Partial Oral Therapy For Osteomyelitis And Endocarditis - Nejm 2019 1b6k1w
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Partial Oral Therapy for Osteomyelitis and Endocarditis — Is It Time? Helen W. Boucher, M.D. Antimicrobial resistance threatens health and global security, with an estimated 162,000 deaths per year in the United States caused by multidrugresistant infections.1 Surveillance and stewardship through the use of narrow-spectrum therapy, shorter durations of therapy, and oral rather than parenteral therapy, as well as the development of new medicines and diagnostics and improvements in infection prevention through a “One Health” approach — with connections among human patients, animals, and the environment taken into — are key strategies for combating antimicrobial resistance.2,3 Osteomyelitis and infective endocarditis are heterogeneous infections, often involving prosthetic devices. Care provided by infectious-diseases physicians, orthopedic surgeons, and cardiologists, as well as input from pharmacists and microbiologists, are critical to therapeutic success against these common infections. On the basis of the predictable bactericidal activity, absorption, and tissue penetration of antimicrobial agents, published guidelines recommend surgery when indicated and parenteral therapy, except in certain cases,4-8 for these infections. In this issue of the Journal, results from two trials show that partial oral therapy may be an acceptable option in the treatment of osteomyelitis and infective endocarditis affecting the left side of the heart.9,10 The Oral versus Intravenous Antibiotics for Bone and t Infection (OVIVA) trial evaluated standard parenteral therapy as compared with an early switch to oral therapy for the treatment of bone and t infections, including those involving prosthetic ts and hardware. Infec-
tious-diseases experts devised and tailored the therapy for each patient; adjunctive rifampin and follow-on oral therapy were allowed. The primary composite end point, definite treatment failure within 1 year, was defined as the presence of at least one clinical, microbiologic, or histologic criterion of failure. Of the 1054 patients enrolled from 26 U.K. centers, most had Staphylococcus aureus infections; the next-most-common infecting organism was coagulase-negative staphylococci, followed by streptococci, pseudomonas, other gram-negative rods, and culture-negative infections involving the lower extremities. Methicillin-resistant S. aureus (MRSA) was identified in 19 participants (10.2%); 5 participants were infected with S. lugdunensis, 2 were infected with extended-spectrum beta-lactamase–producing gram-negative organisms, and 35 were infected with AmpC-producing gram-negative organisms. The duration of therapy was long — a median of 78 days in the intravenous group and 71 days in the oral group; 76.7% of participants continued antibiotic therapy past 6 weeks, and measured adherence was high. Treatment failure occurred in 14.6% of the participants in the intravenous group and 13.2% of those in the oral group (difference, −1.4 percentage points; 95% confidence interval [CI], −5.6 to 2.9); the results were consistent across relevant populations and subgroups. In a sensitivity analysis according to surgical procedure, although the numbers were small and the results not significant, better outcomes were associated with oral therapy than with intravenous therapy among participants who did not undergo débridement, and better
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
487
The
n e w e ng l a n d j o u r na l
outcomes were associated with intravenous therapy than with oral therapy among patients who underwent débridement with implant retention or single-stage revisions. Patients who were treated with intravenous therapy had a median length of hospital stay that was 3 days longer and more often discontinued therapy because of intravenous catheter complications than did patients who received oral therapy; there were no significant between-group differences in the incidence of Clostridium difficile infection (1.7% in the intravenous group and 1.0% in the oral group) or serious adverse events. The Partial Oral Treatment of Endocarditis (POET) trial compared single-agent parenteral therapy with partial combination oral antibiotic therapy for adults with native or prosthetic-valve infective endocarditis on the left side of the heart caused by streptococcus species, Enterococcus faecalis, S. aureus, or coagulase-negative staphylococci. The continuation phase was selected for the switch from intravenous to oral medication on the basis of studies showing that most serious complications occur in the first 10 to 14 days.8,11 Patients were clinically stable before the switch on the basis of strict criteria; repeat transesophageal echocardiography was required to be performed within 48 hours before the switch to rule out abscess or other complications. Oral antibiotic regimens were designed to include at least two agents with different mechanisms of action and were based on pharmacokinetic–pharmacodynamic analyses to enhance synergy and decrease the risk of resistance. The primary composite outcome included death, unplanned cardiac surgery, embolic events, and relapse of bloodstream infection. Nearly 2000 patients in Denmark were screened in order to enroll 400 patients with infective endocarditis on the left side of the heart; most of the patients were male, 27% had prosthetic-valve endocarditis, and 35 patients had cardiac devices. The primary outcome occurred in 12.1% of the patients in the intravenously treated group and in 9.0% of the patients in the orally treated group (difference, 3.1 percentage points; 95% CI, −3.4 to 9.6). Analysis of the reasons for treatment failure (i.e., the separate components of the primary outcome) showed a nonsignificant between-group difference in mortality, with 13 patients (6.5%) in the intravenously treated group and 7 patients
488
of
m e dic i n e
(3.5%) in the orally treated group dying. Treatment-limiting adverse events were reported at similar rates in the two treatment groups. Each trial showed noninferiority of partial oral therapy to intravenous therapy, and the two strategies had similarly acceptable side-effect profiles. It is noteworthy that oral therapy was asso ciated with as many serious adverse events as intravenous therapy. Close monitoring of outpatients who are taking oral therapy may be warranted; indeed, it may be time to update outpatient parenteral antimicrobial therapy guidelines to include some oral antibiotic regimens.11 The strengths of these trials were the use of real-world inclusion criteria, allowance for standard surgical and medical therapies, diagnostic rigor, involvement of expert physicians, close clinical monitoring (two to three outpatient visits per week in the POET trial), and relatively long — and little loss to — follow-up. The limitations included their open-label design (mitigated by use of adjudication committees who were not aware of the treatment assignments), multiple pathogens and treatment regimens (singleagent and combination therapies), heterogeneous populations (bone and t infections with or without hardware, variable surgical interventions in the OVIVA trial, and native and prostheticvalve infective endocarditis on the left side of the heart with or without surgery in the POET trial), and inclusion of few antibiotic-resistant organisms, all of which can bias the results toward noninferiority. Both trials used elaborate treatment algorithms requiring expert supervision and highlight the need for a robust infectiousdiseases workforce. The POET trial included only five patients who inject drugs and no patients who were infected with MRSA, used treatment regimens that are not available or used in the United States (several regimens included agents with Food and Drug istration [FDA] warnings), and mandated frequent outpatient infectious-diseases visits, all of which limit generalizability. It is worth noting that the FDA usually requires two well controlled trials before concluding efficacy, unless a single trial is highly statistically persuasive on its own or additional pertinent confirmatory evidence is available. Both trials show that pragmatic strategy trials can be accomplished to address pressing questions — here regarding the role of oral antibiotics
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
Editorials
in common, serious infections. I hope that U.S. research leaders working with both government agencies and private research foundations will find ways to execute similar trials or to collaborate with colleagues abroad to study therapies available to our patients. The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB), the Wellcome Trust, the National Institutes of Health, and others have advocated for clinical trials networks to advance our ability to address pressing questions.12 On the basis of these data, targeted oral therapy may have a role in the treatment of selected patients who have osteomyelitis or infective endocarditis on the left side of the heart and the health care infrastructure to close monitoring. At this time, it is premature to recommend a widespread early switch to oral therapy for bone and t infection or step down to combination oral antibiotic therapy for infective endocarditis on the left side of the heart. Subsequent trials might benefit from standardization of either antibiotic therapy or surgery, accepting that this may affect the ease of enrollment. Further studies are needed to confirm these findings and will further inform these strategies and advance stewardship to decrease antimicrobial resistance. Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org. From the Tufts Center for Integrated Management of Antimicrobial Resistance and Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine, Boston. 1. Burnham JP, Olsen MA, Kollef MH. Re-estimating annual deaths due to multidrug-resistant organism infections. Infect Control Hosp Epidemiol 2019;40:112-3. 2. Presidential Advisory Council on Combatting Antibiotic Re-
sistant Bacteria. Key strategies to enhance infection prevention and antibiotic stewardship: report with recommendations for human and animal health. Washington, DC:Department of Health and Human Services, September 2018 (https://www.hhs .gov/sites/default/f iles/f inal-ips-report-10-03-2018.pdf). 3. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016;62(10):e51-e77. 4. Osmon DR, Berbari EF, Berendt AR, et al. Executive summary: diagnosis and management of prosthetic t infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1-10. 5. Berbari EF, Kanj SS, Kowalski TJ, et al. Executive summary: 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015;61:859-63. 6. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines 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. 7. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015;132:1435-86. 8. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC): endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36: 3075-128. 9. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2019;380:415-24. 10. Li H-K, Rombach I, Zambellas R, et al. Oral versus intravenous antibiotics for bone and t infection. N Engl J Med 2019; 380:425-36. 11. Norris AH, Shrestha NK, Allison GM, et al. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clin Infect Dis 2019;68(1):e1-e35. 12. Clinical trial networks for antibiotic development: why they’re important and how they should be developed. London:Wellcome Trust, 2016 (https://wellcome.ac.uk/sites/default/f iles/clinical -trial-networks-for-antibiotic-development-wellcome-oct16.pdf). DOI: 10.1056/NEJMe1817264 Copyright © 2019 Massachusetts Medical Society.
Coronary By Surgery — An ART for Dedicated Surgeons Stuart J. Head, M.D., Ph.D., and Arie P. Kappetein, M.D., Ph.D. Coronary-artery by grafting (CABG), introduced in the 1960s, remains the standard revascularization treatment for complex coronary disease.1 The left internal thoracic artery, with its excellent patency when used as a graft, is the conduit of choice for anastomosis to the left
anterior descending coronary artery. However, the selection of the second conduit remains a matter of debate. Most CABG procedures are performed with a left internal-thoracic-artery graft and saphenous-vein grafts, despite guidelines advocating the use of more arterial grafts.
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
489
n e w e ng l a n d j o u r na l
of
m e dic i n e
Edi t or i a l s
Partial Oral Therapy for Osteomyelitis and Endocarditis — Is It Time? Helen W. Boucher, M.D. Antimicrobial resistance threatens health and global security, with an estimated 162,000 deaths per year in the United States caused by multidrugresistant infections.1 Surveillance and stewardship through the use of narrow-spectrum therapy, shorter durations of therapy, and oral rather than parenteral therapy, as well as the development of new medicines and diagnostics and improvements in infection prevention through a “One Health” approach — with connections among human patients, animals, and the environment taken into — are key strategies for combating antimicrobial resistance.2,3 Osteomyelitis and infective endocarditis are heterogeneous infections, often involving prosthetic devices. Care provided by infectious-diseases physicians, orthopedic surgeons, and cardiologists, as well as input from pharmacists and microbiologists, are critical to therapeutic success against these common infections. On the basis of the predictable bactericidal activity, absorption, and tissue penetration of antimicrobial agents, published guidelines recommend surgery when indicated and parenteral therapy, except in certain cases,4-8 for these infections. In this issue of the Journal, results from two trials show that partial oral therapy may be an acceptable option in the treatment of osteomyelitis and infective endocarditis affecting the left side of the heart.9,10 The Oral versus Intravenous Antibiotics for Bone and t Infection (OVIVA) trial evaluated standard parenteral therapy as compared with an early switch to oral therapy for the treatment of bone and t infections, including those involving prosthetic ts and hardware. Infec-
tious-diseases experts devised and tailored the therapy for each patient; adjunctive rifampin and follow-on oral therapy were allowed. The primary composite end point, definite treatment failure within 1 year, was defined as the presence of at least one clinical, microbiologic, or histologic criterion of failure. Of the 1054 patients enrolled from 26 U.K. centers, most had Staphylococcus aureus infections; the next-most-common infecting organism was coagulase-negative staphylococci, followed by streptococci, pseudomonas, other gram-negative rods, and culture-negative infections involving the lower extremities. Methicillin-resistant S. aureus (MRSA) was identified in 19 participants (10.2%); 5 participants were infected with S. lugdunensis, 2 were infected with extended-spectrum beta-lactamase–producing gram-negative organisms, and 35 were infected with AmpC-producing gram-negative organisms. The duration of therapy was long — a median of 78 days in the intravenous group and 71 days in the oral group; 76.7% of participants continued antibiotic therapy past 6 weeks, and measured adherence was high. Treatment failure occurred in 14.6% of the participants in the intravenous group and 13.2% of those in the oral group (difference, −1.4 percentage points; 95% confidence interval [CI], −5.6 to 2.9); the results were consistent across relevant populations and subgroups. In a sensitivity analysis according to surgical procedure, although the numbers were small and the results not significant, better outcomes were associated with oral therapy than with intravenous therapy among participants who did not undergo débridement, and better
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
487
The
n e w e ng l a n d j o u r na l
outcomes were associated with intravenous therapy than with oral therapy among patients who underwent débridement with implant retention or single-stage revisions. Patients who were treated with intravenous therapy had a median length of hospital stay that was 3 days longer and more often discontinued therapy because of intravenous catheter complications than did patients who received oral therapy; there were no significant between-group differences in the incidence of Clostridium difficile infection (1.7% in the intravenous group and 1.0% in the oral group) or serious adverse events. The Partial Oral Treatment of Endocarditis (POET) trial compared single-agent parenteral therapy with partial combination oral antibiotic therapy for adults with native or prosthetic-valve infective endocarditis on the left side of the heart caused by streptococcus species, Enterococcus faecalis, S. aureus, or coagulase-negative staphylococci. The continuation phase was selected for the switch from intravenous to oral medication on the basis of studies showing that most serious complications occur in the first 10 to 14 days.8,11 Patients were clinically stable before the switch on the basis of strict criteria; repeat transesophageal echocardiography was required to be performed within 48 hours before the switch to rule out abscess or other complications. Oral antibiotic regimens were designed to include at least two agents with different mechanisms of action and were based on pharmacokinetic–pharmacodynamic analyses to enhance synergy and decrease the risk of resistance. The primary composite outcome included death, unplanned cardiac surgery, embolic events, and relapse of bloodstream infection. Nearly 2000 patients in Denmark were screened in order to enroll 400 patients with infective endocarditis on the left side of the heart; most of the patients were male, 27% had prosthetic-valve endocarditis, and 35 patients had cardiac devices. The primary outcome occurred in 12.1% of the patients in the intravenously treated group and in 9.0% of the patients in the orally treated group (difference, 3.1 percentage points; 95% CI, −3.4 to 9.6). Analysis of the reasons for treatment failure (i.e., the separate components of the primary outcome) showed a nonsignificant between-group difference in mortality, with 13 patients (6.5%) in the intravenously treated group and 7 patients
488
of
m e dic i n e
(3.5%) in the orally treated group dying. Treatment-limiting adverse events were reported at similar rates in the two treatment groups. Each trial showed noninferiority of partial oral therapy to intravenous therapy, and the two strategies had similarly acceptable side-effect profiles. It is noteworthy that oral therapy was asso ciated with as many serious adverse events as intravenous therapy. Close monitoring of outpatients who are taking oral therapy may be warranted; indeed, it may be time to update outpatient parenteral antimicrobial therapy guidelines to include some oral antibiotic regimens.11 The strengths of these trials were the use of real-world inclusion criteria, allowance for standard surgical and medical therapies, diagnostic rigor, involvement of expert physicians, close clinical monitoring (two to three outpatient visits per week in the POET trial), and relatively long — and little loss to — follow-up. The limitations included their open-label design (mitigated by use of adjudication committees who were not aware of the treatment assignments), multiple pathogens and treatment regimens (singleagent and combination therapies), heterogeneous populations (bone and t infections with or without hardware, variable surgical interventions in the OVIVA trial, and native and prostheticvalve infective endocarditis on the left side of the heart with or without surgery in the POET trial), and inclusion of few antibiotic-resistant organisms, all of which can bias the results toward noninferiority. Both trials used elaborate treatment algorithms requiring expert supervision and highlight the need for a robust infectiousdiseases workforce. The POET trial included only five patients who inject drugs and no patients who were infected with MRSA, used treatment regimens that are not available or used in the United States (several regimens included agents with Food and Drug istration [FDA] warnings), and mandated frequent outpatient infectious-diseases visits, all of which limit generalizability. It is worth noting that the FDA usually requires two well controlled trials before concluding efficacy, unless a single trial is highly statistically persuasive on its own or additional pertinent confirmatory evidence is available. Both trials show that pragmatic strategy trials can be accomplished to address pressing questions — here regarding the role of oral antibiotics
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
Editorials
in common, serious infections. I hope that U.S. research leaders working with both government agencies and private research foundations will find ways to execute similar trials or to collaborate with colleagues abroad to study therapies available to our patients. The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB), the Wellcome Trust, the National Institutes of Health, and others have advocated for clinical trials networks to advance our ability to address pressing questions.12 On the basis of these data, targeted oral therapy may have a role in the treatment of selected patients who have osteomyelitis or infective endocarditis on the left side of the heart and the health care infrastructure to close monitoring. At this time, it is premature to recommend a widespread early switch to oral therapy for bone and t infection or step down to combination oral antibiotic therapy for infective endocarditis on the left side of the heart. Subsequent trials might benefit from standardization of either antibiotic therapy or surgery, accepting that this may affect the ease of enrollment. Further studies are needed to confirm these findings and will further inform these strategies and advance stewardship to decrease antimicrobial resistance. Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org. From the Tufts Center for Integrated Management of Antimicrobial Resistance and Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine, Boston. 1. Burnham JP, Olsen MA, Kollef MH. Re-estimating annual deaths due to multidrug-resistant organism infections. Infect Control Hosp Epidemiol 2019;40:112-3. 2. Presidential Advisory Council on Combatting Antibiotic Re-
sistant Bacteria. Key strategies to enhance infection prevention and antibiotic stewardship: report with recommendations for human and animal health. Washington, DC:Department of Health and Human Services, September 2018 (https://www.hhs .gov/sites/default/f iles/f inal-ips-report-10-03-2018.pdf). 3. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016;62(10):e51-e77. 4. Osmon DR, Berbari EF, Berendt AR, et al. Executive summary: diagnosis and management of prosthetic t infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1-10. 5. Berbari EF, Kanj SS, Kowalski TJ, et al. Executive summary: 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015;61:859-63. 6. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines 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. 7. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015;132:1435-86. 8. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC): endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36: 3075-128. 9. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2019;380:415-24. 10. Li H-K, Rombach I, Zambellas R, et al. Oral versus intravenous antibiotics for bone and t infection. N Engl J Med 2019; 380:425-36. 11. Norris AH, Shrestha NK, Allison GM, et al. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clin Infect Dis 2019;68(1):e1-e35. 12. Clinical trial networks for antibiotic development: why they’re important and how they should be developed. London:Wellcome Trust, 2016 (https://wellcome.ac.uk/sites/default/f iles/clinical -trial-networks-for-antibiotic-development-wellcome-oct16.pdf). DOI: 10.1056/NEJMe1817264 Copyright © 2019 Massachusetts Medical Society.
Coronary By Surgery — An ART for Dedicated Surgeons Stuart J. Head, M.D., Ph.D., and Arie P. Kappetein, M.D., Ph.D. Coronary-artery by grafting (CABG), introduced in the 1960s, remains the standard revascularization treatment for complex coronary disease.1 The left internal thoracic artery, with its excellent patency when used as a graft, is the conduit of choice for anastomosis to the left
anterior descending coronary artery. However, the selection of the second conduit remains a matter of debate. Most CABG procedures are performed with a left internal-thoracic-artery graft and saphenous-vein grafts, despite guidelines advocating the use of more arterial grafts.
n engl j med 380;5 nejm.org January 31, 2019
The New England Journal of Medicine ed from nejm.org at Univ of Florida Health Science Lib on January 31, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.
489
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