- Email: [email protected]
Pharmaceutical waste and antimicrobial resistance
Correspondence
retrospectively reviewed the records of 416 consecutive patients presenting to the medical unit of the Heartlands Hospital (Birmingham, UK). An infection specialist independently indicated whether they felt the patient required urgent treatment for sepsis. 415 patients were evaluable, of whom 140 (34%) were classified as septic by at least one sepsis definition (figure). SIRS-based criteria classified 83 patients (20%; 95% CI 16–24) as septic. NICE-recommended criteria identified significantly more, classifying 137 patients (33%; 29–38) as septic—an absolute difference of 7–19% (Z test for 95% CI difference in proportions, p<0·0001). The qSOFA tool defined just 17 patients (4%; 95% CI 3–6) as septic. Compared with a consultant’s clinical impression of sepsis, SIRS-based criteria had a sensitivity of 76% (95% CI 60–87) and specificity of 87% (83–90). Using NICE guidelines, sensitivity was similar, at 84% (71–94), but specificity fell to 73% (68–78). qSOFA scoring had the lowest sensitivity at 13% (5–27) but highest specificity at 97% (95–99). 22 people were admitted to the intensive therapy unit (ITU) or died within 14 days. Of these, nine (41%) were identified by both SIRS-based and NICE sepsis definitions. NICE guidance identified seven additional patients. qSOFA identified seven patients from the death or the ITU group, all of whom were identified by NICE, and five of whom were identified by SIRS-based definitions. Implementation of NICE sepsis guidance will have considerable operational effect, with one third of medical admissions classed as requiring urgent antibiotics. Whether this is clinically justified is not clear: improved sensitivity has come at the cost of significantly reduced specificity. This reduction will lead to an increase in the administration of unnecessary—or at least unnecessarily broad-spectrum—antibiotics with implications for stewardship, 578
complications, and increased bacterial resistance. qSOFA, although capable of identifying the sickest patients, is unlikely to be sensitive enough to recognise those at significant risk of later deterioration. Hospitals need to implement NICE guidance cautiously and in parallel with robust antibiotic stewardship systems. NICE recommendations need to be subject to ongoing research with the aim of clarifying their sensitivity and specificity and identifying how they can be improved. We declare no competing interests.
Melinda Munang, Saleem Chaudhri, Methini Himayakanthan, Steven Laird, Amy Moltu, Natasha Naworynsky, Christopher Pollard, Tahir Saeed, Paul Scott, Cathleen Chan, Maya Sussman, Shaun Thein, George Trafford, Ariyur Balaji, Neil Jenkins, *Ed Moran [email protected] Department of Infectious Diseases (MM, SC, SL, AM, NN, CP, TS, PS, ST, GT,NJ, EM) and Department of Acute Medicine (MH, MS, AB), Heartlands Hospital, Birmingham B9 5SS, UK 1
2
3
Donnelly JP, Safford MM, Shapiro NI, Baddley JW, Wang HE. Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) Classification: a retrospective population-based cohort study. Lancet Infect Dis 2017; published online March 3. http://dx.doi.org/10.1016/S14733099(17)30117-2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315: 801–10. Freitag A, Constanti M, O’Flynn N, Faust SN, Guideline Development Group. Suspected sepsis: summary of NICE guidance. BMJ 2016; 354: i4030.
Pharmaceutical waste and antimicrobial resistance On Sept 21, 2016, the United Nations called a meeting on antimicrobial resistance with policymakers to address antimicrobial resistance comprehensively and multisectorally.1 An estimated 700 000 people around the world die each year from
drug-resistant strains of common bacterial infections, tuberculosis, and malaria,2 and total global deaths caused by antibiotic-resistant infections are estimated to reach 10 million per year by 2050, with economic losses exceeding US$100 trillion. Thus, the recent discovery of drug resistant bacteria at several pharmaceutical manufacturing sites in three Indian cities—Hyderabad, New Delhi, and Chennai—is concerning. Of 34 sites tested, 16 were found to be harbouring bacteria resistant to antibiotics.3 At four of these sites, resistance to three major classes of antibiotics was detected, including carbapenems. The pharmaceutical companies involved export antibiotics to several countries including highincome nations such as the UK, USA, and France.3 In India, regulations for the release of pharmaceutical waste into rivers or the environment are minimal.4 Waste fluid containing active pharmaceutical ingredients from antibiotic manufacturing plants is released into the surrounding soil and water, and this process perhaps favours the selection of resistant organisms.3 Moreover, sewage treatment plants in India, which are supposed to purify water, are in poor shape, in need of constant repairs, and used beyond their limits.5 Upon purification by these sewage water plants, water can still be contaminated with antibiotic-resistant bacteria that can pose a serious threat to public health.4 We suggest that regulations should be imposed on pharmaceutical manufacturing units operating in India, which are contributing to the spread of antimicrobial resistance. 3 India is a major producer of generic medications and active pharmaceutical ingredients (APIs). Lenient regulations can affect India’s relationships with high-income countries in Europe and North America, which are the major importers of the country’s medications and APIs. Indian practitioners run several antimicrobial stewardship www.thelancet.com/infection Vol 17 June 2017
Correspondence
programmes to combat antimicrobial resistance and their efforts are undermined by the questionable practices of the pharmaceutical manufacturing units.3 Public availability of information about the origin of APIs and evidence of good manufacturing practice compliance of the manufactured APIs imported by the European Union and the USA can improve transparency. WHO good manufacturing practice guidelines for workplace safety, environmental protection, pollution prevention, and adoption of cleaner production technology should be adopted and enforced consistently for all the countries that are responsible for antimicrobial resistance.2 We declare no competing interests.
*Akram Ahmad, Isha Patel, Muhammad Umair Khan, Zaheer ud-din Babar [email protected] Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, 56000, Malaysia (AA); Department of Pharmacy Practice, Administration and Research, Marshall University School of Pharmacy, Marshall University, Huntington, WV, USA (IP); Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia (MUK); and Department of Pharmacy, University of Huddersfield, UK (Zu-dB) 1
2
3
4 5
General Assembly of the United Nations. High-level Meeting on Antimicrobial Resistance. Sept 21, 2016. http://www.un.org/ pga/71/event-latest/high-level-meeting-onantimicrobial-resistance (accessed Feb 14, 2017). SumOfUs. Bad Medicine: how the pharmaceutical industry is contributing to the global rise of antiobiotic-resistant superbugs. June, 2015. http://changingmarket.wpengine. com/wp-content/uploads/2016/12/BADMEDICINE-Report-FINAL.pdf (accessed Feb 19, 2017). Changing Markets, Ecostorm. Superbugs in the supply chain: how pollution from antibiotics factories in India and China is fuelling the global rise of drug-resistant infections. October, 2016. https://epha.org/wp-content/uploads/2016/10/ Superbugsinthesupplychain_CMreport.pdf (accessed Feb 14, 2017). Laxminarayan R, Chaudhury RR. Antibiotic resistance in India: drivers and opportunities for action. PLoS Med 2016; 13: e1001974. R Kaur, SP Wani, AK Singh, K Lal. Wastewater production, treatment and use in India. UN-Water Activity Information System. Second regional workshop of the project Safe Use of Wastewater in Agriculture; New Dehli, India; May 16–18, 2012.
www.thelancet.com/infection Vol 17 June 2017
e-learning for global antimicrobial stewardship In their Correspondence, Elizabeth Robilotti and colleagues1 highlighted the demand and need for open access, globally accessible educational resources for health-care professionals across all health economies, and discussed the resources they offer in response to this need. To support this demand, the British Society for Antimicrobial Chemotherapy (BSAC) developed a massive open online course (MOOC) on antimicrobial stewardship in partnership with the University of Dundee, Scotland, UK. Free at the point of access, it has been accessed by almost 33 000 learners in 163 countries since October, 2015. Assessment of its use and impact is highlighted in the appendix. The course empowers health-care professionals to provide safe, high-quality antibiotic use and to assess the effectiveness of using strategies, tools, and interventions in antimicrobial stewardship to drive improvement in their locality and practice. Adding to its global value, the open access course is available in English2 and Mandarin,3 with Spanish and Russian versions planned. Future Learn, the platform host, has partnered directly with BSAC, providing a global learning platform for concise, open access courses for all health-care communities and a market reach of 5·5 million learners worldwide. The first two courses, “Challenges in antibiotic resistance: point prevalence surveys” and “Challenges in antibiotic resistance: Gram-negative bacteria”, opened for registration on March 13, 2017. Early 2018 will see the launch of an e-book on antimicrobial stewardship. The remit is broader and deeper than the MOOC—eg, it encompasses stewardship in the non-hospital setting and in special populations. The value and preference of a range of e-learning tools to augment traditional faceto-face and practice-based learning, termed hybrid learning, has been identified in three large surveys of the stewardship educational needs and
existing activity of Indian, African, and Russian health-care professionals (D Nathwani, unpublished). These surveys were supported by the UK Foreign and Commonwealth Office Science and Innovation Fund. Lastly, we are members of the Conscience of Antimicrobial Resistance Alliance, 4 established to support implementation of the UN Resolution on Antimicrobial Resistance.5 BSAC is proposed to lead the education subbranch to develop indicators against which to measure the availability, implementation, and success of educational initiatives across the world. We look forward to hearing from other potential partners who would like to work with us in this important venture. We declare no competing interests.
Dilip Nathwani, *Tracey Guise, Mark Gilchrist, on behalf of BSAC [email protected]
See Online for appendix
Academic Health Sciences Partnership in Tayside, Ninewells Hospital and Medical School, Dundee, UK (DN); British Society for Antimicrobial Chemotherapy, Birmingham B1 3NJ, UK (TG); and Infectious Diseases, Imperial College Healthcare NHS Trust, London, UK (MG) 1
2
3
4
5
Robilotti E, Holubar M, Nahrgang S, van de Sande-Bruinsma N, Lo Fo Wong D, Deresinski S. Educating front-line clinicians about antimicrobial resistance. Lancet Infec Dis 2017; 17: 257–58. Future Learn. Antimicrobial stewardship: managing antibiotic resistance. https://www. futurelearn.com/courses/antimicrobialstewardship (accessed April 21, 2017). Future Learn. Antimicrobial stewardship: managing antibiotic resistance (in Mandarin). https://www.futurelearn.com/courses/ antimicrobial-stewardship-mandarin (accessed April 21, 2017). Forum on Antibiotics. An alliance to support the UN Resolution on Antimicrobial Resistance. http://www.forumonantibiotics. org/alliance (accessed April 21, 2017). General Assembly of the United Nations. Press release: high-level meeting on antimicrobial resistance. Sept 21, 2016. http://www.un.org/pga/71/2016/09/21/pressrelease-hl-meeting-on-antimicrobialresistance/ (accessed April 21, 2017).
For Future Learn see www.futurelearn.com
Staphylococcus aureus in critical care The Article by James Price and colleagues1 describes an important study that explores the role of health579
retrospectively reviewed the records of 416 consecutive patients presenting to the medical unit of the Heartlands Hospital (Birmingham, UK). An infection specialist independently indicated whether they felt the patient required urgent treatment for sepsis. 415 patients were evaluable, of whom 140 (34%) were classified as septic by at least one sepsis definition (figure). SIRS-based criteria classified 83 patients (20%; 95% CI 16–24) as septic. NICE-recommended criteria identified significantly more, classifying 137 patients (33%; 29–38) as septic—an absolute difference of 7–19% (Z test for 95% CI difference in proportions, p<0·0001). The qSOFA tool defined just 17 patients (4%; 95% CI 3–6) as septic. Compared with a consultant’s clinical impression of sepsis, SIRS-based criteria had a sensitivity of 76% (95% CI 60–87) and specificity of 87% (83–90). Using NICE guidelines, sensitivity was similar, at 84% (71–94), but specificity fell to 73% (68–78). qSOFA scoring had the lowest sensitivity at 13% (5–27) but highest specificity at 97% (95–99). 22 people were admitted to the intensive therapy unit (ITU) or died within 14 days. Of these, nine (41%) were identified by both SIRS-based and NICE sepsis definitions. NICE guidance identified seven additional patients. qSOFA identified seven patients from the death or the ITU group, all of whom were identified by NICE, and five of whom were identified by SIRS-based definitions. Implementation of NICE sepsis guidance will have considerable operational effect, with one third of medical admissions classed as requiring urgent antibiotics. Whether this is clinically justified is not clear: improved sensitivity has come at the cost of significantly reduced specificity. This reduction will lead to an increase in the administration of unnecessary—or at least unnecessarily broad-spectrum—antibiotics with implications for stewardship, 578
complications, and increased bacterial resistance. qSOFA, although capable of identifying the sickest patients, is unlikely to be sensitive enough to recognise those at significant risk of later deterioration. Hospitals need to implement NICE guidance cautiously and in parallel with robust antibiotic stewardship systems. NICE recommendations need to be subject to ongoing research with the aim of clarifying their sensitivity and specificity and identifying how they can be improved. We declare no competing interests.
Melinda Munang, Saleem Chaudhri, Methini Himayakanthan, Steven Laird, Amy Moltu, Natasha Naworynsky, Christopher Pollard, Tahir Saeed, Paul Scott, Cathleen Chan, Maya Sussman, Shaun Thein, George Trafford, Ariyur Balaji, Neil Jenkins, *Ed Moran [email protected] Department of Infectious Diseases (MM, SC, SL, AM, NN, CP, TS, PS, ST, GT,NJ, EM) and Department of Acute Medicine (MH, MS, AB), Heartlands Hospital, Birmingham B9 5SS, UK 1
2
3
Donnelly JP, Safford MM, Shapiro NI, Baddley JW, Wang HE. Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) Classification: a retrospective population-based cohort study. Lancet Infect Dis 2017; published online March 3. http://dx.doi.org/10.1016/S14733099(17)30117-2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315: 801–10. Freitag A, Constanti M, O’Flynn N, Faust SN, Guideline Development Group. Suspected sepsis: summary of NICE guidance. BMJ 2016; 354: i4030.
Pharmaceutical waste and antimicrobial resistance On Sept 21, 2016, the United Nations called a meeting on antimicrobial resistance with policymakers to address antimicrobial resistance comprehensively and multisectorally.1 An estimated 700 000 people around the world die each year from
drug-resistant strains of common bacterial infections, tuberculosis, and malaria,2 and total global deaths caused by antibiotic-resistant infections are estimated to reach 10 million per year by 2050, with economic losses exceeding US$100 trillion. Thus, the recent discovery of drug resistant bacteria at several pharmaceutical manufacturing sites in three Indian cities—Hyderabad, New Delhi, and Chennai—is concerning. Of 34 sites tested, 16 were found to be harbouring bacteria resistant to antibiotics.3 At four of these sites, resistance to three major classes of antibiotics was detected, including carbapenems. The pharmaceutical companies involved export antibiotics to several countries including highincome nations such as the UK, USA, and France.3 In India, regulations for the release of pharmaceutical waste into rivers or the environment are minimal.4 Waste fluid containing active pharmaceutical ingredients from antibiotic manufacturing plants is released into the surrounding soil and water, and this process perhaps favours the selection of resistant organisms.3 Moreover, sewage treatment plants in India, which are supposed to purify water, are in poor shape, in need of constant repairs, and used beyond their limits.5 Upon purification by these sewage water plants, water can still be contaminated with antibiotic-resistant bacteria that can pose a serious threat to public health.4 We suggest that regulations should be imposed on pharmaceutical manufacturing units operating in India, which are contributing to the spread of antimicrobial resistance. 3 India is a major producer of generic medications and active pharmaceutical ingredients (APIs). Lenient regulations can affect India’s relationships with high-income countries in Europe and North America, which are the major importers of the country’s medications and APIs. Indian practitioners run several antimicrobial stewardship www.thelancet.com/infection Vol 17 June 2017
Correspondence
programmes to combat antimicrobial resistance and their efforts are undermined by the questionable practices of the pharmaceutical manufacturing units.3 Public availability of information about the origin of APIs and evidence of good manufacturing practice compliance of the manufactured APIs imported by the European Union and the USA can improve transparency. WHO good manufacturing practice guidelines for workplace safety, environmental protection, pollution prevention, and adoption of cleaner production technology should be adopted and enforced consistently for all the countries that are responsible for antimicrobial resistance.2 We declare no competing interests.
*Akram Ahmad, Isha Patel, Muhammad Umair Khan, Zaheer ud-din Babar [email protected] Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, 56000, Malaysia (AA); Department of Pharmacy Practice, Administration and Research, Marshall University School of Pharmacy, Marshall University, Huntington, WV, USA (IP); Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia (MUK); and Department of Pharmacy, University of Huddersfield, UK (Zu-dB) 1
2
3
4 5
General Assembly of the United Nations. High-level Meeting on Antimicrobial Resistance. Sept 21, 2016. http://www.un.org/ pga/71/event-latest/high-level-meeting-onantimicrobial-resistance (accessed Feb 14, 2017). SumOfUs. Bad Medicine: how the pharmaceutical industry is contributing to the global rise of antiobiotic-resistant superbugs. June, 2015. http://changingmarket.wpengine. com/wp-content/uploads/2016/12/BADMEDICINE-Report-FINAL.pdf (accessed Feb 19, 2017). Changing Markets, Ecostorm. Superbugs in the supply chain: how pollution from antibiotics factories in India and China is fuelling the global rise of drug-resistant infections. October, 2016. https://epha.org/wp-content/uploads/2016/10/ Superbugsinthesupplychain_CMreport.pdf (accessed Feb 14, 2017). Laxminarayan R, Chaudhury RR. Antibiotic resistance in India: drivers and opportunities for action. PLoS Med 2016; 13: e1001974. R Kaur, SP Wani, AK Singh, K Lal. Wastewater production, treatment and use in India. UN-Water Activity Information System. Second regional workshop of the project Safe Use of Wastewater in Agriculture; New Dehli, India; May 16–18, 2012.
www.thelancet.com/infection Vol 17 June 2017
e-learning for global antimicrobial stewardship In their Correspondence, Elizabeth Robilotti and colleagues1 highlighted the demand and need for open access, globally accessible educational resources for health-care professionals across all health economies, and discussed the resources they offer in response to this need. To support this demand, the British Society for Antimicrobial Chemotherapy (BSAC) developed a massive open online course (MOOC) on antimicrobial stewardship in partnership with the University of Dundee, Scotland, UK. Free at the point of access, it has been accessed by almost 33 000 learners in 163 countries since October, 2015. Assessment of its use and impact is highlighted in the appendix. The course empowers health-care professionals to provide safe, high-quality antibiotic use and to assess the effectiveness of using strategies, tools, and interventions in antimicrobial stewardship to drive improvement in their locality and practice. Adding to its global value, the open access course is available in English2 and Mandarin,3 with Spanish and Russian versions planned. Future Learn, the platform host, has partnered directly with BSAC, providing a global learning platform for concise, open access courses for all health-care communities and a market reach of 5·5 million learners worldwide. The first two courses, “Challenges in antibiotic resistance: point prevalence surveys” and “Challenges in antibiotic resistance: Gram-negative bacteria”, opened for registration on March 13, 2017. Early 2018 will see the launch of an e-book on antimicrobial stewardship. The remit is broader and deeper than the MOOC—eg, it encompasses stewardship in the non-hospital setting and in special populations. The value and preference of a range of e-learning tools to augment traditional faceto-face and practice-based learning, termed hybrid learning, has been identified in three large surveys of the stewardship educational needs and
existing activity of Indian, African, and Russian health-care professionals (D Nathwani, unpublished). These surveys were supported by the UK Foreign and Commonwealth Office Science and Innovation Fund. Lastly, we are members of the Conscience of Antimicrobial Resistance Alliance, 4 established to support implementation of the UN Resolution on Antimicrobial Resistance.5 BSAC is proposed to lead the education subbranch to develop indicators against which to measure the availability, implementation, and success of educational initiatives across the world. We look forward to hearing from other potential partners who would like to work with us in this important venture. We declare no competing interests.
Dilip Nathwani, *Tracey Guise, Mark Gilchrist, on behalf of BSAC [email protected]
See Online for appendix
Academic Health Sciences Partnership in Tayside, Ninewells Hospital and Medical School, Dundee, UK (DN); British Society for Antimicrobial Chemotherapy, Birmingham B1 3NJ, UK (TG); and Infectious Diseases, Imperial College Healthcare NHS Trust, London, UK (MG) 1
2
3
4
5
Robilotti E, Holubar M, Nahrgang S, van de Sande-Bruinsma N, Lo Fo Wong D, Deresinski S. Educating front-line clinicians about antimicrobial resistance. Lancet Infec Dis 2017; 17: 257–58. Future Learn. Antimicrobial stewardship: managing antibiotic resistance. https://www. futurelearn.com/courses/antimicrobialstewardship (accessed April 21, 2017). Future Learn. Antimicrobial stewardship: managing antibiotic resistance (in Mandarin). https://www.futurelearn.com/courses/ antimicrobial-stewardship-mandarin (accessed April 21, 2017). Forum on Antibiotics. An alliance to support the UN Resolution on Antimicrobial Resistance. http://www.forumonantibiotics. org/alliance (accessed April 21, 2017). General Assembly of the United Nations. Press release: high-level meeting on antimicrobial resistance. Sept 21, 2016. http://www.un.org/pga/71/2016/09/21/pressrelease-hl-meeting-on-antimicrobialresistance/ (accessed April 21, 2017).
For Future Learn see www.futurelearn.com
Staphylococcus aureus in critical care The Article by James Price and colleagues1 describes an important study that explores the role of health579