Correspondence
Antibiotic resistance needs global solutions We read with great interest the Commission by Ramanan Laxminarayan and colleagues1 about the need for global solutions to deal with the challenges posed by antibiotic resistance. The number of drug-resistant bacteria is rapidly increasing at an alarming rate. In fact, antibiotic resistance is one of the most serious threats in the history of medicine, and new antibiotics and alternative strategies should be sought as soon as possible to tackle this complex problem. We believe that traditionally used medicinal plant species harbour endophytes. Endophytes are microbes (bacteria and fungi) that live in plants without causing any disease symptoms, and are known to help the host plant in various ways, including protecting it from pathogens. Plants with antimicrobial properties are likely to have endophytes that produce novel antimicrobial bioactive compounds. Reports from published work show that the natural products derived from endophytes have antibacterial,2 antifungal, 3 and even antiviral 4 properties; therefore, endophytes could serve as an alternative source of novel antibiotics and could be useful in tackling antibiotic resistance. In many countries, plants are used in traditional medicine systems. If these medicinally important plant species are studied systematically for their endophytes and the natural products derived from endophytes, then these might provide several leads that could play an important part in dealing with antibiotic resistance. However, we should not preclude the importance of endophytes from species of monocotyledons, dicotyledons, gymnosperms, ferns, mosses, green algae, and red algae that are not reported as having medicinal uses. www.thelancet.com/infection Vol 14 July 2014
In addition to a clear plan, systematic coordinated efforts, both national and international, are needed to explore the potential of endophytes to produce novel antibiotics for various types of antibiotic-resistant bacteria (panel).5 Meaningful collaboration at local, national, regional, and international level is the key to success, and to achieve this, the scientific community could consider the establishment of an international consortium. In this regard, we call upon all leading scientists and policy makers (both at national and international level) who are involved directly or indirectly in the research to find new antibiotics (by using alternative strategies), to establish such a consortium to explore the potential of endophytes in producing novel antibiotics. This international consortium could be a part of a global plan to tackle antibiotic resistance and share the responsibilities of finding solutions. We declare no competing interests.
Tahmina Monowar, *Subhash J Bhore [email protected] Department of Biotechnology, Faculty of Applied Sciences, AIMST University, Bedong-Semeling Road, 08100 Bedong, Kedah, Malaysia (TM, SJB); and Department of Microbiology, Faculty of Medicine, AIMST University, Kedah, Malaysia (TM) 1
2
3
4
5
Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013; 13: 1057–98. Ding L, Maier A, Fiebig HH, Lin WH, Hertweck C. A family of multicyclic indolosesquiterpenes from a bacterial endophyte. Org Biomol Chem 2011; 9: 4029–31. Miller CM, Miller RV, Garton-Kenny D, et al. Ecomycins, unique antimycotics from Pseudomonas viridiflava. J Appl Microbiol 1998; 84: 937–44. Ding L, Münch J, Goerls H, et al. Xiamycin, a pentacyclic indolosesquiterpene with selective anti-HIV activity from a bacterial mangrove endophyte. Bioorg Med Chem Lett 2010; 20: 6685–87. CDC. Antibiotic resistance threats in the United States, 2013. Atlanta: Centers for Disease Control and Prevention, 2013. http://www.cdc.gov/drugresistance/ threat-report-2013/ (accessed Nov 15, 2013).
Panel: Antibiotic resistance threats categorised into three levels of concern5 Urgent • Clostridium difficile • Carbapenem-resistant Enterobacteriaceae • Multidrug-resistant Neisseria gonorrhoeae Serious • Multidrug-resistant Acinetobacter spp • Multidrug-resistant Campylobacter spp • Fluconazole-resistant Candida spp* • Extended spectrum β-lactamase producing Enterobacteriaceae • Vancomycin-resistant Enterococcus spp • Multidrug-resistant Pseudomonas aeruginosa • Multidrug-resistant non-typhoidal Salmonella spp • Multidrug-resistant Salmonella Typhi • Multidrug-resistant Shigella spp • Methicillin-resistant Staphylococcus aureus • Multidrug-resistant Streptococcus pneumoniae • Multidrug-resistant tuberculosis Of concern • Vancomycin-resistant S aureus • Erythromycin-resistant group A Streptococcus spp • Clindamycin-resistant group B Streptococcus spp *All data are for bacteria, except for Candida (which is a fungus).
We read with great interest the recent Commission by Ramanan Laxminarayan and colleagues1 about antibiotic resistance and the need for global solutions. This problem has many different facets that can vary between regions and countries. In south Asia it is easy to buy antibiotics over the counter without a prescription, which obviously leads to overuse of these drugs and paves the way to resistance. But one could argue that in countries such as Nepal, where there might not be doctors in remote areas, antibiotic use without a doctor’s prescription could be essential to cure an illness, and perhaps even to save a life. But clearly, guidelines need to be formed and implemented, both for antibiotics that require a prescription and for those that do not. Doctors in Nepal and India are finding it more difficult to treat common infections, such as those in neonates and of the urinary tract, with the older generation of antibiotics. We increasingly use, when available, the 549
Correspondence
next generation of more powerful and expensive antibiotics, and are setting the stage for a time when antibiotics might no longer be effective for many infections. Another major reason for antibiotic resistance is the use of antibiotics in animals (eg, tetracycline in chicken feed) in subtherapeutic doses to promote growth. This important point was also highlighted very clearly in the article.1 As mentioned, many high-income countries have enacted laws to curb the practice of adding antibiotics to animal feed, even as early as 1971, to avoid antibiotic resistance in people. It is therefore time for countries like India and Nepal, and other low-income countries, to use antibiotics in animals only for the treatment of infections. Indiscriminate, subtherapeutic use of antibiotics for animal growth promotion must be stopped by governments; by increasing awareness in the general population about drug resistance, and by enacting laws so that antibiotics for saving human lives will continue to be effective, and the likelihood of resistance will decrease. If India takes the lead in this venture, it will probably be easier for smaller countries in the vicinity like Nepal to follow suit, because its pharmaceutical commerce is closely linked with India. I declare no competing interests.
Buddha Basnyat [email protected] Oxford University Clinical Research Unit, Patan Academy of Health Science, 252 Kathmandu, Nepal 1
Laxminarayan R, Duse A, Chand W, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013; 13: 1057–98.
I read with interest Simon Howard and colleagues’ Comment 1 on the increasing threat of antibiotic resistance and the necessity for a strong global response. That antibiotic use results in selective pressure favouring resistant bacteria is beyond dispute, and this is certainly a large part of the story, but not the entire one. Antibiotic resistance is probably ancient. 2 Researchers analysing 550
sediment samples obtained from deep below the earth’s surface at two sites in the USA found a diverse array of bacteria with resistance to 13 different antibiotics, and 90% of samples were resistant to at least one antibiotic. Perhaps most surprising, some of the bacterial strains were thought to be completely isolated from past human exposure, which raises the likelihood that they developed novel antibiotic resistance.2 In another study,3 30 000-year-old ice cores from the Beringian permafrost in Canada were collected. DNA segments from flora and fauna characteristic of the Arctic Pleistocene epoch were extracted and analysed. Metagenomic analysis revealed a highly diverse array of genes encoding resistance to multiple antibiotics such as β-lactams, tetracyclines, and glycopeptide antibiotics, including the VanA gene that confers the highest resistance to vancomycin.3 That antibiotic resistance pre-dates the anthropogenic antibiotic era might seem surprising, but it should not be. Bacteria are estimated to have originated more than 3·8 billion years ago, and antibiotics might be at least hundreds of millions of years old.4 In an effort to survive in competitive environments, bacteria and other pathogens have developed mechanisms to compete with other species, which include the production of antibiotics. As Howard and colleagues note,1 in one of history’s most famous examples, the mould Penicillium chrysogenum produces a substance that inhibits the growth of Gram-positive bacteria, which led to the discovery of the antibiotic penicillin.5 The widespread use of antibiotics has certainly accelerated the pace of antibiotic resistance that occurs naturally. The degree of resistance that exists, and the extensive head start that bacteria already have, increases the threat of antibiotic resistance even more. The pace of new antibiotic discovery and licensing has certainly
slowed in recent years, which threatens our ability in the future to fight off lifethreatening infections. But somewhere out there is probably a gene yet to be expressed that encodes a resistance mechanism to an antibiotic yet to be invented. Perhaps somewhere in the Beringian permafrost or the bathroom sink of a hospital near you… I declare no competing interests.
Jeffrey Jenks [email protected] University of California, San Diego Division of Infectious Diseases, La Jolla, CA 92093-0711, USA 1
2
3 4
5
Howard SJ, Catchpole M, Watson J, Davies SC. Antibiotic resistance: global response needed. Lancet Infect Dis 2013; 13: 1001–03. Brown MG, Balkwill DL. Antibiotic resistance in bacteria isolated from the deep terrestrial subsurface. Microb Ecol 2009; 57: 484–93. D’Costa VM, King CE, Kalan L, et al. Antibiotic resistance is ancient. Nature 2011; 477: 457–61. Wright DG, Poinar H. Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol 2012; 20: 157–59. Rifkind D, Freeman G. The Nobel prize winning discoveries in infectious diseases. London: Academic Press, 2005.
We agree with Ramanan Laxminarayan and colleagues1 that antimicrobial resistance (AMR) in bacteria that cause community and health-careassociated infections (HAI) in lowincome countries poses a serious threat to global health. In the first 60 years of antibiotic use, resistance predominantly emerged from hospitals in highincome countries; now, health-care environments in low-income countries have also become an important crucible for the evolution of resistance. The increased resistance is eroding the effectiveness of local management strategies for life-threatening diseases such as pneumonia and meningitis. Increased interconnectedness means that resistance genes emerging in one place rapidly become a global threat. AMR and HAI are tightly related issues that are both poorly described in low-income settings, and basic data on the burden of disease are extremely scarce.2 The Global Burden of Disease studies have never estimated the effect of either HAI or AMR, but this is hardly surprising, in view of the www.thelancet.com/infection Vol 14 July 2014
Antibiotic resistance needs global solutions We read with great interest the Commission by Ramanan Laxminarayan and colleagues1 about the need for global solutions to deal with the challenges posed by antibiotic resistance. The number of drug-resistant bacteria is rapidly increasing at an alarming rate. In fact, antibiotic resistance is one of the most serious threats in the history of medicine, and new antibiotics and alternative strategies should be sought as soon as possible to tackle this complex problem. We believe that traditionally used medicinal plant species harbour endophytes. Endophytes are microbes (bacteria and fungi) that live in plants without causing any disease symptoms, and are known to help the host plant in various ways, including protecting it from pathogens. Plants with antimicrobial properties are likely to have endophytes that produce novel antimicrobial bioactive compounds. Reports from published work show that the natural products derived from endophytes have antibacterial,2 antifungal, 3 and even antiviral 4 properties; therefore, endophytes could serve as an alternative source of novel antibiotics and could be useful in tackling antibiotic resistance. In many countries, plants are used in traditional medicine systems. If these medicinally important plant species are studied systematically for their endophytes and the natural products derived from endophytes, then these might provide several leads that could play an important part in dealing with antibiotic resistance. However, we should not preclude the importance of endophytes from species of monocotyledons, dicotyledons, gymnosperms, ferns, mosses, green algae, and red algae that are not reported as having medicinal uses. www.thelancet.com/infection Vol 14 July 2014
In addition to a clear plan, systematic coordinated efforts, both national and international, are needed to explore the potential of endophytes to produce novel antibiotics for various types of antibiotic-resistant bacteria (panel).5 Meaningful collaboration at local, national, regional, and international level is the key to success, and to achieve this, the scientific community could consider the establishment of an international consortium. In this regard, we call upon all leading scientists and policy makers (both at national and international level) who are involved directly or indirectly in the research to find new antibiotics (by using alternative strategies), to establish such a consortium to explore the potential of endophytes in producing novel antibiotics. This international consortium could be a part of a global plan to tackle antibiotic resistance and share the responsibilities of finding solutions. We declare no competing interests.
Tahmina Monowar, *Subhash J Bhore [email protected] Department of Biotechnology, Faculty of Applied Sciences, AIMST University, Bedong-Semeling Road, 08100 Bedong, Kedah, Malaysia (TM, SJB); and Department of Microbiology, Faculty of Medicine, AIMST University, Kedah, Malaysia (TM) 1
2
3
4
5
Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013; 13: 1057–98. Ding L, Maier A, Fiebig HH, Lin WH, Hertweck C. A family of multicyclic indolosesquiterpenes from a bacterial endophyte. Org Biomol Chem 2011; 9: 4029–31. Miller CM, Miller RV, Garton-Kenny D, et al. Ecomycins, unique antimycotics from Pseudomonas viridiflava. J Appl Microbiol 1998; 84: 937–44. Ding L, Münch J, Goerls H, et al. Xiamycin, a pentacyclic indolosesquiterpene with selective anti-HIV activity from a bacterial mangrove endophyte. Bioorg Med Chem Lett 2010; 20: 6685–87. CDC. Antibiotic resistance threats in the United States, 2013. Atlanta: Centers for Disease Control and Prevention, 2013. http://www.cdc.gov/drugresistance/ threat-report-2013/ (accessed Nov 15, 2013).
Panel: Antibiotic resistance threats categorised into three levels of concern5 Urgent • Clostridium difficile • Carbapenem-resistant Enterobacteriaceae • Multidrug-resistant Neisseria gonorrhoeae Serious • Multidrug-resistant Acinetobacter spp • Multidrug-resistant Campylobacter spp • Fluconazole-resistant Candida spp* • Extended spectrum β-lactamase producing Enterobacteriaceae • Vancomycin-resistant Enterococcus spp • Multidrug-resistant Pseudomonas aeruginosa • Multidrug-resistant non-typhoidal Salmonella spp • Multidrug-resistant Salmonella Typhi • Multidrug-resistant Shigella spp • Methicillin-resistant Staphylococcus aureus • Multidrug-resistant Streptococcus pneumoniae • Multidrug-resistant tuberculosis Of concern • Vancomycin-resistant S aureus • Erythromycin-resistant group A Streptococcus spp • Clindamycin-resistant group B Streptococcus spp *All data are for bacteria, except for Candida (which is a fungus).
We read with great interest the recent Commission by Ramanan Laxminarayan and colleagues1 about antibiotic resistance and the need for global solutions. This problem has many different facets that can vary between regions and countries. In south Asia it is easy to buy antibiotics over the counter without a prescription, which obviously leads to overuse of these drugs and paves the way to resistance. But one could argue that in countries such as Nepal, where there might not be doctors in remote areas, antibiotic use without a doctor’s prescription could be essential to cure an illness, and perhaps even to save a life. But clearly, guidelines need to be formed and implemented, both for antibiotics that require a prescription and for those that do not. Doctors in Nepal and India are finding it more difficult to treat common infections, such as those in neonates and of the urinary tract, with the older generation of antibiotics. We increasingly use, when available, the 549
Correspondence
next generation of more powerful and expensive antibiotics, and are setting the stage for a time when antibiotics might no longer be effective for many infections. Another major reason for antibiotic resistance is the use of antibiotics in animals (eg, tetracycline in chicken feed) in subtherapeutic doses to promote growth. This important point was also highlighted very clearly in the article.1 As mentioned, many high-income countries have enacted laws to curb the practice of adding antibiotics to animal feed, even as early as 1971, to avoid antibiotic resistance in people. It is therefore time for countries like India and Nepal, and other low-income countries, to use antibiotics in animals only for the treatment of infections. Indiscriminate, subtherapeutic use of antibiotics for animal growth promotion must be stopped by governments; by increasing awareness in the general population about drug resistance, and by enacting laws so that antibiotics for saving human lives will continue to be effective, and the likelihood of resistance will decrease. If India takes the lead in this venture, it will probably be easier for smaller countries in the vicinity like Nepal to follow suit, because its pharmaceutical commerce is closely linked with India. I declare no competing interests.
Buddha Basnyat [email protected] Oxford University Clinical Research Unit, Patan Academy of Health Science, 252 Kathmandu, Nepal 1
Laxminarayan R, Duse A, Chand W, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013; 13: 1057–98.
I read with interest Simon Howard and colleagues’ Comment 1 on the increasing threat of antibiotic resistance and the necessity for a strong global response. That antibiotic use results in selective pressure favouring resistant bacteria is beyond dispute, and this is certainly a large part of the story, but not the entire one. Antibiotic resistance is probably ancient. 2 Researchers analysing 550
sediment samples obtained from deep below the earth’s surface at two sites in the USA found a diverse array of bacteria with resistance to 13 different antibiotics, and 90% of samples were resistant to at least one antibiotic. Perhaps most surprising, some of the bacterial strains were thought to be completely isolated from past human exposure, which raises the likelihood that they developed novel antibiotic resistance.2 In another study,3 30 000-year-old ice cores from the Beringian permafrost in Canada were collected. DNA segments from flora and fauna characteristic of the Arctic Pleistocene epoch were extracted and analysed. Metagenomic analysis revealed a highly diverse array of genes encoding resistance to multiple antibiotics such as β-lactams, tetracyclines, and glycopeptide antibiotics, including the VanA gene that confers the highest resistance to vancomycin.3 That antibiotic resistance pre-dates the anthropogenic antibiotic era might seem surprising, but it should not be. Bacteria are estimated to have originated more than 3·8 billion years ago, and antibiotics might be at least hundreds of millions of years old.4 In an effort to survive in competitive environments, bacteria and other pathogens have developed mechanisms to compete with other species, which include the production of antibiotics. As Howard and colleagues note,1 in one of history’s most famous examples, the mould Penicillium chrysogenum produces a substance that inhibits the growth of Gram-positive bacteria, which led to the discovery of the antibiotic penicillin.5 The widespread use of antibiotics has certainly accelerated the pace of antibiotic resistance that occurs naturally. The degree of resistance that exists, and the extensive head start that bacteria already have, increases the threat of antibiotic resistance even more. The pace of new antibiotic discovery and licensing has certainly
slowed in recent years, which threatens our ability in the future to fight off lifethreatening infections. But somewhere out there is probably a gene yet to be expressed that encodes a resistance mechanism to an antibiotic yet to be invented. Perhaps somewhere in the Beringian permafrost or the bathroom sink of a hospital near you… I declare no competing interests.
Jeffrey Jenks [email protected] University of California, San Diego Division of Infectious Diseases, La Jolla, CA 92093-0711, USA 1
2
3 4
5
Howard SJ, Catchpole M, Watson J, Davies SC. Antibiotic resistance: global response needed. Lancet Infect Dis 2013; 13: 1001–03. Brown MG, Balkwill DL. Antibiotic resistance in bacteria isolated from the deep terrestrial subsurface. Microb Ecol 2009; 57: 484–93. D’Costa VM, King CE, Kalan L, et al. Antibiotic resistance is ancient. Nature 2011; 477: 457–61. Wright DG, Poinar H. Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol 2012; 20: 157–59. Rifkind D, Freeman G. The Nobel prize winning discoveries in infectious diseases. London: Academic Press, 2005.
We agree with Ramanan Laxminarayan and colleagues1 that antimicrobial resistance (AMR) in bacteria that cause community and health-careassociated infections (HAI) in lowincome countries poses a serious threat to global health. In the first 60 years of antibiotic use, resistance predominantly emerged from hospitals in highincome countries; now, health-care environments in low-income countries have also become an important crucible for the evolution of resistance. The increased resistance is eroding the effectiveness of local management strategies for life-threatening diseases such as pneumonia and meningitis. Increased interconnectedness means that resistance genes emerging in one place rapidly become a global threat. AMR and HAI are tightly related issues that are both poorly described in low-income settings, and basic data on the burden of disease are extremely scarce.2 The Global Burden of Disease studies have never estimated the effect of either HAI or AMR, but this is hardly surprising, in view of the www.thelancet.com/infection Vol 14 July 2014
