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					 ANALYSIS




Meeting the challenge of
            A concerted global response is needed to tackle rising rates of antibiotic resistance.
           Without it, we risk returning to the pre-antibiotic era warn Otto Cars and colleagues




A
              ntibiotics changed the world.            than double the mortality from malaria.                              Unblocking collective action
              Since their discovery almost                Antibiotic resistance is becoming important                       Although the essential components of control
              eight decades ago, they have             in high income countries. In England and                             of antibiotic resistance have long been well
              revolutionised the treatment of          Wales, for example, the number of registered                         known, success has been limited in changing
              infections, transforming once            deaths in which meticillin resistant Staphylo-                       policies and efficiently responding to the prob-
deadly diseases into manageable health                 coccus aureus (MRSA) is mentioned increased                          lem.11 12 The relative lack of data on the mor-
problems. The growing phenomenon of bac-               from less than 50 in 1993 to more than 1600                          bidity and mortality attributable to antibiotic
terial resistance, caused by the use and abuse         in 2006. In 2007 there was a slight decrease.3                       resistance, including the economic impact on
of antibiotics and the simultaneous decline            The European Centre for Disease Preven-                              individuals as well as on health care and socie-
in research and development of new medi-               tion and Control, in its first epidemiological                       ties, may explain the weak reaction from politi-
cines, is now threatening to take us back to           report on communicable diseases in Europe,                           cians, public health workers, and consumers to
a pre-antibiotic era. Without effective treat-         states that the most important disease threat                        this threat to public health.
ment and prevention of bacterial infections,           in Europe is from micro-organisms that have                             Individual stakeholders might well recog-
we also risk rolling back important achieve-           become resistant to antibiotics.4 5                                  nise the problem, but because it is complex,
ments of modern medicine such as major                    The emergence of antibiotic resistance is                         antibiotic resistance often becomes no one’s
surgery, organ transplantation, and cancer             further complicated by the fact that bacte-                          responsibility, which blocks collective action.
chemotherapy.                                          ria and their resistance genes are travelling                        Action is urgently needed in three key areas:
   Data from low income and middle income              faster and further.6 7 We are facing not only                        leadership on international and national levels,
countries indicate that, because of the devel-         epidemics but pandemics of antibiotic resist-                        change in the behaviour of consumers and pro-
opment of resistance to first line antibiotics,        ance.8 Airlines now carry more than two                              viders, and the development of antibacterial
70% of hospital acquired neonatal infections           billion passengers annually, vastly increas-                         agents to match current public health needs.
could not be successfully treated by using             ing the opportunities for rapid spread of
WHO’s recommended regimen.1 A recently                 infectious agents, including antibiotic resist-                      International and national leadership
published study of Tanzanian children con-             ant bacteria, internationally.9 The spread of                        International organisations
firmed that ineffective treatment of blood-            resistance is also facilitated by worldwide dis-                     In 1998, the World Health Assembly adopted
stream infections due to antibiotic resistance         tribution of food.10 Another important factor                        a resolution urging member states to take
predicts fatal outcome independently of                is poor hygiene in hospitals as well as in the                       action on the problem of antimicrobial resist-
underlying diseases.2 In that hospital based           community, augmenting the rapid spread                               ance.13 In 2000, the World Health Organiza-
study, mortality from bloodstream infections           of antibiotic resistant bacteria in vulnerable                       tion requested a massive effort to prevent the
caused by Gram negative bacteria was more              populations.                                                         “health care catastrophe of tomorrow,”7 and
                                                                                                                            shortly thereafter presented a global strategy
                                                                                                                            for the containment of antimicrobial resistance,
                                                                                                                            calling for a multidisciplinary and coordinated
                                                                                                                            approach.14 However, sufficient financial and
                                                                                                                            human resources to implement the strategy
                                                                                                                            were never provided. Member states recog-
                                                                                                                            nised this lack of leadership and initiated a
                                                                                                                            new resolution, adopted by the World Health
                                                                                                                            Assembly in 2005, requesting the director
                                                                                                                            general to strengthen WHO’s leadership role
                                                                                                                            in containing antimicrobial resistance and to
                                                                                                                            provide more technical support.15
                                                                                                                               Little has taken place to implement the
                                                                                                                            resolution. The difficulties of enforcing these
                                                                                                                            recommendations on a global level are evi-
                                                                                                          JOHN DURHAm/SPL




                                                                                                                            dent, and the links between the well formu-
                                                                                                                            lated strategies at the level of global society
                                                                                                                            and the acceptance level by national policy-
                                                                                                                            makers are weak. WHO, international profes-
Different degrees of sensitivity to antibiotics exhibited by Staphylococcus aureus                                          sional organisations, and other international

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                                                                                                                                          ANALYSIS




antibiotic resistance
stakeholders must provide coordination and        scriber,24 and antibiotics could therefore suc-        SuMMArY
resources for generating up to date information   cessfully be replaced by better information            pOINtS
on the burden and the magnitude of antibiotic     and follow-up.
resistance at regional and subregional levels.       The role of the patients as consumers is
                                                                                                         Antibiotics are a prerequisite for many of the
Evidence is needed on effective interventions     growing stronger. They need access to infor-
                                                                                                         advanced technologies in today’s healthcare
for prevention and control of antibiotic resist-  mation and knowledge to reduce their expec-
                                                                                                         Although antibacterial resistance is growing,
ance at national and local levels, and more       tations of antibiotics in self limiting infections,    development of new antibiotics has declined
emphasis on prevention of infectious diseases     and doctors need new tools to help them jus-           A new paradigm in which antibiotics are
is needed. Solving basic problems such as lack    tify their treatment decisions.25 It could be          considered as a non-renewable resource is
of safe drinking water, poor nutrition, and dys-  unrealistic to expect people to restrict their         needed
functional sanitation will go a long way toward   antibiotic use in favour of a common good to           The know-do gap in control of bacterial
curbing the needless use of antibiotics as quick- prevent resistance—but if the arguments for            resistance to antibiotics must be tackled on
fix solutions to avoidable diseases.7             restricting the use of antibiotics can be made         international, national, and individual levels
                                                  sufficiently convincing, reduced demand
At national level                                 from the consumer may be the strongest                   With existing incentives, current levels of
Strategies for containing antibiotic resistance force driving change. Studies increasingly              innovation are clearly inadequate.32 Propos-
in low income countries are still blocked by emphasise the risk for the individual when                 als on how to break this trend have been put
patients’ poverty and weak health systems,16 taking an antibiotic, including the risks of               forward. Some have suggested arrangements
and many high income countries with well becoming a long term carrier of antibiotic                     that would increase the anticipated revenue
developed regulations and policies lack coor- resistant bacteria,26 27 which might confer a             by lengthening the period of patent protec-
dinated strategies against antibiotic resistance. greater risk in a subsequent severe infection.        tion or exclusivity over data submitted for
Although the European Union has responded Reliable information on the adverse effects of                drug registration. However, antibiotics already
to the resistance problem, antibiotics are still antibiotics on the microbiological flora might         have small markets and emergence of resist-
sold over the counter                                                      provide a stronger           ance may further reduce the expected return
without a prescription All antibiotic use, appropriate                     incentive for not using      of investment, so these incentives are likely
in some EU countries, or not, “uses up” some of the                        antibiotics unnecessar-      to do little to stimulate greater innovation for
violating existing laws effectiveness of that antibiotic                   ily than would more          antibacterials.33 There are also scientific chal-
and regulations, and                                                       general messages about       lenges for development of new antibiotics.34
in all countries self medication with leftover risks for society through the development of                If today’s market cannot deliver what
medicines occurs.17 The root causes of certain resistance. For prescribers and other drug               the public needs, we must envisage other
behaviours need to be tackled, and the ulti- providers, multifaceted interventions includ-              approaches that better engage both public
mate responsibility for coordinating the work ing so called academic detailing are effective            and private sector resources.35 One model is
lies with the government.                         to increase adherence to recommendations in           product development partnerships (PDPs),
   National mandated multidisciplinary pro- both high income settings and low income                    arrangements between public organisations
grammes can move from recommendations settings.28 29                                                    and private companies to develop drugs when
to implementation and audits.18 For example,                                                            markets otherwise fail to meet public health
in Sweden the government is funding Strama, Developing new antibacterials                               priorities. This approach is now used for some
a nationwide multidisciplinary and multi- For many years, needs for antibacterial drugs                 drug projects targeting other neglected infec-
faceted action programme against antibiotic were met by the pharmaceutical industry, and                tious diseases, such as malaria and tubercu-
resistance. Antibiotic sales have been reduced the apparent symbiosis between the interests             losis.36 Mechanisms creating supplements or
without measurable negative consequences, of the community and those of the industry                    replacing revenues in small and resource poor
and resistance remains low.19 In Chile, after prevailed. Today we see a different scenario.             markets are another approach. Advanced mar-
a mass media campaign, regulatory meas- Existing antibiotics are losing their effect at an              ket commitments (AMCs) create a fund that
ures were implemented to make antibiotics alarming pace, but development of new anti-                   guarantees a certain price for drugs that meet
available by prescription only, resulting in biotics is declining. More than a dozen new                therapeutic targets where there is a demand
an initial decrease of 35% in antibiotic sales.20 classes of antibiotics were developed in the          for the drug. A recent example is the pneumo-
                                                  1930s through the 1960s, but only two new             coccal vaccine AMC.37
Behavioural change                                classes have been developed since then.30                A gap analysis of drugs currently under
Social constraints and cultural views of infec- Nor does the trend of declining innovation              development in light of current resistance
tious conditions influence the use of antibi- seem to be reversing. In a study of the top               patterns and trends would give priority to
otics.21 Although the public’s demand for 15 pharmaceutical companies, only 1.6% of                     the most urgently needed antibiotics and
antibiotics often is perceived as high even for drugs in development were antibiotics, none             give incentives for developing antibacterials
conditions without a clinical indication for of which were from novel classes and leaving               with new mechanisms of action. But no mat-
antibiotic treatment,22 23 studies have shown need unmet for multiresistant Gram negative               ter how innovation is accelerated, any public
that this demand is overestimated by the pre- infections.31                                             investment must be matched by public health

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 ANALYSIS



accountability. The use of new antibiotics must                     (Sida), ReAct is working towards five objectives: identify and         2008;8:125-32.
                                                                    facilitate removal of critical evidence gaps that block action      20 Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact
be safeguarded by regulations and practices                                                                                                of regulatory measures on antibiotic sales in Chile. Rev
                                                                    to contain antibiotic resistance; develop strategic options
that ensure rational use, to avoid repeating the                    to remove barriers to innovation of new antibiotics and                Méd Chile 2002;130:1265-72.
mistakes we have made by overusing the old                                                                                              21 Harbarth S, Samore MH. Antimicrobial resistance
                                                                    diagnostics; advocate for better access to and use of effective        determinants and future control. Emerg Infect
ones.                                                               and affordable antibiotics for those in need; promote global           Dis 2005;11(6). www.cdc.gov/ncidod/EID/
   Another lack is efficient and affordable diag-                   consensus for a new paradigm on the use of antibiotics;                vol11no06/05-0167.htm
                                                                    increase awareness of antibiotic resistance as a threat to global   22 Chen C, Chen YM, Hwang KL, Lin SJ, Yang CC, Tsay RW, et
nostics with high sensitivity and specificity to                    public health and engage key stake holders in action.                  al. Behavior, attitudes, and knowledge about antibiotic
distinguish bacterial from viral diseases, and                      Competing interests: None declared.
                                                                                                                                           usage among residents of Changhua, Taiwan. J Microbiol
                                                                                                                                           Immunol Infect 2005;38:53-9.
to identify resistance patterns in bacteria. Such                   provenance and peer review: Not commissioned; externally            23 Trepka M, Belongia E, Chyou P-H, Davis J, Schwartz B.
diagnostics would reduce inappropriate use of                       peer reviewed.                                                         The effect of a community intervention trial on parental
antibiotics and minimise the delays of treat-                                                                                              knowledge and awareness of antibiotic resistance
                                                                    1    Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z,               and appropriate antibiotic use in children. Pediatrics
ment, thereby saving lives.                                              Goldmann DA. Hospital-acquired neonatal infections in             2001;107:6.
                                                                         developing countries. Lancet 2005;365:1175-88.                 24 Macfarlane J, Holmes W, Macfarlane R, Britten N.
                                                                    2    Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile              Influence of patients’ expectations on antibiotic
Moving to concerted action                                               DS, Jureen R, et al. Antimicrobial resistance predicts            management of acute lower respiratory tract illness
A fundamentally changed view of antibiotics                              death in Tanzanian children with bloodstream                      in general practice: questionnaire study. BMJ
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is needed. They must be looked on as a com-                              2007;7:43.                                                     25 Del Mar C. Prescribing antibiotics in primary care. BMJ
mon good, where individuals must be aware                           3    National Statistics. MRSA deaths decrease in 2007www.             2007;335:407-8.
that their choice to use an antibiotic will affect                       statistics.gov.uk/cci/nugget.asp?id=1067                       26 Sjölund M, Wreiber K, Andersson DI, Blaser MJ,
                                                                    4    European Centre for Disease Prevention and Control.               Engstrand L. Long-term persistence of resistant
the possibility of effectively treating bacterial                        Annual epidemiological report on communicable                     Enterococcus species after antibiotics to eradicate
infections in other people. All antibiotic use,                          diseases in Europe. December 2007. http://ecdc.                   Helicobacter pylori. Ann Intern Med 2003 16;139:483-7.
                                                                         europa.eu/pdf/ECDC_epi_report_2007.pdf                         27 Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto
appropriate or not, “uses up” some of the                           5    ReAct—Action on Antibiotic Resistance. Burden of                  LS, Douglas RM. Effect of beta lactam antibiotic use
effectiveness of that antibiotic, diminishing our                        resistance to multi-resistant gram-negative bacilli               in children on pneumococcal resistance to penicillin:
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on Antibiotic Resistance believes that for cur-                          resistance%20to%20Multi%20resist%20and%20                         Turnidge JD. A community-based intervention to reduce
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infections as part of their right to health, all of                      Staphylococcus aureus as a public-health threat. Lancet           prescribing practices in health centers of Khartoum
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nity is rapidly closing.                                                 diseases 2000: overcoming antimicrobial resistance.               drugs: as antibiotic discovery stagnate and a public
otto Cars professor, Infectious Diseases, Department of                  2000. www.who.int/infectious-disease-report/2000/                 health crisis brews. July 2004. www.idsociety.org/
medical Sciences, Uppsala University, Uppsala, Sweden                    index.html                                                        badbugsnodrugs.html
otto.cars@medsci.uu.se                                              8    Cantón R, Coque TM. The CTX-M β-lactamase pandemic.            31 Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr.
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liselotte Diaz Högberg researcher, Department of medical            9    World Health Organization. World health report 2007:              for the future. Clin Infect Dis 2004;38:1279-86.
Sciences, Uppsala University                                             a safer future: global public health security in the 21st      32 Projan SJ. Why is big pharma getting out of antibacterial
Mary Murray freelance consultant; member of the WHO                      century. 2007. www.who.int/whr/2007/whr07_en.pdf                  drug discovery? Curr Opin Microbiol 2003;6:427-30.
expert panel on national drug policy; visiting research fellow      10   Butaye P, Michael G B, Schwarz S, Barrett TJ, Brisabois A,     33 Outterson K, Samora JB, Keller-Cuda K. Will longer
and freelance consultant on rational use of medicines, Wee               White DG. The clonal spread of multidrug-resistant non-           antimicrobial patents improve global public health?
                                                                         typhi Salmonella serotypes. Microb Infect 2006;8:1891-            Lancet Infect Dis 2007;7:559-66.
Jasper, University of South Australia School of Pharmacy and
                                                                         7.                                                             34 Payne D, Tomasz A. The challenge of antibiotic resistant
medical Sciences, Adelaide, Australia
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olle Nordberg former executive director, Dag Hammarskjöld                time for action. BMJ 1998;317:613-4.                              and prospects for new antimicrobial agents. Curr Opin
Foundation, Uppsala                                                 12   Hawkey PM. Action against antibiotic resistance: no time          Microbiol 2004;7:435-8.
satya sivaraman journalist, New Delhi, India                             to lose. Lancet 1998;351:1298-9.                               35 Cars O, So A, Högberg L, Manz C. Innovating for bacterial
                                                                    13   World Health Assembly. Emerging and other                         resistance. ESCMID News 2007;2:22-4.
Cecilia stålsby lundborg associate professor and professor,              communicable diseases: antimicrobial resistance. May           36 Moran M. A breakthrough in R&D for neglected
Division of International Health (IHCAR), Department of Public           1998. http://mednet3.who.int/prioritymeds/report/                 diseases: new ways to get the drugs we need. PLoS Med
Health Sciences, Karolinska Institutet, Stockholm and Nordic             append/microb_wha5117.pdf                                         2005;2:e302.
School of Public Health, Göteborg, Sweden                           14   World Health Organization. Global strategy for                 37 Document prepared by the World Band and GAVI under
Anthony D so director, Program on Global Health and                      containment of antimicrobial resistance. 2001. www.               the guidance of Governments of Italy, Canada, and the
Technology Access, Terry Sanford Institute of Public Policy,             who.int/drugresistance/WHO_Global_Strategy_English.               United Kingdom. AMC Pilot Proposal. 7 September
                                                                         pdf                                                               2006. www.vaccineamc.org/files/AMCPilotProposal.pdf
Duke University, Durham, NC, USA
                                                                    15   World Health Assembly. Improving the containment of            38 Laxminarayan R, Malani A, Howard D, Smith DL.
Göran tomson professor international health system                       antimicrobial resistance. May 2005. www.tufts.edu/                Extending the cure: policy responses to the growing
research and director of doctoral programme, Division of                 med/apua/Chapters/WHA58_27-en.pdf                                 threat of antibiotic resistance. Alexandria: Resources for
International Health (IHCAR), Department of Public Health           16   Okeke IN, Aboderin OA, Byarugaba DK, Ojo KK, Opintan              the Future, 2007. www.extendingthecure.org/research_
Sciences, Karolinska Institutet, Stockholm and medical                   JA. Growing problem of multidrug-resistant enteric                and_downloads.html
management Centre (mmC), Karolinska Institutet, Stockholm                pathogens in Africa. Emerg Infect Dis 2007;13(11).
                                                                                                                                        Cite this as: BMJ 2008;337:a1438
                                                                         www.cdc.gov/EID/content/13/11/1640.htm
Accepted: 15 may 2008                                               17   Grigoryan L, Haaijer-Ruskamp FM, Johannes Burgerhof
Contributors and sources: OC, LDH, mm, SS, CSL, and ADS                  GM, Mechtler R, Deschepper R, Tambic-Andrasevic A,
                                                                         et al. Self-medication with antibiotics in the general
are members of the international secretariat and all authors
are active members of ReAct – Action on Antibiotic Resistance            population: a survey in nineteen European countries.             professor Cars
(www.reactgroup.org), a growing global network of individuals
                                                                         Emerg Infect Dis 2006;12(3). www.cdc.gov/ncidod/EID/
                                                                         vol12no03/05-0992.htm
                                                                                                                                          discusses the
and organisations working towards the mission that current
and future generations should have access to antibiotic
                                                                    18   Carbon C, Cars O, Christiansen K. Moving from                    implications
                                                                         recommendation to implementation and audit: part
treatment as a part of their right to health. ReAct was initiated        1. Current recommendations and programs: a critical              of antibiotic
in 2004 by Strama, the Swedish strategic programme against
antibiotic resistance (www.strama.se); the Dag Hammarskjöld
                                                                         commentary. Clin Microbiol Infect 2002;8(suppl 2):92-
                                                                         106.
                                                                                                                                          resistance in a
Foundation (www.dhf.uu.se), and the Division of International       19   Mölstad S, Erntell M, Hanberger H, Melander E, Norman            video interview
                                                                         C, Skoog G, et al. Sustained reduction of antibiotic
Health (IHCAR) at Karolinska Institutet, Stockholm, Sweden.
Supported by the Swedish Development Cooperation Agency
                                                                         use and low bacterial resistance: 10-year follow-up              on bmj.com.
                                                                         of the Swedish Strama programme. Lancet Infect Dis


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