British Journal of Clinical Pharmacology
DOI:10.1111/bcp.12385
Editorial
From an evolutionary perspective, all ‘new’ antimicrobial targets are old: time to think outside the box Jennifer H. Martin1 & Albert Ferro2 1
University of Queensland School of Medicine and Princess Alexandra Hospital, Brisbane 4102, Queensland, Australia and 2Department of Clinical
Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King’s College London, London SE1 9NH, UK
Since the development of the sulfonamides and penicillin in the 1930s and 40s, the aim of antimicrobial research and development (R and D) has been to discover ‘new’ targets. This strategy has been very effective. However, it has also driven the ever-growing problem of resistance that is now reducing treatment effectiveness. With the highly successful evolutionary mechanism of selective pressure, we are now literally running out of targets, and the time between a new agent becoming available and resistance developing is decreasing. Indeed, many in the field of antimicrobial R and D believe that resistance will become so prevalent in the future as to preclude potentially the effective use of antibiotics in clinical medicine. The themed section in this month’s BJCP in part spotlights the need to protect antimicrobial treatments for the future. Antimicrobial resistance (AMR) constitutes one of the world’s most pressing public health threats [1], is a major global health security risk and is very expensive, with AMR-induced GDP losses estimated at 0.4 to 1.6% [2]. The themed section goes further to consider strategies outside the realm of traditional clinical pharmacology stewardship and infectious diseases practice that could be used to engage healthcare facility administrators, the agricultural industry and policy makers to work together to employ effective strategies for improving antimicrobial development and use. Arguably the greatest risk . . . to human health comes in the form of antibiotic-resistant bacteria. We live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far behind the curve we allow ourselves to fall [2]. Although this looming problem is appreciated by clinicians in hospital and academic settings, the problem is one that cannot effectively be solved by one group acting in © 2015 The British Pharmacological Society
isolation. Rather, it needs to be tackled across the spectrum of basic and clinical pharmacology, as well as at the levels of drug regulation, policy and reimbursement. The pursuit of new drug targets is an invaluable part of the strategy to combat AMR, but it cannot any longer be the sole approach because the practical reality is that pharmaceutical industry-funded drug discovery and development can take up to 20 years. Further, even if successful in phase III studies, novel antimicrobials are only likely to be used in a relatively small number of patients, unlike for example in cancer or cardiovascular therapeutics. This underlies the rapid reduction in pharmaceutical development of new antimicrobial therapies, with only two new antibacterial agents released in the period 2008–12 compared with 16 between 1983–87 [3]. As O’Brien discusses in the present issue [4], no single strategy can solve the issue of the dwindling supply of new agents. O’Brien is part of the predominantly European public-private partnership Innovative Medicines Initiative (IMI), which supports a multipronged research and funding approach involving government, industry, academia and other partners to support and make viable drug development, start-ups and marketing incentives for R and D innovation. He suggests that hurdles of registration, reimbursement and clinical trial development require investment and support, and that one way forward is for regulatory and pricing frameworks to be re-examined to support streamlined assessment drugs with, for example, a novel mechanism of activity. Similarly to the IMI, more than 25 national health organizations in the USA signed a joint statement co-led by the Center for Disease Control and the Center for Disease Dynamics, Economics and Policy to support multifaceted action to preserve antibiotic effectiveness and prevent resistance in 2012 [4]. In addition to better support of R and D in AMR, this themed section also contains articles that highlight Br J Clin Pharmacol
/ 79:2
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165–167
/
165
Editorial
strategic ways to address the issue of AMR. Aree & Price [5] discuss how infections could be prevented and spread of resistance decreased by better tracking of resistant bacteria and improving the use of today’s antibiotics. This recommendation is not just applicable to the Western world, where teaching of pharmacological principles around prescribing and the institution of stewardship have become part of the culture, but in developing countries also. It is known that antimicrobial use naturally selects for preexisting resistant populations of bacteria and that the speed with which resistance spreads is driven by microbial exposure to all antimicrobials, whether appropriately prescribed or not. Thus, even if all inappropriate antimicrobial use was eliminated and rigorous stewardship was implemented in third world countries, antimicrobial-resistant infections would still occur (albeit more slowly). To illustrate this, AMR was recently discovered among bacteria found in caves geologically isolated from the surface of the planet for 4 million years [6]. Further, AMR was found even to synthetic antibiotics that did not exist until recently, some strains being already resistant to 14 structurally different commercially available antibiotics. These discoveries expose a frightening reality. AMR is likely to exist already to drugs we have not yet even developed. Further, they show that stewardship, whilst important for slowing the speed of AMR development (which is useful to enable discovery of new agents and helpful in complicated prescribing areas such as that described in [7]) cannot prevent what is essentially an evolutionary pathway for microbe survival. Thus, the paradigm needs to shift wider than just the development of newer antimicrobials and to consider other methods of improving infection control. As with antibacterial drugs, there is also the difficult and expensive problem of designing more effective antiviral therapies to cope with increasing resistance in viruses. This is covered in this issue by the US/Australian team of Phillips et al. [8] Their article looks at new understandings of the immunopathogenesis of viral resistance and how this, combined with clinical pharmacology expertise, can advance antiviral therapy and slow resistance. Such multidisciplinary collaborations in viral therapies and vaccine development could be a future strategy for other antimicrobial therapy research to address AMR. For example, although many million of dollars have been spent on drug design for common pneumococcal disease, it still results in a huge burden of morbidity and mortality. Over the last 10 years, several pneumococcal vaccines have been developed for use. The latest of these, pneumococcal conjugate vaccine PCV13, protects against 13 strains of pneumococci, and after its introduction in 2010 cases of pneumococcal disease resistant to penicillin decreased by 66% compared with the pre-PCV13 period [9]. Developments in new diagnostic tests and routine screening for resistant microbes, a problem particularly in people with deficient immune systems, are likely to be 166
/ 79:2
/
Br J Clin Pharmacol
helpful concomitant strategies to circumvent treating patients with AMR. Some of these, as used in a haematology population, are discussed by Slavin et al. [7]. Simple policies such as the prevention of infections by simple and relatively cheap measures (such as ‘cleaning, isolating and screening’) and preventing the spread of resistance by better systems for tracking AMR (especially in the third world and in people travelling to third world countries and returning ‘home’), are areas all hospital managers and health policy makers locally can adopt and share. Together with support for the types of individualized strategies discussed by Slavin et al. more targeted use of the correct dose and choice of therapy is enabled, thereby minimizing the speed of the spread of AMR. Martin’s team [10] discusses novel developments to antagonize virulence pathways using a biologically plausible and novel set of approaches. As for the methods discussed by Slavin et al. these are designed not necessarily to promote the development of new antimicrobials or mechanisms of killing bacteria, but to apply new nonantimicrobial methods to prevent or overcome infection. It is perhaps also important to remember that patients using antimicrobials are usually very different from clinical trial populations. This can result in under-dosing and development of resistance for a number of reasons. Specifically, drugs are used in different diseases, in different ethnic groups, in different combinations with different resistance patterns. Furthermore, drug dosing is often not examined in patients who are obese or have otherwise abnormal body composition/habitus, nor in patients who exhibit changing pharmacokinetics such as those with organ failure. Cranswick et al. [11] discuss this issue in the context of some of these vulnerable groups – pregnancy, neonatology and paediatrics – and the need for funding to support and validate pharmacometric pharmacokinetic/ pharmacodynamic modelling in these populations. Future research avenues are well covered by Slavin et al., e.g. better PK/PD optimization of older agents (especially in specific patient groups such as haematology transplants), combination therapies, altering microbiota to change the environment in which microbes can become pathogenic, but also include other therapies such as the development of neutralizing toxins (e.g. from Clostridium species) and development of new immune therapies. These include manipulation of the innate immune system to attack microbes, sequestration of host nutrients such as iron so that microbes cannot reproduce, attacking host targets rather than microbial targets, for example classes of cell wall and lipopolysaccharide therapies and the infusion of anti-inflammatory monoclonal antibodies. All of these need clinical testing in humans. Some have already been tested and suggest potential efficacy [12] but others appear ineffective in humans [13, 14]. Some may also require concomitant antimicrobial therapy. Further, after the ill-fated TGN 1412 study [15], this clinical trial area has been under scrutiny. Nevertheless, it is clear both that the
Editorial
‘old model’ is unlikely to be helpful going forward and that pharmaceutical industry R and D has to be creative regarding antimicrobial development and timely availability to the clinic. There are a number of important issues which the articles in this themed section do not discuss, including the huge scale of antimicrobial use in agriculture (where over 50% of current antimicrobial use occurs) and antimicrobial pollution of the water used by many people particularly in the third world. These are undoubtedly important issues. What the articles collected here do demonstrate very effectively, however, is that the increasing lack of antimicrobial options for clinical use cannot be improved merely by incremental improvements of stewardship in first world countries or continued hope for pharmaceutical development of new agents under the current clinical trial, regulatory and reimbursement systems. New approaches, based on novel insights into the nature of disease and resistance, coupled to novel treatment approaches using vaccines, immune boosters and host modulation, are needed.
8 Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol 2015; 79: 182–94. 9 Singleton R, Wenger J, Klejka JA, Bulkow LR, Thompson A, Sarkozy D, Emini EA, Gruber WC, Scott DA. The 13-valent pneumococcal conjugate vaccine for invasive pneumococcal disease in Alaska native children: results of a clinical trial. Pediatr Infect Dis J 2013; 32: 257–63. 10 Heras B, Scanlon MJ, Martin JL. Targeting virulence not viability in the search for future antibacterials. Br J Clin Pharmacol 2015; 79: 208–15. 11 Gwee A, Cranswick N. Anti-infectives use in children and pregnancy: current deficiencies and future challenges. Br J Clin Pharmacol 2015; 79: 216–21. 12 Weisman LE, Thackray HM, Steinhorn RH, Walsh WF, Lassiter HA, Dhanireddy R, Brozanski BS, Palmer KG, Trautman MS, Escobedo M, Meissner HC, Sasidharan P, Fretz J, Kokai-Kun JF, Kramer WG, Fischer GW, Mond JJ. A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. Pediatrics 2011; 128: 271–9.
1 Howell L. Global risk 2013, 8th ed. Centre for Disease Control. Available at http://www.cdc.gov/drugresistance/ threat-report-2013/pdf/ar-threats-2013-508.pdf (last accessed 8 April 2014).
13 Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013; 309: 1154–62.
2 Howell L. An initiative of the risk response network, in Global Risks Report. 2013, World Economic Forum.
14 Larosa SP. Sepsis: menu of new approaches replaces one therapy for all. Cleve Clin J Med 2002; 69: 65–73.
3 Joint Statement on Antibiotic Resistance from 25 National Health Organizations and the Centers for Disease Control and Prevention. Available at http://www.cddep.org/sites/ cddep.org/files/publication_files/3._consensus_statement -1.pdf?issuusl=ignore (last accessed 8 April 2014).
15 Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in cytokine release assays. J Immunotoxicol 2013; 10: 75–82.
4 O’Brien S. Meeting the societal needs for new antibiotics: the challenges for the pharmaceutical industry. Br J Clin Pharmacol 2015; 79: 168–72.
RECEIVED
5 Aree A, Price N. Antimicrobial stewardship – can we afford to do without it? Br J Clin Pharmacol 2015; 79: 173–81.
ACCEPTED
6 Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, Barton HA, Wright GD. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS ONE 2012; 7: e34953. doi: 10.1371/journal.pone.0034953.
CORRESPONDENCE
REFERENCES
7 Trubiano JA, Worth LJ, Thursky KA, Slavin MA. The prevention and management of infections due to multidrug resistant organisms in haematology patients. Br J Clin Pharmacol 2015; 79: 195–207.
17 March 2014
18 March 2014
Professor Jennifer H. Martin MBChB (Otago), MA (Oxon), FRACP, PhD (Monash), Level 7, Translational Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia. Tel.: +61405341676 Fax: +61 7 34437 7779 E-mail: [email protected]
Br J Clin Pharmacol
/ 79:2
/
167
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DOI:10.1111/bcp.12385
Editorial
From an evolutionary perspective, all ‘new’ antimicrobial targets are old: time to think outside the box Jennifer H. Martin1 & Albert Ferro2 1
University of Queensland School of Medicine and Princess Alexandra Hospital, Brisbane 4102, Queensland, Australia and 2Department of Clinical
Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King’s College London, London SE1 9NH, UK
Since the development of the sulfonamides and penicillin in the 1930s and 40s, the aim of antimicrobial research and development (R and D) has been to discover ‘new’ targets. This strategy has been very effective. However, it has also driven the ever-growing problem of resistance that is now reducing treatment effectiveness. With the highly successful evolutionary mechanism of selective pressure, we are now literally running out of targets, and the time between a new agent becoming available and resistance developing is decreasing. Indeed, many in the field of antimicrobial R and D believe that resistance will become so prevalent in the future as to preclude potentially the effective use of antibiotics in clinical medicine. The themed section in this month’s BJCP in part spotlights the need to protect antimicrobial treatments for the future. Antimicrobial resistance (AMR) constitutes one of the world’s most pressing public health threats [1], is a major global health security risk and is very expensive, with AMR-induced GDP losses estimated at 0.4 to 1.6% [2]. The themed section goes further to consider strategies outside the realm of traditional clinical pharmacology stewardship and infectious diseases practice that could be used to engage healthcare facility administrators, the agricultural industry and policy makers to work together to employ effective strategies for improving antimicrobial development and use. Arguably the greatest risk . . . to human health comes in the form of antibiotic-resistant bacteria. We live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far behind the curve we allow ourselves to fall [2]. Although this looming problem is appreciated by clinicians in hospital and academic settings, the problem is one that cannot effectively be solved by one group acting in © 2015 The British Pharmacological Society
isolation. Rather, it needs to be tackled across the spectrum of basic and clinical pharmacology, as well as at the levels of drug regulation, policy and reimbursement. The pursuit of new drug targets is an invaluable part of the strategy to combat AMR, but it cannot any longer be the sole approach because the practical reality is that pharmaceutical industry-funded drug discovery and development can take up to 20 years. Further, even if successful in phase III studies, novel antimicrobials are only likely to be used in a relatively small number of patients, unlike for example in cancer or cardiovascular therapeutics. This underlies the rapid reduction in pharmaceutical development of new antimicrobial therapies, with only two new antibacterial agents released in the period 2008–12 compared with 16 between 1983–87 [3]. As O’Brien discusses in the present issue [4], no single strategy can solve the issue of the dwindling supply of new agents. O’Brien is part of the predominantly European public-private partnership Innovative Medicines Initiative (IMI), which supports a multipronged research and funding approach involving government, industry, academia and other partners to support and make viable drug development, start-ups and marketing incentives for R and D innovation. He suggests that hurdles of registration, reimbursement and clinical trial development require investment and support, and that one way forward is for regulatory and pricing frameworks to be re-examined to support streamlined assessment drugs with, for example, a novel mechanism of activity. Similarly to the IMI, more than 25 national health organizations in the USA signed a joint statement co-led by the Center for Disease Control and the Center for Disease Dynamics, Economics and Policy to support multifaceted action to preserve antibiotic effectiveness and prevent resistance in 2012 [4]. In addition to better support of R and D in AMR, this themed section also contains articles that highlight Br J Clin Pharmacol
/ 79:2
/
165–167
/
165
Editorial
strategic ways to address the issue of AMR. Aree & Price [5] discuss how infections could be prevented and spread of resistance decreased by better tracking of resistant bacteria and improving the use of today’s antibiotics. This recommendation is not just applicable to the Western world, where teaching of pharmacological principles around prescribing and the institution of stewardship have become part of the culture, but in developing countries also. It is known that antimicrobial use naturally selects for preexisting resistant populations of bacteria and that the speed with which resistance spreads is driven by microbial exposure to all antimicrobials, whether appropriately prescribed or not. Thus, even if all inappropriate antimicrobial use was eliminated and rigorous stewardship was implemented in third world countries, antimicrobial-resistant infections would still occur (albeit more slowly). To illustrate this, AMR was recently discovered among bacteria found in caves geologically isolated from the surface of the planet for 4 million years [6]. Further, AMR was found even to synthetic antibiotics that did not exist until recently, some strains being already resistant to 14 structurally different commercially available antibiotics. These discoveries expose a frightening reality. AMR is likely to exist already to drugs we have not yet even developed. Further, they show that stewardship, whilst important for slowing the speed of AMR development (which is useful to enable discovery of new agents and helpful in complicated prescribing areas such as that described in [7]) cannot prevent what is essentially an evolutionary pathway for microbe survival. Thus, the paradigm needs to shift wider than just the development of newer antimicrobials and to consider other methods of improving infection control. As with antibacterial drugs, there is also the difficult and expensive problem of designing more effective antiviral therapies to cope with increasing resistance in viruses. This is covered in this issue by the US/Australian team of Phillips et al. [8] Their article looks at new understandings of the immunopathogenesis of viral resistance and how this, combined with clinical pharmacology expertise, can advance antiviral therapy and slow resistance. Such multidisciplinary collaborations in viral therapies and vaccine development could be a future strategy for other antimicrobial therapy research to address AMR. For example, although many million of dollars have been spent on drug design for common pneumococcal disease, it still results in a huge burden of morbidity and mortality. Over the last 10 years, several pneumococcal vaccines have been developed for use. The latest of these, pneumococcal conjugate vaccine PCV13, protects against 13 strains of pneumococci, and after its introduction in 2010 cases of pneumococcal disease resistant to penicillin decreased by 66% compared with the pre-PCV13 period [9]. Developments in new diagnostic tests and routine screening for resistant microbes, a problem particularly in people with deficient immune systems, are likely to be 166
/ 79:2
/
Br J Clin Pharmacol
helpful concomitant strategies to circumvent treating patients with AMR. Some of these, as used in a haematology population, are discussed by Slavin et al. [7]. Simple policies such as the prevention of infections by simple and relatively cheap measures (such as ‘cleaning, isolating and screening’) and preventing the spread of resistance by better systems for tracking AMR (especially in the third world and in people travelling to third world countries and returning ‘home’), are areas all hospital managers and health policy makers locally can adopt and share. Together with support for the types of individualized strategies discussed by Slavin et al. more targeted use of the correct dose and choice of therapy is enabled, thereby minimizing the speed of the spread of AMR. Martin’s team [10] discusses novel developments to antagonize virulence pathways using a biologically plausible and novel set of approaches. As for the methods discussed by Slavin et al. these are designed not necessarily to promote the development of new antimicrobials or mechanisms of killing bacteria, but to apply new nonantimicrobial methods to prevent or overcome infection. It is perhaps also important to remember that patients using antimicrobials are usually very different from clinical trial populations. This can result in under-dosing and development of resistance for a number of reasons. Specifically, drugs are used in different diseases, in different ethnic groups, in different combinations with different resistance patterns. Furthermore, drug dosing is often not examined in patients who are obese or have otherwise abnormal body composition/habitus, nor in patients who exhibit changing pharmacokinetics such as those with organ failure. Cranswick et al. [11] discuss this issue in the context of some of these vulnerable groups – pregnancy, neonatology and paediatrics – and the need for funding to support and validate pharmacometric pharmacokinetic/ pharmacodynamic modelling in these populations. Future research avenues are well covered by Slavin et al., e.g. better PK/PD optimization of older agents (especially in specific patient groups such as haematology transplants), combination therapies, altering microbiota to change the environment in which microbes can become pathogenic, but also include other therapies such as the development of neutralizing toxins (e.g. from Clostridium species) and development of new immune therapies. These include manipulation of the innate immune system to attack microbes, sequestration of host nutrients such as iron so that microbes cannot reproduce, attacking host targets rather than microbial targets, for example classes of cell wall and lipopolysaccharide therapies and the infusion of anti-inflammatory monoclonal antibodies. All of these need clinical testing in humans. Some have already been tested and suggest potential efficacy [12] but others appear ineffective in humans [13, 14]. Some may also require concomitant antimicrobial therapy. Further, after the ill-fated TGN 1412 study [15], this clinical trial area has been under scrutiny. Nevertheless, it is clear both that the
Editorial
‘old model’ is unlikely to be helpful going forward and that pharmaceutical industry R and D has to be creative regarding antimicrobial development and timely availability to the clinic. There are a number of important issues which the articles in this themed section do not discuss, including the huge scale of antimicrobial use in agriculture (where over 50% of current antimicrobial use occurs) and antimicrobial pollution of the water used by many people particularly in the third world. These are undoubtedly important issues. What the articles collected here do demonstrate very effectively, however, is that the increasing lack of antimicrobial options for clinical use cannot be improved merely by incremental improvements of stewardship in first world countries or continued hope for pharmaceutical development of new agents under the current clinical trial, regulatory and reimbursement systems. New approaches, based on novel insights into the nature of disease and resistance, coupled to novel treatment approaches using vaccines, immune boosters and host modulation, are needed.
8 Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol 2015; 79: 182–94. 9 Singleton R, Wenger J, Klejka JA, Bulkow LR, Thompson A, Sarkozy D, Emini EA, Gruber WC, Scott DA. The 13-valent pneumococcal conjugate vaccine for invasive pneumococcal disease in Alaska native children: results of a clinical trial. Pediatr Infect Dis J 2013; 32: 257–63. 10 Heras B, Scanlon MJ, Martin JL. Targeting virulence not viability in the search for future antibacterials. Br J Clin Pharmacol 2015; 79: 208–15. 11 Gwee A, Cranswick N. Anti-infectives use in children and pregnancy: current deficiencies and future challenges. Br J Clin Pharmacol 2015; 79: 216–21. 12 Weisman LE, Thackray HM, Steinhorn RH, Walsh WF, Lassiter HA, Dhanireddy R, Brozanski BS, Palmer KG, Trautman MS, Escobedo M, Meissner HC, Sasidharan P, Fretz J, Kokai-Kun JF, Kramer WG, Fischer GW, Mond JJ. A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. Pediatrics 2011; 128: 271–9.
1 Howell L. Global risk 2013, 8th ed. Centre for Disease Control. Available at http://www.cdc.gov/drugresistance/ threat-report-2013/pdf/ar-threats-2013-508.pdf (last accessed 8 April 2014).
13 Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013; 309: 1154–62.
2 Howell L. An initiative of the risk response network, in Global Risks Report. 2013, World Economic Forum.
14 Larosa SP. Sepsis: menu of new approaches replaces one therapy for all. Cleve Clin J Med 2002; 69: 65–73.
3 Joint Statement on Antibiotic Resistance from 25 National Health Organizations and the Centers for Disease Control and Prevention. Available at http://www.cddep.org/sites/ cddep.org/files/publication_files/3._consensus_statement -1.pdf?issuusl=ignore (last accessed 8 April 2014).
15 Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in cytokine release assays. J Immunotoxicol 2013; 10: 75–82.
4 O’Brien S. Meeting the societal needs for new antibiotics: the challenges for the pharmaceutical industry. Br J Clin Pharmacol 2015; 79: 168–72.
RECEIVED
5 Aree A, Price N. Antimicrobial stewardship – can we afford to do without it? Br J Clin Pharmacol 2015; 79: 173–81.
ACCEPTED
6 Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, Barton HA, Wright GD. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS ONE 2012; 7: e34953. doi: 10.1371/journal.pone.0034953.
CORRESPONDENCE
REFERENCES
7 Trubiano JA, Worth LJ, Thursky KA, Slavin MA. The prevention and management of infections due to multidrug resistant organisms in haematology patients. Br J Clin Pharmacol 2015; 79: 195–207.
17 March 2014
18 March 2014
Professor Jennifer H. Martin MBChB (Otago), MA (Oxon), FRACP, PhD (Monash), Level 7, Translational Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia. Tel.: +61405341676 Fax: +61 7 34437 7779 E-mail: [email protected]
Br J Clin Pharmacol
/ 79:2
/
167
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
