PERSPECTIVE cybersecurity in health care

if feasible solutions are to be of the information system can Disclosure forms provided by the author are available with the full text of this article found. Although we cannot pre- guide policy development. Third, at NEJM.org. dict exactly what an adversary will effective regulation may help en- do, we can take control of our sure the fidelity of medical de- From the Center for Biomedical Informatics, own environments, and we must vices; finding the right balance by Countway Library of Medicine, and the De- partment of Pediatrics, Harvard Medical watch potential adversaries closely. establishing security without cre- School, Boston. Just as public health strategies ating yet another expensive and have been developed to detect distracting set of compliance 1. Filkins B. SANS health care cyberthreat and track emerging epidemics, standards will require prior defi- report: widespread compromises detected, compliance nightmare on horizon. Norse. identify population risks and vul- nition by stakeholders (patients, February 2014. nerabilities, and prevent or ame- providers, and institutions) — 2. Ponemon Institute. 2013 Cost of data liorate adverse effects, analogous perhaps in a forum hosted by the breach study: global analysis. May 2013. 3. Krebs on Security. Wash. hospital hit by approaches can be used to im- Institute of Medicine, to build on $1.03 million cyberheist. April 2013 (http:// prove cybersecurity in health care its reports on privacy and data krebsonsecurity.com/2013/04/wash-hospital delivery organizations. First, ac- security.5 -hit-by-1-03-million-cyberheist). 4. Maron DF. A new cyber concern: hack at- tive and real-time surveillance The threats of cyberattack are tacks on medical devices. Scientific American. and communication of emerging clear and present in health care. June 2013 (http://www.scientificamerican cyberthreats could be used to It is time to organize, convene, .com/article/a-new-cyber-concern-hack/). 5. National Research Council, Committee profile threats and ultimately in- and focus in a way that that truly on Maintaining Privacy and Security in Health fluence public policy and preven- protects our patients, providers, Care Applications of the National Information tion. Second, risk-based analysis and institutions. Technology has Infrastructure. For the record: protecting electronic health information. Washington, and modeling that take into ac- unquestionably improved health DC: National Academy Press, 1997. count current and possible care. Let’s be sure that its prom- threats, the resulting risks, and ised benefits continue to be de- DOI: 10.1056/NEJMp1404358 the vulnerabilities and resilience livered safely. Copyright © 2014 Massachusetts Medical Society.

HISTORY OF MEDICINE The Origins of Antimalarial-Drug Resistance Randall M. Packard, Ph.D. Related article, p. 411 rugs have been used to treat ly used synthetic antimalarial dur- alternative synthetic antimalarial Dand prevent malaria for cen- ing the 1960s and 1970s. drugs were deployed to both turies. Bark from the cinchona Although the use of antima- treat and prevent malaria. Among tree, which contained an array larial drugs has a long history, these were sulfadoxine–pyrimeth­ of alkaloids with antimalarial the emergence of antimalarial- amine and mefloquine.1 properties, appeared in Western drug resistance is a relatively re- Various degrees of resistance therapeutics in the 17th century. cent phenomenon. Chloroquine- to these replacement therapies One of the alkaloids, quinine, resistant forms of Plasmodium emerged relatively quickly, though was isolated in 1820 and became falciparum malaria first appeared it was found that when used in the drug of choice for treating in Thailand in 1957 (see map). combinations, these drugs could malaria until World War II, when They then spread through South still be effective in treating ma- supplies of the drug for much of and Southeast Asia and by the laria. The disadvantages of the the world were cut off by the 1970s were being seen in sub- new therapies were their increased Japanese occupation of cinchona- Saharan Africa and South Amer- cost — which made them less growing regions in Southeast ica. The rise in chloroquine resis- available to the populations that Asia. Efforts to create alterna- tance contributed to a worldwide were at greatest risk — and in tives to quinine led to the search increase in malaria-related mortal- some cases, their adverse side ef- for synthetic antimalarial drugs. ity, particularly in sub-Saharan fects. Chloroquine, first developed in Africa. In an effort to combat It was in the context of the the 1930s, became the most wide- resistant strains, a number of search for new and safer antima-

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Chloroquine resistance 1957 1960s 1970s 1980s 1990–2006 Countries where P. falciparum malaria is endemic

History of Chloroquine-Resistant P. falciparum Malaria. Data are from the Worldwide Antimalarial Resistance Network. larials that would be effective in mounting pressure from national social and biologic dynamics of treating falciparum malaria that health programs, the WHO re- antimalarial-drug resistance. The artemisinin-based drugs emerged versed its policy in 2010, and gem-mining industry in the Pailin from China. Artemisinin had ACTs have subsequently become province of Cambodia attracted a been used by Chinese herbalists the first-line treatment for falci- continual flow of newcomers for centuries and was rediscov- parum malaria in many countries. from neighboring regions of ered by Chinese biomedical re- COLORUnfortunately, FIGURE the WHO’s fear Cambodia, Thailand, Vietnam, Draft 1 7/31/14 searchers in the 1970s. It did notAuthor thatPackard the generalized use of ACTs and Myanmar (Burma), as well become widely available outsideFig # would1 hasten the development of as from Bangladesh. About 1000 Title P falciparum malaria-chloroquin China until the 1990s. resistanceresist appears to have been to 1200 migrant workers arrived In an effort to prevent the de-ME justified.474 x 200 As Ashley and colleagues each month,3 many of them DE Malina velopment of resistance to arte-Artist reportkls in this issue of the Journal coming from areas where the AUTHOR PLEASE NOTE: misinin-based drugs, the WorldFigure has (pagesbeen redrawn and type411–423), has been reset resistance to prevalence of malaria was much Health Organization (WHO) rec- artemisinin-basedPlease check carefully drugs has ap- lower, and an estimated 80% of Issue date 7/31/14 ommended that they be used peared in multiple locations in these workers had no immunity only in combination with other Southeast Asia. to the disease. The mining activ- antimalarials. The first widely There is a tendency to view ity created hundreds of shafts, available artemisinin combination the development of antimalarial- which collected water from seep- therapy, or ACT, was Coartem, drug resistance as an inevitable age and rains. These shafts cre- which combined an artemisinin outcome of the drugs’ wide- ated breeding sites for a highly derivative, artemether, with a spread use.2 Yet antimalarial re- efficient malaria vector, Anopheles long-acting antibiotic, lumefan- sistance has been accelerated by dirus, which bred in very high trine. The combination drug the way the drugs are used and numbers and was hard to control proved to be 97% effective in by the social and economic con- with the insecticide dichlorodi- curing the most deadly forms of ditions in which they are used. phenyltrichloroethane (DDT) be- falciparum malaria. Despite the A closer look at the genesis of cause the insect did not rest in- product’s effectiveness, the WHO chloroquine resistance along the side huts. The miners, who stayed sought to restrict its use to the Thailand–Cambodia border, which for 3 to 4 months, lived in the treatment of complicated cases became ground zero for the open air and slept under very ru- of falciparum malaria, fearing emergence of chloroquine resis- dimentary shelters. They were that wider use would contribute tance in the 1950s and 1960s, thus exposed to multiple infec- to resistance. But in the face of reveals a great deal about the tive bites. The convergence of a

398 n engl j med 371;5 nejm.org july 31, 2014 The New England Journal of Medicine Downloaded from nejm.org on September 16, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. PERSPECTIVE The Origins of Antimalarial-Drug Resistance

highly efficient vector, a nonim- areas contributed to the wider An intensive campaign is cur- mune population, and mining dissemination of chloroquine re- rently under way to eliminate arte- conditions that encouraged both sistance throughout South and misinin resistance in the greater vector breeding and malaria Southeast Asia. Mekong Delta region and prevent transmission fueled recurrent epi- Mass drug-administration its further spread. These efforts demics of malaria, which appar- (MDA) programs elsewhere in focus on identifying and treating ently started in the 1940s or early the world during the 1950s and to cure all cases of malaria in 1950s; 80% of the cases were 1960s may also have contributed the region. Whether these efforts P. falciparum. to the rise of chloroquine resis- will be successful is unclear. But In 1955, public health authori- tance. There is a strong correla- efforts to address the social and ties in Pailin began distributing tion between the geographic areas economic conditions that contrib- chloroquine to workers daily; where MDA programs were initi- ute to the spread of malaria and later, the frequency was reduced ated and the places where chlo- foster antimalarial resistance, in- to twice a week. In 1960, they roquine resistance first emerged. cluding the marketing of mono- began administering chloroquine Also contributing to the develop- therapies and counterfeit drugs, indirectly through medicated salt. ment of resistance was the wide- are essential steps for preventing This method increased coverage spread availability of chloroquine artemisinin-based drugs from fol- but made it difficult to ensure in shops and private pharmacies, lowing the path of chloroquine. that each worker consumed an lax regulation of use of the drug, Given the cyclical history of drug adequate dose of the drug. The and the absence of effective pri- development followed by the repeated application of subcura- mary care systems. emergence of resistance, it is also tive concentrations of chloroquine It is not surprising that Pailin critical that investments continue to a highly infected population was an early site for the emer- to be made in the development set the stage for the emergence gence of artemisinin resistance. and production of new genera- of chloroquine-resistant strains of Some observers have suggested tions of antimalarial therapies. P. falciparum. The subsequent that malaria parasites in that re- Disclosure forms provided by the author transmission of resistant strains gion may be particularly prone to are available with the full text of this article at NEJM.org. of falciparum to new waves of mutation. Yet it is clear that al- nonimmune workers, month af- though the drugs have changed, From the Department of the History of ter month, and their treatment the social and economic condi- Medicine, Johns Hopkins School of Medi- cine, Baltimore. An audio interview with high but often tions under which they are used with Dr. Packard noncurative doses of have not. Pailin remains the center 1. Packard RM. The making of a tropical dis- is available at NEJM.org chloroquine ampli- of an extensive migrant labor sys- ease: a short history of malaria. Baltimore: Johns Hopkins University Press, 2007. fied resistance. By 1973, 90% of tem, with limited health resources. 2. White NJ. Antimalarial drug resistance. falciparum malaria cases were re- In addition, the widespread avail- J Clin Invest 2004;113:1084-92. sistant to chloroquine, and 70% ability in the region of cheap 3. Verdrager J. Localized permanent epidem- ics: the genesis of chloroquine resistance in exhibited high levels of resistance. counterfeit drugs containing sub- Plasmodium falciparum. Southeast Asian J From the Thai–Cambodian clinical quantities of artemisinin Trop Med Public Health 1995;26:23-8. border, resistant falciparum ma- and the marketing and use of non- 4. Dondorp AM, Yeung S, White L, et al. Arte- misinin resistance: current status and sce- laria spread to surrounding areas combination forms of the drug narios for containment. Nat Rev Microbiol along with the returning migrant have created an ideal mix of condi- 2010;8:272-80.

workers. Secondary patterns of tions for both the development and DOI: 10.1056/NEJMp1403340 4 dispersal from these surrounding spread of artemisinin resistance. Copyright © 2014 Massachusetts Medical Society.

Big Marijuana — Lessons from Big Tobacco Kimber P. Richter, Ph.D., M.P.H., and Sharon Levy, M.D., M.P.H.

he United States is divided clude protection of individual collection of tax revenue, and Tover the legalization of mar- rights, elimination of criminal elimination of the black market. ijuana. Arguments in favor in- sentencing for minor offenses, Counterarguments include the

n engl j med 371;5 nejm.org july 31, 2014 399 The New England Journal of Medicine Downloaded from nejm.org on September 16, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.