Leukemia
1160
acute bacterial skin and skin-structure infections are not admitted to the hospital but rather are treated at home with oral antibiotics after surgical drainage of the infected area. In fact, it is difficult for most hospitals in western European countries to include patients in trials with these inclusion criteria. Maria Núñez-Núñez, Pharm.D. Hospital Universitario Virgen Macarena Seville, Spain
Jesús Rodríguez-Baño, M.D., Ph.D. University of Seville Seville, Spain No potential conflict of interest relevant to this letter was reported. 1. Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF,
Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014;370:2169-79. 2. Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014;370:2180-90. 3. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F. Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010-2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 2013;19(9):E377-E385. DOI: 10.1056/NEJMc1407925
To the Editor: In their studies based on intentionto-treat analyses, Boucher et al. and Corey et al. concluded that the new treatments were not inferior to the conventional treatment. Although these are reasonable conclusions, problems such as high dropout rates, which are detrimental to a superiority trial, can be advantageous in a noninferiority study.1 This is because an intention-totreat analysis is more likely to narrow the difference between the treatment groups and yield a
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
noninferior result, potentially leading to a type I the etiologic organisms are susceptible to penierror. Because of this inherent risk in noninferior- cillins. ity studies, Piaggio et al.2 and Le Henanff et al.3 Martin Cormican, M.D. state that both the intention-to-treat analysis and National University of Ireland, Galway the per-protocol analysis are of equal impor- Galway, Ireland tance, and they advise that the two should be [email protected] presented together to enable readers to assess No potential conflict of interest relevant to this letter was rethe validity of the study results. For this reason, ported. we ask the authors to present the per-protocol 1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guideanalysis with the intention-to-treat analysis, lines for the diagnosis and management of skin and soft-tissue which we believe will add confidence to their infections. Clin Infect Dis 2005;41:1373-406. [Errata, Clin Infect Dis 2005;41:1830, 2006;42:1219.] data set. 2. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guideJihoon Baang, M.D. Susan Fisher, Ph.D. Temple University School of Medicine Philadelphia, PA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Guidance for Industry: non-inferiority clinical trials. Silver
Spring, MD: Food and Drug Administration, 2010 (http://www .fda.gov/downloads/Drugs/Guidances/UCM202140.pdf). 2. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006;295:115260. [Erratum, JAMA 2006;296:1842.] 3. Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:1147-51. DOI: 10.1056/NEJMc1407925
To the Editor: If, in the course of hospital rounds focusing on antimicrobial stewardship, I saw a patient who had been prescribed parenteral vancomycin for a minimum of 3 days followed by linezolid for a total of 10 to 14 days for a nonpurulent skin infection, I would point to this course of treatment as an example of unusual prescribing.1,2 If this treatment was continued after methicillin-susceptible S. aureus or Streptococcus pyogenes had been isolated, I would find it hard to justify as being rational in terms of prudent prescribing principles, toxicity, and cost. Yet, in the DISCOVER 1 and DISCOVER 2 studies of dalbavancin, this regimen is presented as conventional therapy for 651 patients with skin infection, including 127 patients with laboratory-confirmed methicillin-susceptible S. aureus and 13 patients with Strep. pyogenes. It would be unhelpful if this article promotes the idea that this is conventional prescribing for skin infection, especially after the microbiologic characteristics indicate that
lines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):e18-e55. [Erratum, Clin Infect Dis 2011;53:319.] DOI: 10.1056/NEJMc1407925
Dr. Boucher and Colleagues Reply: NúñezNúñez and Rodríguez-Baño and Cormican raise questions about our study design and the location of treatment. The DISCOVER studies were designed in accordance with published treatment guidelines and regulatory guidance.1,2 Vancomycin remains the “reference standard” empirical therapy for serious methicillin-resistant S. aureus (MRSA) infections globally.1 As the incidence of MRSA skin infections increases, empirical therapy with anti-MRSA agents such as vancomycin is recommended. Our patients were seriously ill: 85% had fever, the size of the area of the skin infection was large (median, >300 cm2), more than half the patients had the systemic inflammatory response syndrome, and MRSA was frequently identified. Accordingly, these patients received initial parenteral and subsequent oral anti-MRSA therapy. Since these were global trials, the choice of oral step-down therapy in the group of patients who received the comparison drug had to be an agent approved in many countries. Linezolid meets this criterion, is active against streptococci and MRSA, and has an oral formulation. In the United States, rates of MRSA can be greater than 50%, and vancomycin followed by linezolid is among the most common regimens used. Regarding hospitalization, the demographic characteristics of our study population are consistent with those of hospitalized patients with skin infections in Europe. The nearly 2000 European patients in the REACH (Current Management of Patients Hospitalized with Com-
n engl j med 371;12 nejm.org september 18, 2014
1161
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
plicated Skin and Soft Tissue Infections across Europe [2010-2011]) study received intravenous antibiotics for a mean of 9.7 days and they were hospitalized for a median of 18.5 days; 10.2% of these patients had MRSA infection.3 Baang and Fisher request an analysis of treatment success in the per-protocol population. Our studies were the first to use the “new” early end point of success at 48 to 72 hours after the first dose of an antibiotic. The primary efficacy analysis was performed in the intentionto-treat population, since this is most relevant for an end point measured at an early time point. Excluding patients from the intention-totreat population could lead to bias, particularly if post-baseline factors are considered. Per-protocol analyses were conducted on the later end points (see Table 2 of the article and Table S3 in the Supplementary Appendix, available with the full text of the article at NEJM.org). In addition, a per-protocol analysis at the early time point was conducted, and treatment success was seen in 486 of 606 patients who received dalbavancin (80.2%) and 481 of 581 patients who received vancomycin–linezolid (82.8%) (absolute difference, −2.5 percentage points; 95% confidence interval, −7.0 to 1.9). However, the use of a perprotocol population only leads to a better estimate of the drug effect if the intention-to-treat population includes a large number of patients who would not benefit from the antibiotic (i.e., those who did not have the disease under study). In DISCOVER 1 and DISCOVER 2, a total of 2% of patients in each treatment group did not meet the protocol requirements for inclusion or exclusion. Thus, as anticipated for these studies, the per-protocol analysis of the early, primary end point resulted in a conclusion similar to that in the intention-to-treat population. Helen W. Boucher, M.D. Tufts Medical Center Boston, MA [email protected]
George H. Talbot, M.D. Talbot Advisors Anna Maria, FL
Michael W. Dunne, M.D. Durata Therapeutics Branford, CT Since publication of their article, the authors report no further potential conflict of interest.
1162
of
m e dic i n e
1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guide-
lines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59(2):e10-e52. 2. Guidance for Industry: acute bacterial skin and skin structure infections — developing drugs for treatment. Silver Spring, MD: Food and Drug Administration, 2010 (http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071185.pdf). 3. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F. Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010-2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 2013;19(9):E377-E385. DOI: 10.1056/NEJMc1407925
Dr. Corey and Colleagues Reply: In response to Núñez-Núñez and Rodríguez-Baño: vancomycin was an appropriate comparison drug in the SOLO I study because MRSA remains prevalent in most geographic areas, including Europe. In 2012, a total of 17.8% of 37,495 surveillance isolates of S. aureus from 30 European countries were resistant to methicillin1; 10 countries (including Spain) reported MRSA rates between 20% and 50% and 2 reported rates above 50%. Hence, empirical beta-lactam therapy is predicted to be unreliable in treating serious skin infections in Europe. This prediction was confirmed in the study by Garau et al. on management of skin infections in 1995 patients from 10 European countries.2 Among the 402 patients in whom the initial beta-lactam–containing regimen was modified, nearly half (186 patients [46.3%]) had regimens that were modified because of an insufficient therapeutic response. In that study, the mean duration of treatment was 14.6 days and the mean length of hospital stay was 18.5 days (28.9 days for patients with MRSA). Hence, there remains a need for antibiotics that can reduce the length of hospital stay or prevent hospital admission altogether. The infection types in patients in the SOLO I study are representative of those seen in current clinical practice and closely match those in the study by Garau et al. The wide geographic distribution of SOLO I study sites required that the comparison drug be active against MRSA. Our study results were therefore broadly applicable to current management of acute bacterial skin and skin-structure infections in many regions, including Europe.
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at QUEEN MARY AND WESTFIELD COLLEGES on October 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
In response to Baang and Fisher: results in G. Ralph Corey, M.D. patients who could be evaluated clinically were Duke University Medical Center consistent with those in the modified inten- Durham, NC [email protected] tion-to-treat population. The population of patients who could be evaluated clinically in our Hai Jiang, Ph.D. study is synonymous with the per-protocol Greg Moeck, Ph.D. population, since it consisted of all patients in The Medicines Company Parsippany, NJ the modified intention-to-treat population who Since publication of their article, the authors report no furmet the criteria for study inclusion, received the ther potential conflict of interest. full-course of study treatment, and underwent 1. European Centre for Disease Prevention and Control (ECDC). an assessment for clinical cure at the post- Antimicrobial resistance surveillance in Europe 2012: annual therapy evaluation by the site investigator, as report of the European Antimicrobial Resistance Surveillance stated in the legend to Figure 1 of our article. Network (EARS-Net). Stockholm: ECDC, 2013. 2. Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi In addition, Figure 2 of our article and Tables F. Current management of patients hospitalized with compliS4, S7, and S11 in the Supplementary Appendix, cated skin and soft tissue infections across Europe (2010-2011): available at NEJM.org, are all based on the assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect population of patients who could be evaluated 2013;19(9):E377-E385. clinically. DOI: 10.1056/NEJMc1407925
Tofacitinib versus Methotrexate in Rheumatoid Arthritis To the Editor: In the article by Lee et al. (June 19 issue),1 the reported elevation in levels of serum creatinine and low-density lipoprotein (LDL) cholesterol in a proportion of patients in the tofacitinib group may be a cause for concern, given the prevalence of adverse renal and cardiovascular outcomes among patients with rheumatoid arthritis.2,3 Preliminary data suggest that the half-life of tofacitinib is prolonged in patients with impaired renal function, and if this drug simultaneously reduces renal function, it could create a self-perpetuating cycle prolonging its action.4 Apprehension regarding renal function is counterbalanced by the findings of a phase 2b study of tofacitinib involving patients undergoing renal transplantation. This study reported superior allograft function and efficacy that was similar to cyclosporine in preventing rejection of renal allografts.5 Tofacitinib also may suppress renal tubular secretion of creatinine, thus increasing serum levels without truly affecting renal function. Given the coincident increase in serum LDL cholesterol levels in these patients, one might be concerned about the possibility that tofacitinib induced or exacerbated proteinuria. Are data on urinary protein excretion available to
more fully characterize the renal implications of tofacitinib use? Donal Sexton, M.D. National University of Ireland, Galway Galway, Ireland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus
methotrexate in rheumatoid arthritis. N Engl J Med 2014;370: 2377-86. 2. Karstila K, Korpela M, Sihvonen S, Mustonen J. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: follow-up of a populationbased study. Clin Rheumatol 2007;26:2089-95. 3. del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-45. 4. Krishnaswami S, Chow V, Boy M, Wang C, Chan G. Pharmacokinetics of tofacitinib, a Janus kinase inhibitor, in patients with impaired renal function and end-stage renal disease. J Clin Pharmacol 2014;54:46-52. 5. Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446-56. DOI: 10.1056/NEJMc1408607
To the Editor: We have major concerns about the safety of tofacitinib, which was developed as
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