Antibiotic resistance and antibiotic development

Antibiotic resistance and antibiotic development

Reflection and Reaction many parts of the world, patients with HIV now have better access to HBV treatment than their HIV-negative neighbours. Althoug...

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Reflection and Reaction

many parts of the world, patients with HIV now have better access to HBV treatment than their HIV-negative neighbours. Although a strategy to treat HBV/HIV co-infection is important for public health and the higher viral replication seen in HIV patients increases the likelihood of progression to hepatic fibrosis, consideration should be given to making HBV treatment accessible for those without HIV infection. *Richard J Lessells, Janice Main, Graham S Cooke Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham, UK (RJL); Department of Medicine, Imperial College, London, UK (JM, GSC); and Africa Centre for Health and Population Studies, Somkhele, Kwazulu-Natal, South Africa (RJL, GSC) [email protected]

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We declare that we have no conflict of interest. 1 2

Hoffman CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis 2007; 7: 402–09. WHO. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public-health approach. 2006 revision. http://www. who.int/hiv/pub/guidelines/artadultguidelines.pdf (accessed Feb 19, 2008).

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Mphahlele MJ, Lukhwareni A, Burnett RJ, Moropeng LM, Ngobeni JM. High risk of occult hepatitis B virus infection in HIV-positive patients from South Africa. J Clin Virol 2006; 35: 14–20. Nelson M, Bhagani S, Fisher M, et al. A 48-week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis B in HIV/HBV-co-infected individuals. 13th Conference on Retroviruses and Opportunistic Infections; Denver, CO, USA; Feb 5–8, 2006. Abstract 831. Medical Research Council Clinical Trials Unit. Development of antiretroviral therapy in Africa. http://www.ctu.mrc.ac.uk/dart/summary.asp (accessed Feb 19, 2008). Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis 1999; 28: 1032–35. Burnett RJ, Francois G, Kew MC, et al. Hepatitis B virus and human immunodeficiency virus co-infection in sub-Saharan Africa: a call for further investigation. Liver Int 2005; 25: 201–13. Matthews GV, Bartholomeusz A, Locarnini S, et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS 2006; 20: 863–70. Ramos B, Nunez M, Martin-Carbonero L, et al. Hepatitis B virus genotypes and lamivudine resistance mutations in HIV/hepatitis B virus-coinfected patients. J Acquir Immune Defic Syndr 2007; 44: 557–61. Santos EA, Sucupira MVF, Arabe J, Gomes SA. Hepatitis B virus variants in an HIV-HBV co-infected patient at different periods of antiretroviral treatment with and without lamivudine. BMC Infect Dis 2004; 4: 29. Coleman PF. Detecting hepatitis B surface antigen mutants. Emerg Infect Dis 2006; 12: 198–203.

Antibiotic resistance and antibiotic development Kevin Outterson and colleagues1 should be congratulated for raising awareness of the converging problems of rising antibiotic resistance and declining antibiotic development.1 However, their conclusions are problematic for patients with life-threatening infections and for the healthcare providers searching for drugs to save such patients. The authors favour antibiotic preservation efforts in lieu of creating incentives for antibiotic development. Conservation is important to prolong the useful lives of current antibiotics, but it cannot mitigate the need to continually develop new antibiotics to treat drug-resistant infections. Unfortunately, very few novel antibiotics are being developed that can treat infections resistant to current antibiotics.2–4 At the same time, life-threatening infections caused by multidrug-resistant, and increasingly pan-resistant, organisms are sky-rocketing in incidence.5–8 Outterson and colleagues1 write that they “characterise the glass as half full rather than half empty”. For those of us in the front-line who are watching patients die from drug-resistant infections while running out of antibiotics to throw at them, the glass is neither half-full nor halfempty: it is moving ever closer to being empty. Outterson and colleagues’ cost calculations for patent extensions are based on a 2-year extension for all topselling drugs at the same time.1 However, previous prohttp://infection.thelancet.com Vol 8 April 2008

posals have been for a 6-month to 2-year extension, with length determined based on cost-benefit considerations.8 Furthermore, only antibiotics that treat serious or lifethreatening infections caused by organisms resistant to current agents would be eligible for the programme. In view of the difficulty in developing new priority antibiotics, no more than a handful of drugs will be eligible for a patent extension at any one time. Of greatest importance, however, is that the authors do not account for the money priority antibiotics can save society by reducing the enormous costs of multidrug-resistant infections. Our analysis suggested that, by mitigating such costs, wildcard patent extension may well be cost effective.9 Another problematic assumption is that prolonging patents will encourage pharmaceutical companies to heavily market their drugs, thereby hurting antibiotic conservation efforts. Companies market their drugs aggressively from the time they receive approval from the US Food and Drug Administration. There is no evidence that the longer the patent protection a company has, the more judicious is their initial marketing: they want an economic return and brand identification as soon as possible. Indeed, Outterson and colleagues’ own examples of exuberant pharmaceutical marketing were for drugs that were nowhere near the end of their patents. 211

Reflection and Reaction

Outterson and co-workers propose alternative solutions, which is more than some critics of patent extensions have done.10 However, the primary limitation of antibiotic conservation is not lack of reimbursement. The primary limitation is that conservation does not eliminate the need to develop new antibiotics, it only buys us more time to come up with new antibiotics. Furthermore, the authors’ suggestion that nosocomial infections can be greatly reduced by “many proven techniques” is very optimistic. Nosocomial infections will inevitably continue to occur as patients are exposed to health-care environments. Outterson and co-workers’ assertion that government grant-funded research can eliminate the need for industry participation in antibiotic development is problematic. The US$55 billion spent by US biotechnology/pharmaceutical corporations on research and development far exceeds the $29 billion annual National Institutes of Health budget.11,12 It is naive to think that government will fill this gap, or have the same efficiency for identifying and developing drugs as industry. Because governments seldom develop drugs, it is not surprising that there are very few drugs of any class13,14—and no antibiotics in the USA15 or Europe—that have been developed by government-sponsored scientists without industry participation. Government-funded research propels drug development forward, but it cannot replace industry drug development. I welcome ongoing discussion with the authors. The convergence of antibiotic resistance and lack of antibiotic development is far too complicated a problem, with far too severe a set of consequences, for any individual or group to hold a monopoly on developing solutions. It is time for the biomedical scientific community, industry, clinicians, government, and society at large to draw together to debate this issue in an open, transparent way, so that workable solutions can be developed.

Brad Spellberg Division of Infectious Diseases, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA, USA and David Geffen School of Medicine at UCLA, LA, CA, USA [email protected] I have received consulting fees from Pfizer and research support from Astellas, Gilead, Elan, Enzon, Novartis, Merck, and Pfizer. I am on the speakers’ bureau of Merck, Pfizer, and Astellas. I am a shareholder in NovaDigm Therapeutics Inc and a member of the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. The Infectious Diseases Society of America fully endorses my comments. 1 2

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Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007; 7: 559–66. Bradley JS, Guidos R, Baragona S, et al. Anti-infective research and development—problems, challenges, and solutions. Lancet Infect Dis 2007; 7: 68–78. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004; 38: 1279–86. Talbot GH, Bradley J, Edwards JE, et al. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 2006; 42: 657–68. CDC. Antimicrobial resistance: a growing threat to public health. Atlanta, GA: Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control, 2002. Palumbi SR. Humans as the world’s greatest evolutionary force. Science 2001; 293: 1786–90. Alanis AJ. Resistance to antibiotics: are we in the post-antibiotic era? Arch Med Res 2005; 36: 697–705. IDSA. Bad bugs, no drugs: as antibiotic discovery stagnates…a public health crisis brews. Alexandria, VA: Infectious Diseases Society of America, 2004. http://www.idsociety.org/WorkArea/showcontent.aspx?id=5554 (accessed Feb 19, 2008). Spellberg B, Miller LG, Kuo MD, Bradley J, Scheld WM, Edwards JE. Societal costs versus savings from wild-card patent extension legislation to spur critically needed antibiotic development. Infection 2007; 35: 167–74. Generic Pharmaceutical Association. Legislation promoted as a countermeasure against bioterrorism would counter bipartisan measures to constrain prescription costs. Arlington, VA: Generic Pharmaceutical Association, 2006. Burrill & Company. Biopharmaceutical industry research & development tops $55 billion in 2006. San Francisco: Burrill & Company, 2007. http://www. burrillandco.com/burrill/pr_1171302475 (accessed Feb 19, 2008). National Institutes of Health. Summary of the FY 2007 President’s budget. Bethesda, MD: National Institutes of Health, 2007. http://officeofbudget. od.nih.gov/pdf/Press%20info%20final.pdf (accessed Feb 25, 2008). DiMassa JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151–85. Leaf C. Why we’re losing the war on cancer. Fortune Magazine, March 22, 2004. http://money.cnn.com/magazines/fortune/fortune_archive/2004/03/22/36 5076/index.htm (accessed Feb 25, 2008). FDA. Electronic orange book query. Rockville, MD: US Food and Drug Administration. http://www.fda.gov/cder/ob/ (accessed Jan 7, 2008).

Author’s reply Antimicrobial resistance is an important public-health issue. On that much, we are agreed. The more pressing problem is finding the right mix of policy responses. Brad Spellberg supports a radical change in patent law: wildcard patents.1 We question the fairness, efficiency, and costeffectiveness of wildcard patents and patent extensions. 212

Fairness is an issue because wildcard patents increase the prices of other drugs. Wildcard patents and extensions will be a US$45 billion hidden tax increase on heart disease, depression, and other common ailments, both domestically and internationally.2 Public policy should also be concerned about efficiency: whether funds might be better spent in other ways to http://infection.thelancet.com Vol 8 April 2008