INSIGHTS
RNAi Therapeutics
p. 1069
Putting diamond defects to work pp. 1072 and 1073
INFECTIOUS DISEASE
A sustainable model for antibiotics How can we foster the development of novel drugs against resistant bacteria? By Manos Perros
D
espite the alarming increase in the prevalence of drug-resistant bacterial infections, far fewer new antibiotics have been approved in the past decade than at the peak in the 1980s (1). The situation is particularly alarming for serious infections by Gramnegative bacteria, some of which are becoming untreatable by modern antibiotics (2–4). Particularly in low- and middle-income countries, untreatable infections are becoming an everyday reality in hospital and care settings (5). Increasing recognition of this
1062
problem is spurring a number of public and private initiatives on both sides of the Atlantic (6–8). To more effectively counter the threat of emerging resistance, we must increase the number of innovative new antibiotics in development and harness advances in diagnostic technology to preserve their efficacy. The paucity of new antibiotic approvals is the tip of the iceberg. Innovation in antimicrobial research lags behind other disease areas such as oncology, where elucidation of the signal transduction pathways has led INFECTIOUS
to more effective and better-tolerated treatments, and where, more recently, greater understanding of immunology has delivered life-saving immunotherapeutics. To foster similar breakthrough innovation in antibiotics, corrective actions are needed to rekindle basic research, provide substrate for innovative drug discovery efforts, and help evolve clinical practice. Basic research in pathogenic bacteria has suffered a double blow of chronic underfunding and short-term focus. First, underfunding relative to other DISEASE sciencemag.org SCIENCE
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
Downloaded from www.sciencemag.org on March 5, 2015
Pseudomonas aeruginosa
PHOTO: LINDA M. STANNARD/UNIVERSITY OF CAPE TOWN/SCIENCE SOURCE/PHOTO RESEARCHERS; ILLUSTRATION: C. SMITH/SCIENCE
PERSPECTIVES
Percentage of isolates resistant
Number of doses prescribed (millions)
major diseases (e.g., HIV/AIDS, which is often taken as an examRising resistance ple of how pharmaceutical innovation can transform a disease) 14 30 12.6 has limited the generation of 11.6 new knowledge. Second, the lack 12 11 25 10.3 of new antibiotics being gener9.8 10 9.1 ated in biotech and pharmaceu20 tical companies has prompted a 7.6 8 number of academic laboratories 15 6 5.9 5.8 5.8 and research institutes to engage 5.3 6 4.52 in activities more typically asso4.13 10 3.84 ciated with drug discovery, such 4 as screening compound libraries 5 1.39 2 or optimizing chemical leads for 0.34 0.28 0.2 0.03 0.04 0 0 0 antibacterial activity and drug0 0 like properties, funded through 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 research grants aiming to close the gap left by companies exitCarbapenem prescriptions Third-generation cephalosporin resistance Carbapenem resistance ing the field. This has been to the detriment of innovative, basic Carbapenem resistance. The percentage of Klebsiella pneumoniae isolates resistant to third-generation cephalosporins and research required to better uncarbapenems has risen in the United States between 1999 and 2010 [adapted from (13)]. Also shown are the cumulative numbers derstand the infectious organof units prescribed for the carbapenems imipenen, meropenem, ertapenem, and doripenem in the United States between 1999 and isms so that we can develop new 2010 (19). Third-generation cephalosporin prescriptions have remained relatively constant at about 30 to 35 million doses prescribed therapeutic modalities. per year throughout this period. Pharmaceutical research and development has suffered from this deficit a solution to this challenge within reach. A care units (13). An argument could be made of new knowledge and technology available recently launched public-private partnership that because 90% of patients could be treated for antibacterial drug discovery; indeed, initiative [Innovative Medicines Initiative’s by a cephalosporin, carbapenems should be only two new classes of systemic antibacteTRANSLOCATION consortium (6)] uses subreserved as a second-line defense. However, rial antibiotics have been brought to market stantial resources from academia and indusin the absence of a rapid, reliable diagnostic, in the past 30 years. The discovery of antibitry to understand and address the challenges delaying use of this drug when resistance is otics with novel modes of action has proved of making new drugs that can penetrate the suspected might cost that patient’s life. to be a substantial scientific challenge, deenvelope of Gram-negative bacteria. HowDiagnosis of bacterial infections tradispite the effort deployed in screening both ever, for each fundamental insight that leads tionally involves culturing the organisms small-molecule libraries and more tradito a new antibiotic, several others are likely and testing for resistance against the drugs. tional natural products. to be dead-ends. Increased research efforts Although highly accurate, such cultures reOur own experience at AstraZeneca is into other fundamental aspects of bacterial quire 2 to 3 days to read out; during this similar to but varies slightly from that dephysiology, such as development of resistime, patients are treated empirically. Techscribed by Payne et al., who found that hightance, virulence, or the interaction with the nologies are now available that can detect throughput screening of chemical libraries host immune system, are thus vital. Other multiple pathogens and common resistance was less likely to provide starting points for approaches, such as that of random screengenes in primary samples, cutting down the antibiotic drug discovery programs than for ing for natural products from newly cultured diagnosis time to hours [see, for example, other therapeutic indications (9). Between bacteria (12), can produce leads against im(14, 15)]. Improvements that would help 2001 and 2010, we performed 65 highportant pathogens, but antibiotics against wider adoption of these technologies in throughput screens using chemically diverse the tougher Gram-negatives will be harder the clinic include further reducing time to libraries to identify antibiotic leads. We to find in this way. readout, such that the diagnostic can guide identified attractive chemical leads against At the other end of the spectrum, clinical the choice of the right drug(s) as early as 19 distinct molecular targets. Of those, use and prescription practices have a key possible; validating for different biological several were active against Gram-positive role to play in the response to resistance. The fluids or matrices; and adapting the techpathogens, but none had activity against practice of prescribing novel broad-spectrum nology for use in low- and middle-income Gram-negative bacterial cells, despite comantibiotics empirically, without prior knowlcountries—all technological challenges that parable levels of potency against isolated edge of the pathogen(s) responsible for the could be solved with the right incentives molecular targets. This is likely due to the infection, and of the drug(s) to which the and rewards to drive increased investment highly effective barrier of the Gram-negative pathogen(s) are sensitive, accelerates the into this area. The United Kingdom’s Lonenvelope and the multiple diffusion and efemergence of resistance to new classes of gitude Prize 2014 (7) and the launch of an flux mediators that it encompasses (10). drugs. For instance, resistance to third-genNIH-sponsored award for a rapid bacterial Greater understanding of the bacterial pereration cephalosporins is seen in only 5 to diagnostic (8) are certainly timely not only meability processes and insights from crystal 10% of Klebsiella pneumoniae isolates in the for facilitating development of those techstructures of bacterial porins (11) is putting United States and northern Europe, yet panologies, but also to raise awareness and tients are often treated with a carbapenem on encourage adoption of more rational presuspicion of such resistance (see the figure). scription practices. AstraZeneca Innovative Medicines and Early Development, This in turn leads to the emergence of highly The greatest reward from advanced diGatehouse Drive, Waltham, MA 02451, USA. E-mail: [email protected] carbapenem-resistant bacteria in intensive agnostics could well lie upstream in the SCIENCE sciencemag.org
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
1063
INSIGHTS | P E R S P E C T I V E S
REFERENCES AND NOTES
1. H. W. Boucher et al., Infectious Diseases Society of America, Clin. Infect. Dis. 56, 1685 (2013). 2. D. M. Livermore, Int. J. Antimicrob. Agents 39, 283 (2012). 3. I. Karaiskos, H. Giamarellou, Expert Opin. Pharmacother. 15, 1351 (2014). 4. P. M. Hawkey, A. M. Jones, J. Antimicrob. Chemother. 64 (suppl. 1), i3 (2009). 5. S. Baker, Science 347, 1064 (2015). 6. See www.imi.europa.eu/content/translocation. 7. See https://longitudeprize.org/. 8. See www.nih.gov/about/director/09182014_statement_ brain-amr.htm. 9. D. J. Payne et al., Nat. Rev. Drug Discov. 6, 29 (2007). 10. J. M. Pagès, C. E. James, M. Winterhalter, Nat. Rev. Microbiol. 6, 893 (2008). 11. S. Biswas et al., Nat. Struct. Mol. Biol. 14, 1108 (2007). 12. L. L. Ling et al., Nature 517, 455 (2015). 13. N. P. Braykov, M. R. Eber, E. Y. Klein, D. J. Morgan, R. Laxminarayan, Infect. Control Hosp. Epidemiol. 34, 259 (2013). 14. F. C. Tenover et al., J. Clin. Microbiol. 51, 3780 (2013). 15. E. Mylonakis et al., Clin. Infect. Dis. 10.1093/cid/ciu959 (2015). 16. N. R. Pace, Science 276, 734 (1997). 17. A. Y. Peleg, H. Seifert, D. L. Paterson, Clin. Microbiol. Rev. 21, 538 (2008). 18. B. Spellberg, J. H. Rex, Nat. Rev. Drug Discov. 12, 963 (2013). 19. Data reproduced with permission from IMS Health International MIDAS Data 1999-2010. ACKNOWLEDGMENTS
I thank P. Bradford for critical review. The views expressed in this article are those of the author and do not necessarily represent the views of, nor should be attributed to, AstraZeneca.
10.1126/science.aaa3048
1064
INFECTIOUS DISEASE
A return to the pre-antimicrobial era? The effects of antimicrobial resistance will be felt most acutely in lower-income countries dependency wards in South Asia (6). These outbreaks were caused by particularly virufter many years out of the limelight, lent variants, which induced a rapid-onset antimicrobial resistance (AMR) in bacteremia resulting in a 75% mortality rate bacteria is firmly back on the internain the infected children. The presence of tional political and scientific agenda NDM-1 within an already broadly antimicro(1, 2). The potential impact of AMR bial-resistant and highly virulent strain seon hospital-acquired bacterial infecverely restricted the treatment options, with tions such as Staphylococcus aureus and a direct impact on patient mortality. This Acinetobacter baumannii in higher-income and many other studies have shown that countries has created both fear and a surge AMR genes thrive in low-income settings of motivation aimed at providing new soluand can combine effortlessly with other retions for the problem (3, 4). The political sistance mechanisms. Further, these widewill and momentum to tackle AMR lies in ranging combinations of drug resistance higher-income countries, but the mechanisms can be maintained medical, social, and economic and then transferred within and effects of AMR are likely to be between numerous bacterial felt more in lower-income counspecies. tries, particularly those in South The reasons behind the apand Southeast Asia and in subparent amplification of the Saharan Africa. The identificacurrent risk in AMR infections tion and development of new in lower-income countries are drugs is a potential solution but intricate and occasionally geoINFECTIOUS DISEASE is challenging and costly; any graphically driven, but there are novel therapies introduced into low-income common themes that highlight the key issettings without a suitable infrastructure to sues. First, the bacterial pathogens found understand and prevent the rapid developin lower-income settings (such as typhoid ment of resistance will likely be expensive fever and tuberculosis meningitis) typically and futile. cause more severe infections than those in In many countries at the lower end of the higher-income countries. Second, antimiglobal economic ladder, infections caused crobials are widely available for purchase by multidrug resistant (MDR) and extended in the community without medical consuldrug resistant (XDR) bacteria are a common tation and without government policies rereality. Variants of bacterial pathogens carrystricting their use; community overuse and ing novel AMR mechanisms disproportionunderdosing are common. Third, the mediately originate in lower-income countries, cal treatment, range of available antimicrowith downstream consequences both within bials, and health care facilities are generally and outside the region in which they apbetter in higher-income countries; the risk pear. This phenomenon was highlighted in associated with having a poor outcome af2008 by the emergence of the carbapenem ter infection with a resistant pathogen is resistance–inducing New Delhi metallo-βtherefore greater in lower-income counlactamase–1 (NDM-1) (5). This gene induces tries. Fourth, very few patients receive any broad resistance against carbapenems and form of conclusive diagnostic testing beother β-lactams and was first identified in a fore, or indeed after, they are treated with Klebsiella pneumoniae strain isolated from an empiric antimicrobial regime. For exama Swedish national upon returning from ple, febrile infections across Asia are comIndia. The plasmids carrying this gene have monly treated with a fluoroquinolone or a since become common and are having dra1 Hospital for Tropical Diseases, Wellcome Trust Major matic impact on the efficacy of carbapenems Overseas Programme, Oxford University Clinical Research and other β-lactams in hospitals. A recent Unit, Ho Chi Minh City, Vietnam. 2Centre for Tropical Medicine, report described hospital outbreaks of Oxford University, Oxford, UK. 3 London School of Hygiene and Tropical Medicine, London, UK. E-mail: [email protected] Klebsiella pneumoniae in children on high-
By Stephen Baker1,2,3
A
sciencemag.org SCIENCE
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
ILLUSTRATION: C. SMITH/SCIENCE
discovery phase, where rapid diagnostics would enable the development and clinical adoption of pathogen-targeted antibiotics. The wide genetic diversity of pathogenic bacteria (16) has been an obstacle to the development of broad-spectrum drugs. Molecules that target individual pathogens of particular importance should be easier to identify and optimize for selectivity and toleration, and more rapid to develop in targeted patient populations. One such pathogen could be Acinetobacter baumannii, which is often resistant to current treatments and is associated with high mortality rates (17). Such narrowly targeted drugs should be premium priced, as they would be used to treat a small number of patients with serious, otherwise untreatable infections (18). Rapid molecular diagnostics paired with pathogen-targeted antibiotics would usher in an era of “personalized health care” for patients suffering from bacterial infections. Most patients would continue to be treated with older, inexpensive, and still effective antibiotics. Rapid diagnostics could help identify those patients requiring new-generation drugs that target highly pathogenic or resistant strains, limiting unnecessary use and slowing the emergence of resistance: altogether, a more sustainable practice, both in terms of clinical care and antibiotic stewardship. ■
A sustainable model for antibiotics Manos Perros Science 347, 1062 (2015); DOI: 10.1126/science.aaa3048
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 5, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6226/1062.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6226/1062.full.html#related This article cites 15 articles, 7 of which can be accessed free: http://www.sciencemag.org/content/347/6226/1062.full.html#ref-list-1 This article has been cited by 1 articles hosted by HighWire Press; see: http://www.sciencemag.org/content/347/6226/1062.full.html#related-urls This article appears in the following subject collections: Pharmacology, Toxicology http://www.sciencemag.org/cgi/collection/pharm_tox
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 5, 2015
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
RNAi Therapeutics
p. 1069
Putting diamond defects to work pp. 1072 and 1073
INFECTIOUS DISEASE
A sustainable model for antibiotics How can we foster the development of novel drugs against resistant bacteria? By Manos Perros
D
espite the alarming increase in the prevalence of drug-resistant bacterial infections, far fewer new antibiotics have been approved in the past decade than at the peak in the 1980s (1). The situation is particularly alarming for serious infections by Gramnegative bacteria, some of which are becoming untreatable by modern antibiotics (2–4). Particularly in low- and middle-income countries, untreatable infections are becoming an everyday reality in hospital and care settings (5). Increasing recognition of this
1062
problem is spurring a number of public and private initiatives on both sides of the Atlantic (6–8). To more effectively counter the threat of emerging resistance, we must increase the number of innovative new antibiotics in development and harness advances in diagnostic technology to preserve their efficacy. The paucity of new antibiotic approvals is the tip of the iceberg. Innovation in antimicrobial research lags behind other disease areas such as oncology, where elucidation of the signal transduction pathways has led INFECTIOUS
to more effective and better-tolerated treatments, and where, more recently, greater understanding of immunology has delivered life-saving immunotherapeutics. To foster similar breakthrough innovation in antibiotics, corrective actions are needed to rekindle basic research, provide substrate for innovative drug discovery efforts, and help evolve clinical practice. Basic research in pathogenic bacteria has suffered a double blow of chronic underfunding and short-term focus. First, underfunding relative to other DISEASE sciencemag.org SCIENCE
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
Downloaded from www.sciencemag.org on March 5, 2015
Pseudomonas aeruginosa
PHOTO: LINDA M. STANNARD/UNIVERSITY OF CAPE TOWN/SCIENCE SOURCE/PHOTO RESEARCHERS; ILLUSTRATION: C. SMITH/SCIENCE
PERSPECTIVES
Percentage of isolates resistant
Number of doses prescribed (millions)
major diseases (e.g., HIV/AIDS, which is often taken as an examRising resistance ple of how pharmaceutical innovation can transform a disease) 14 30 12.6 has limited the generation of 11.6 new knowledge. Second, the lack 12 11 25 10.3 of new antibiotics being gener9.8 10 9.1 ated in biotech and pharmaceu20 tical companies has prompted a 7.6 8 number of academic laboratories 15 6 5.9 5.8 5.8 and research institutes to engage 5.3 6 4.52 in activities more typically asso4.13 10 3.84 ciated with drug discovery, such 4 as screening compound libraries 5 1.39 2 or optimizing chemical leads for 0.34 0.28 0.2 0.03 0.04 0 0 0 antibacterial activity and drug0 0 like properties, funded through 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 research grants aiming to close the gap left by companies exitCarbapenem prescriptions Third-generation cephalosporin resistance Carbapenem resistance ing the field. This has been to the detriment of innovative, basic Carbapenem resistance. The percentage of Klebsiella pneumoniae isolates resistant to third-generation cephalosporins and research required to better uncarbapenems has risen in the United States between 1999 and 2010 [adapted from (13)]. Also shown are the cumulative numbers derstand the infectious organof units prescribed for the carbapenems imipenen, meropenem, ertapenem, and doripenem in the United States between 1999 and isms so that we can develop new 2010 (19). Third-generation cephalosporin prescriptions have remained relatively constant at about 30 to 35 million doses prescribed therapeutic modalities. per year throughout this period. Pharmaceutical research and development has suffered from this deficit a solution to this challenge within reach. A care units (13). An argument could be made of new knowledge and technology available recently launched public-private partnership that because 90% of patients could be treated for antibacterial drug discovery; indeed, initiative [Innovative Medicines Initiative’s by a cephalosporin, carbapenems should be only two new classes of systemic antibacteTRANSLOCATION consortium (6)] uses subreserved as a second-line defense. However, rial antibiotics have been brought to market stantial resources from academia and indusin the absence of a rapid, reliable diagnostic, in the past 30 years. The discovery of antibitry to understand and address the challenges delaying use of this drug when resistance is otics with novel modes of action has proved of making new drugs that can penetrate the suspected might cost that patient’s life. to be a substantial scientific challenge, deenvelope of Gram-negative bacteria. HowDiagnosis of bacterial infections tradispite the effort deployed in screening both ever, for each fundamental insight that leads tionally involves culturing the organisms small-molecule libraries and more tradito a new antibiotic, several others are likely and testing for resistance against the drugs. tional natural products. to be dead-ends. Increased research efforts Although highly accurate, such cultures reOur own experience at AstraZeneca is into other fundamental aspects of bacterial quire 2 to 3 days to read out; during this similar to but varies slightly from that dephysiology, such as development of resistime, patients are treated empirically. Techscribed by Payne et al., who found that hightance, virulence, or the interaction with the nologies are now available that can detect throughput screening of chemical libraries host immune system, are thus vital. Other multiple pathogens and common resistance was less likely to provide starting points for approaches, such as that of random screengenes in primary samples, cutting down the antibiotic drug discovery programs than for ing for natural products from newly cultured diagnosis time to hours [see, for example, other therapeutic indications (9). Between bacteria (12), can produce leads against im(14, 15)]. Improvements that would help 2001 and 2010, we performed 65 highportant pathogens, but antibiotics against wider adoption of these technologies in throughput screens using chemically diverse the tougher Gram-negatives will be harder the clinic include further reducing time to libraries to identify antibiotic leads. We to find in this way. readout, such that the diagnostic can guide identified attractive chemical leads against At the other end of the spectrum, clinical the choice of the right drug(s) as early as 19 distinct molecular targets. Of those, use and prescription practices have a key possible; validating for different biological several were active against Gram-positive role to play in the response to resistance. The fluids or matrices; and adapting the techpathogens, but none had activity against practice of prescribing novel broad-spectrum nology for use in low- and middle-income Gram-negative bacterial cells, despite comantibiotics empirically, without prior knowlcountries—all technological challenges that parable levels of potency against isolated edge of the pathogen(s) responsible for the could be solved with the right incentives molecular targets. This is likely due to the infection, and of the drug(s) to which the and rewards to drive increased investment highly effective barrier of the Gram-negative pathogen(s) are sensitive, accelerates the into this area. The United Kingdom’s Lonenvelope and the multiple diffusion and efemergence of resistance to new classes of gitude Prize 2014 (7) and the launch of an flux mediators that it encompasses (10). drugs. For instance, resistance to third-genNIH-sponsored award for a rapid bacterial Greater understanding of the bacterial pereration cephalosporins is seen in only 5 to diagnostic (8) are certainly timely not only meability processes and insights from crystal 10% of Klebsiella pneumoniae isolates in the for facilitating development of those techstructures of bacterial porins (11) is putting United States and northern Europe, yet panologies, but also to raise awareness and tients are often treated with a carbapenem on encourage adoption of more rational presuspicion of such resistance (see the figure). scription practices. AstraZeneca Innovative Medicines and Early Development, This in turn leads to the emergence of highly The greatest reward from advanced diGatehouse Drive, Waltham, MA 02451, USA. E-mail: [email protected] carbapenem-resistant bacteria in intensive agnostics could well lie upstream in the SCIENCE sciencemag.org
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
1063
INSIGHTS | P E R S P E C T I V E S
REFERENCES AND NOTES
1. H. W. Boucher et al., Infectious Diseases Society of America, Clin. Infect. Dis. 56, 1685 (2013). 2. D. M. Livermore, Int. J. Antimicrob. Agents 39, 283 (2012). 3. I. Karaiskos, H. Giamarellou, Expert Opin. Pharmacother. 15, 1351 (2014). 4. P. M. Hawkey, A. M. Jones, J. Antimicrob. Chemother. 64 (suppl. 1), i3 (2009). 5. S. Baker, Science 347, 1064 (2015). 6. See www.imi.europa.eu/content/translocation. 7. See https://longitudeprize.org/. 8. See www.nih.gov/about/director/09182014_statement_ brain-amr.htm. 9. D. J. Payne et al., Nat. Rev. Drug Discov. 6, 29 (2007). 10. J. M. Pagès, C. E. James, M. Winterhalter, Nat. Rev. Microbiol. 6, 893 (2008). 11. S. Biswas et al., Nat. Struct. Mol. Biol. 14, 1108 (2007). 12. L. L. Ling et al., Nature 517, 455 (2015). 13. N. P. Braykov, M. R. Eber, E. Y. Klein, D. J. Morgan, R. Laxminarayan, Infect. Control Hosp. Epidemiol. 34, 259 (2013). 14. F. C. Tenover et al., J. Clin. Microbiol. 51, 3780 (2013). 15. E. Mylonakis et al., Clin. Infect. Dis. 10.1093/cid/ciu959 (2015). 16. N. R. Pace, Science 276, 734 (1997). 17. A. Y. Peleg, H. Seifert, D. L. Paterson, Clin. Microbiol. Rev. 21, 538 (2008). 18. B. Spellberg, J. H. Rex, Nat. Rev. Drug Discov. 12, 963 (2013). 19. Data reproduced with permission from IMS Health International MIDAS Data 1999-2010. ACKNOWLEDGMENTS
I thank P. Bradford for critical review. The views expressed in this article are those of the author and do not necessarily represent the views of, nor should be attributed to, AstraZeneca.
10.1126/science.aaa3048
1064
INFECTIOUS DISEASE
A return to the pre-antimicrobial era? The effects of antimicrobial resistance will be felt most acutely in lower-income countries dependency wards in South Asia (6). These outbreaks were caused by particularly virufter many years out of the limelight, lent variants, which induced a rapid-onset antimicrobial resistance (AMR) in bacteremia resulting in a 75% mortality rate bacteria is firmly back on the internain the infected children. The presence of tional political and scientific agenda NDM-1 within an already broadly antimicro(1, 2). The potential impact of AMR bial-resistant and highly virulent strain seon hospital-acquired bacterial infecverely restricted the treatment options, with tions such as Staphylococcus aureus and a direct impact on patient mortality. This Acinetobacter baumannii in higher-income and many other studies have shown that countries has created both fear and a surge AMR genes thrive in low-income settings of motivation aimed at providing new soluand can combine effortlessly with other retions for the problem (3, 4). The political sistance mechanisms. Further, these widewill and momentum to tackle AMR lies in ranging combinations of drug resistance higher-income countries, but the mechanisms can be maintained medical, social, and economic and then transferred within and effects of AMR are likely to be between numerous bacterial felt more in lower-income counspecies. tries, particularly those in South The reasons behind the apand Southeast Asia and in subparent amplification of the Saharan Africa. The identificacurrent risk in AMR infections tion and development of new in lower-income countries are drugs is a potential solution but intricate and occasionally geoINFECTIOUS DISEASE is challenging and costly; any graphically driven, but there are novel therapies introduced into low-income common themes that highlight the key issettings without a suitable infrastructure to sues. First, the bacterial pathogens found understand and prevent the rapid developin lower-income settings (such as typhoid ment of resistance will likely be expensive fever and tuberculosis meningitis) typically and futile. cause more severe infections than those in In many countries at the lower end of the higher-income countries. Second, antimiglobal economic ladder, infections caused crobials are widely available for purchase by multidrug resistant (MDR) and extended in the community without medical consuldrug resistant (XDR) bacteria are a common tation and without government policies rereality. Variants of bacterial pathogens carrystricting their use; community overuse and ing novel AMR mechanisms disproportionunderdosing are common. Third, the mediately originate in lower-income countries, cal treatment, range of available antimicrowith downstream consequences both within bials, and health care facilities are generally and outside the region in which they apbetter in higher-income countries; the risk pear. This phenomenon was highlighted in associated with having a poor outcome af2008 by the emergence of the carbapenem ter infection with a resistant pathogen is resistance–inducing New Delhi metallo-βtherefore greater in lower-income counlactamase–1 (NDM-1) (5). This gene induces tries. Fourth, very few patients receive any broad resistance against carbapenems and form of conclusive diagnostic testing beother β-lactams and was first identified in a fore, or indeed after, they are treated with Klebsiella pneumoniae strain isolated from an empiric antimicrobial regime. For exama Swedish national upon returning from ple, febrile infections across Asia are comIndia. The plasmids carrying this gene have monly treated with a fluoroquinolone or a since become common and are having dra1 Hospital for Tropical Diseases, Wellcome Trust Major matic impact on the efficacy of carbapenems Overseas Programme, Oxford University Clinical Research and other β-lactams in hospitals. A recent Unit, Ho Chi Minh City, Vietnam. 2Centre for Tropical Medicine, report described hospital outbreaks of Oxford University, Oxford, UK. 3 London School of Hygiene and Tropical Medicine, London, UK. E-mail: [email protected] Klebsiella pneumoniae in children on high-
By Stephen Baker1,2,3
A
sciencemag.org SCIENCE
6 MARCH 2015 • VOL 347 ISSUE 6226
Published by AAAS
ILLUSTRATION: C. SMITH/SCIENCE
discovery phase, where rapid diagnostics would enable the development and clinical adoption of pathogen-targeted antibiotics. The wide genetic diversity of pathogenic bacteria (16) has been an obstacle to the development of broad-spectrum drugs. Molecules that target individual pathogens of particular importance should be easier to identify and optimize for selectivity and toleration, and more rapid to develop in targeted patient populations. One such pathogen could be Acinetobacter baumannii, which is often resistant to current treatments and is associated with high mortality rates (17). Such narrowly targeted drugs should be premium priced, as they would be used to treat a small number of patients with serious, otherwise untreatable infections (18). Rapid molecular diagnostics paired with pathogen-targeted antibiotics would usher in an era of “personalized health care” for patients suffering from bacterial infections. Most patients would continue to be treated with older, inexpensive, and still effective antibiotics. Rapid diagnostics could help identify those patients requiring new-generation drugs that target highly pathogenic or resistant strains, limiting unnecessary use and slowing the emergence of resistance: altogether, a more sustainable practice, both in terms of clinical care and antibiotic stewardship. ■
A sustainable model for antibiotics Manos Perros Science 347, 1062 (2015); DOI: 10.1126/science.aaa3048
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 5, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6226/1062.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6226/1062.full.html#related This article cites 15 articles, 7 of which can be accessed free: http://www.sciencemag.org/content/347/6226/1062.full.html#ref-list-1 This article has been cited by 1 articles hosted by HighWire Press; see: http://www.sciencemag.org/content/347/6226/1062.full.html#related-urls This article appears in the following subject collections: Pharmacology, Toxicology http://www.sciencemag.org/cgi/collection/pharm_tox
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 5, 2015
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
