PERSPECTIVE Antimicrobial Resistance Determinants and Future Control ‘Stephan Harbarth* and Matthew H. Samoret. At the beginning of the 21st century, antimicrobial resistance Is common, has developed against every class of antimicrobial drug, and appears to be spreading into new clinical niches. We describe determinants lkely to influence the future epidemiology and health impact of antimicrobiat resistant infections. Understanding these factors will ult- mately optimize preventive strategies for an unpredictable future, “Antibiotic therapy, if indiscriminately used, may tum out to be @ medicinal flood thet temporarily cleans and heals, but ultimately destroys life itself.” Felix Marthlbanez, 1955 ‘or more than 5 decades, the problem of how to contain antimicrobial resistence hes preoccupied policy mak- ers and members of the academic community Nor is this preoccupation suprising since entimicrobiel resistence hhas become e public health concern throughout the world. Pessimistic viewpoints about the low chances of suc- cess to stop the development of antimicrobial resistance have repestedly been reported (1). The fundamental predicament is thet antimicrobial drugs ere e nonrenew- ble resowce. Their duration of benefit and availability appears limited at the biological level, a constraint not seen with therapies for other disease concktions. As pointed out by the commentary in this issue of Emerging Infectious Diseases (2), the emergence of antimicrobial resistance is umevoidable from an evolutionsry perspective. Moreover, for most microorganisms, itis unlikely thet fitness costs of sntimicrobiel resistance will reduce their spreed and clini- cal impact, since subsequent evolution commonly results in the amelioration of these costs (3). ‘This paradigm, which has been framed from a microbi- logic perspective and could be summarized in the slogen “antibiotic therepy: use it and lose it,” prompts questions sbout potential interventions thet could slow down the dis- semination of anlimicrobiel resistence and reduce its “University of Geneva Hespitas, Geneva, Switzerland: and {VA Salt Lake City Heath Care System, Salt Lake City, Utah, USA 704 health impact in the next 2 decades. What will influence the demand and use of antimicrobial drugs in the neer future? Which obstacles towards more judicious use and decreased transmission may get circumvented? How much will heeltheare regulation affect entimicrobiel resistence and our sbility to control its spread? In short, we need to complement anelysis of molecular biology with en exemi- nation of other determinents that are likely to influence the future epidemiology and health impact of antimicrobiel- resistant, bactesiel infections. Thet is the purpose of this tuticle, For space reasons, we will not discuss the problem of viral, protozoal, or fungal resistance, and the controver- sial use of antimicrobial drugs in animal growth promo- tion, but certain analogies may be drawn from the ideas presented here Potential Determinants of the Future Dissemination and Control of Antimicrobial Resistance Factors thet drive uncestainty regarding the future dis- semination and control of antimicrobiel resistance are numerous end diverse. These determinants can be grouped, into 4 categories (Table 1) (4,5). The first group is related, tothe molecular cheractetistics of pathogens, such as vine lence, transmissibility, and survival fitness, which are issues beyond the scope of this article. Moreover, progress in microbiologic detection and identification of infectious pathogens i likely to influence diagnostic uncertainty and, prescribing patterns of entimicrobiel drugs. The second, gxoup of determinants is linked to prescribers of antimicro- ‘bial drugs, physicians, who may change their prescription, patterns. Recent date from different parte of the world show promise in this area. The third group is related to characteristics of patient populations and host-related fac- tors. Not only does this include infection rates and case- ‘mix characteristics, but also consumer attitudes and global migration pettems. A fouth group of determinants is linked tomacro-level factors elated to the heeltheare exvi- ronment. These factors include regulatory policies thet ‘may influence use of antimicrobial drugs, infection control practices, technologie development, and drug discovery. Emerging infectious Diseases - wwwn.cde.gov/eid» Vol. 11, No. 8, June 2005‘Antimicrobial Resistance Determinants and Future Control “Table 1, Potential determinants influencing future dissemination and control of antimicrobial resistance Dimension Determinant Potential control measures and interventions Pathogen and Evohition Evolutionary engineering rmcrobial ecology Survival finess Inhibition of microbial gene expression Virulence Antibodies, antipathogenicty crugs, biologi response ‘maditers Commensal fer Probiotes Laboratory detection and identification Improved rapid diagnostic tests Antimicrobial drug usage pattern Diversty of antimicrobial drug prescribing Training and knowledge Migration, travel, and globalization Physician's Prescibing practice Population ‘characteistes Antimicrobial demand and health Deliefs Transmission and infection rates Healtheare poiey Promotional activities by industry Technologie development Poltice and healthcare policy Case mix and host susceptibily to infections Multimodal interventions Decision support tools ‘Academic dealing and educational campaigns ‘Screening and improved surveilance Immunization; beter control of chronic diseases ble information campaigns Hand hygiene and barr precautions Change in reimbursement patterns Regulation New prevention and treatment approaches. Diagnostic Uncertainty and Progress in Laboratory Detection Diagnostic uncertainty is « key dhiver of drug misuse end overuse, which can lead to antimicrobial selection pressure and increased sates of resistant microbes (5). The risks associated with untreated microbiel infection and the lack of accucete clinical or laboratory prediction methods result in alow threshold for inititing empisicel antimicro- bial deug therapy, especislly if infection could be life- threstening (6) In the future, diagnosis of microbiel infection may be improved at several levels, allowing reduction of antimi- crobiel selection presse. First, new diagnostic tests will facilitate initiation or withdrawal of antimicrobial therapy. soon efter onset of symptoms, especially in the hospital set- ting Several new biological markers, such es procalcitonin, and soluble tiggering receptors expressed on myeloid cells, have been proposed to serve either goal (7,8). Second, moleculer diegnostics may increase diagnostic accuracy. snd enable more prudent anfimicrobiel drug use in the future, Amplification technology with DNA microarrays snd simplified automation opens the potential for rapid test ing Dunne et al. described a scenario in which by the year 2025, sophisticated laboratory platforms with real-time emplifiers will automatically obtein end analyze clinical samples and be able to detect any potentially pathogenic microbe within 30 minutes (@). The threst of bioterrorism may also foster research about rapid molecular diagnostic tests that may be used atthe bedside. Third, new diagnostic tools may be available to repidly distinguish between bac- terial and viral infections in the ambulatory setting Foust, profound changes will be seen in the techniques used to perform molecular identification and antimicrobial suscep- tubilty testing In summery, there are several lines of evi- dence suggesting that e number of molecules, immune- logic, andmicrobial techniques will chenge the way infec- Emerging Infectious Diseases - wwwn.cde.govleid» Vol. 1, No. 8, June 2005 ous diseases are diegnosed end reduce diagnostic uncer tainty in the next 2 decades (10) Prescribing Antimicrobial Agents To most clinicians, the immediate sisk for the patient outweighs the long-term disadvantages of liberal use of sntimicrobial drugs. One of the most promising means of seducing entimicrobial selection pressue without impeis- ing patient safety is cessation of entimicrobiel drug thers- py i patients who do not have e bectesial infection. Great ‘rogiess has been made within the lest 5 years to shorten the duration of trestment with antimicrobial agents (11) Prediction rules designed for the early discontinuation of sntimicrobial agents have been validated by prospective tuils and will further optimize antimicrobial drug use (12) ‘Although antimicrobial drug policies end guidelines may not have been of great help in individual decision meking they may have sensitized the medicel community to the growing problem of antimicrobial drug overuse and resistance, Consequently, in meny industrialized countries, cither the mumber of antimicrobiel agent prescriptions or the volume of antimicrobiel use has decreased over the Lest 10 years, especially in the embulstory setting (Table 2) (1314). A plateau in worldwide entimicrobial consump- tion seems to have been seached, leading to « saturated market, As slated recently by representatives of the phar- maceuticel industry, “The awareness of the xeletionship ‘between use and emerging resistance has led to efforts to decrease, even xestiict, antibiotic use, and therefore decrease the postive influence of resistence on the masket and decrease market potential” (15) Population Characteristics and Technologic Development Case-mix cheractesistics and infection rates both inside and outside the healthcare setting will influence antimicro- 705PERSPECTIVE ‘Table 2. Counties that have decreased either number of antimicrobial drug prescriptions or teal volume of outpatient antimicrobial drugs used within the last 10 years Continent County Europe France Belgium Spain Germany United Kingdom ‘Sweden ‘South Kor Taiwan Australia Canada United States Chile bial drug use and resistance in the futwe An increase in. immunocompromised patients, the growing life-expectan- cy, and the susceptibility of older persons to infections could indixectly contibute to greeter antimicrobial drug use snd dissemination of resistent microbes. Moreover, infec- tious diseases are influenced by developments in other areas of patient care. New technologies and treatments can create new infectious diseases or eliminate existing ones For instance, cancer chemotherapy led to new types of suscep- tible hosts and infectious disease problems, indirectly impelling the dissemination of antimicrobiel resistence ‘within hospitals. Key trends in clinical care end biomedical Aiscovery that are likely to influence antimicrobial resist ance are the increased.use of medical devices end gene ther- spies, and better management of chronic diseases such as iabetes and cancer. These developments will likely reduce some types of resistence problems and help spawn others. Global threats such as the next influenza pandemic may. also affect prescribing of antimicrobial deugs by reversing the trend of decreasing antimicrobial drug consumption (U6). Conversely, climate change may lead to a decrease in. respiratory tract infections end antimicrobial drug use in. the winter months (17) ‘Asian-Pacific region ‘Americas Travel and Globalization Globelization and migration into mege-cities has led to new possibilities of crosstrensmission of antimicrobial resistence (1). Recent events such as the terrorist attack in. Beli, the war in Iraq, and the tamemi in Southeast Ase have led to the transfer of patients infected with paresis. tent gram-negative bacteria such as Acinetobacter spp. to other parts of the world, causing outbresks end public health concems (18). Within the next 2 decedes, global mixing increased population density, and decreased travel times will facilitate the spread of variety of entimicro- bisl-resistent pathogens such es fluoroquinolone-resistent pneumococci and enteric microbes. Since antimicrobial resistence is influenced by interna- tional travel and globelization resistence may, in tum, 706 affect how nations respond to each other. Especially as sus- veillance systems improve in quality, intemetional pres. suce may be applied to induce chenge in counties where antimicrobial agents are abused or where infection control policies are lex. The situation in antimicrobial resistence might become comparable to thet which exists for other infectious problems such as mad cow disease: economic pressure may contribute to compliance end uniformity in control measwes. Nevertheless, approaches to control the global spread of resistence will remain difficult to imple- ‘ment and will requite intensive surveillance end screening, efforts, Health Beliefs and Antimicrobial Drug Demand ‘Although the interplay between health beliefs and demand of antimicrobial drugs is widely recognized, few, if any, systematic studies exist ebout the future influence of the cultural setting on antimicrobial drug use and relat ed resistence rates (19). Sociel constraints and cultural views of infectious conditions thet require entimicrobiel treatment exest @ strong influence on their use, particular- ly for community-aequased pathogens ‘Several counties have recently taken the bold step of Inunching national campaigns to educete physicians and patients sbout antimicrobial misuse andthe threat of resist- ance (Figwe 1). These campsigns show promise in chang ing attitudes and behavior, among both the public end hheeltheare professionals (20). If repeated regularly, the campaigns are likely to reduce inappropriate patient requests for antimicrobial agents, which in conjunction, with physician education models may reduce inappropriate antimicrobial prescription practices (21). Ultimately, they may slow the dissemination of certain anfimicrobidl-resist- ant pathogens (5). For instance, in several countries, such as France and Spain, which use « great amount of entimi- crobial agents, a decrease in pneumococcal resistance rates among invasive isolates has been noted recently. This coin- cides with a decrease in antimicrobial drug use after natiomide cempsigns and the introduction of a conjugete pneumococcal vaccine (22), Nevertheless, uncertainty per- sists ebout possible negative outcomes and countermes- suces taken by the pharmaceutical industry to oppose these campaigns Vaccinology ‘Modern vaccinology (the development of new vac- cines) is likely to contribute to the decressed transmission and impact of antimicrobial-resistant bacteria in the near future 23). More so than antimicrobial agents, vaccines hhave the potential to ducably control infectious agents by blocking their ability to disseminate within e population. ‘This expectation can be illustrated by the example of the new pneumococcal conjugete vaccine. Based on encowag- Emerging infectious Diseases - wwwn.cde.gov/eid» Vol. 11, No. 8, June 2005Figure 1. Posters from nationwide educational campaigns against misuse of antimicrobial drugs ing results from countiies with high prevalence of pnew. mococedl resistance such as Isreel, France, Spein, and the United States, this vaccine will likely reduce the incidence of invasive disease due to resistant pneumococci (22,24). Further progress in pneumococcal vaccine development canbe expected from conjugate vaccines thet include more then 7 serotypes (25). Yet uncertainty remains regarding serotype replacement and the emergence of resistance in nonvaccine serotypes (25) Other vaccines to prevent invasive, antimicrobiel- resistant infections will be Inunched within the next 20, years (23). Potential cendidates are vaccines against mul- ldrugresistent staphylococci and enterococci, but clinical studies need to confirm promising preliminary results Infection Control in the Healthcare Setting While the intense selective presse of antimicrobial drug use has been an important factor in the emergence of resistence, the inconsistent application of infection control guidelines by hospital personnel largely accounts for the dissemination of resistance in the healthcare setting Infection control measures to limit the spread of antimicro- bial resistance are being increasingly well defined. Despite the increase in the prevalence of resistence of several important pathogens, there has been some success in con tuolling its clinical impact. Several countries have recently. reported a stabilization or decrease ininfection sates due to multidrug-resistent Staphylococcus auveus 26). ‘The next 20 yearswill see en increase in infection com tuol research and interventions to improve patient safety. Hand hygiene with alcohol-based hand rubs hes been, shown to decrease the twensmission of resistent orgenisms 7). A campsign sponsored by the World Health Orgenizetion in 2005 is promoting its practice throughout Emerging Infectious Diseases - wwwn.cde.govleid» Vol. 1, No. 8, June 2005 ‘Antimicrobial Resistance Determinants and Future Control the world. Early screening and isolation of patients carry- ing resistent organisms also appear to decrease the spread, of resistant microorganisms and may be more widely implemented (28). Some experts have suggested that mul- timodal approaches that use a combination of different measures (for exemple, aggressive infection control with, active surveillance cultures, hand hygiene, and possibly antimicrobial control) will effectively slow down and even hhalt the increasing trends of heslthcere-associated antimi- crobiel resistence (29) Healthcare Regulation Antimicrobial use is affected by reimbursement poli- cies, financial incentives, and healthcare regulation (19) Forecasting the political and regulatory development in. this area presents a major chellenge. There is abvays a short-term Inck of predictability with regard to political decision-making after unexpected epidemiologic situs- tions, such as the bioterrorist attacks in 2001 and severe acute respiratory syndrome in 2003, which quickly influ enced perceived medical needs (30), Looking at the future impact of heslthcere regulation, ‘many believe that political measwes to control antimicro- ‘bial drug use have only « negligible short-term effect G31). We argue, however, thet heeltheare regulation will ‘powerfully influence antimicrobial drug use in the future ‘To underline this hypothesis, we give 3 exemplesfrom dif- ferent continents Interdiction of Over-the-Counter Sales of ‘Antimicrobial Agents in Chile Seifmedicetion is an important deiver of antimicrobial overuse in low- and middle-income countries. Therefore ssnce 1999, the Chilean Ministry of Health hes stictly enforced existing laws, which resticted purchase of sntimicrobial egents without a medical prescription These segulstory measwes had e sustained impact on entimscro- ‘biel use in the outpatient setting sales of orally used sntimicrobial agents decreased by 43% from US $458 aillion in 1998 to US $26.1 million in 2002 (Figure 2) @. Restriction of Perioperative Antimicrobial Prophylaxis in Belgium Inadequate end prolonged perioperative antimicrobial prophylatis increases resistence to antimicrobial drugs G3). In 1997, a Royal Decree in Belgium limited reim- ‘oursement of antimicrobial drug prophylaxis to specific agents end a 24-hour period after surgery (34). Moreover, 2 fixed fee for antimicrobial costs was attributed to each type of intervention. As shown in Table 3, this reguletory ‘restriction had a sustained effect on the use of antimicro- ‘bial prophylais in Belgum 34)PERSPECTIVE f ott Figure 2. Number of antimicrobial drug packages sold in the out patient setting in Chile, 1088-2002, Package the term used to how sales figures of antimicrobial drugs from wholesalers or pharmacies. If alo used to caleulate the numberof dally defined doses for each marketed antimirobial drug. Data ae from Bavestrello et al(32). Unpublished data from 2001 and 002 were provided by A. Cabello Munoz and L. Bavestrello (Vila del Mat, Chil) ‘Separation of Dispensing and Prescribing in South Korea InEuwope end North America, separetion of entimicro- bial prescribing and dispensing is a well-established sys. tem. In contrast, in many Asian countries, healthcare providers ean © significant proportion of their income fiom dispensing drugs, especially broad-spectrum antimi- cxobiel agents (35). Consequently, physicians have tradi- tionelly compensated for relatively low medical service revenue by prescribing a high volume of antimicrobial agents. In 2000, against the strong opposition of physicians snd the phermaceutical industry, a new Korean govern- ment policy probibited physicians from dispensing drugs and pharmacists from prescribing drugs G6). This new policy decreased overall prescibing of antimicrobial agents and selectively reduced inappropriate prescribing of them for petiente with viral infections (36) Future Directions ‘The uncertainty evolving eround micro and mecro- level determinants influencing antimicrobial resistence makes longterm prediction challenging Although simule- tion studies may provide guidance about short-term trends G7), long-term predictions about the future of entimicro- bial resistence are fraught with difficulties, ax shown by a look back in history. When the antimicrobial drug era began, scientists were impressed by the milestones of, antimicrobial agent discovery and issued predictions sbout the future of antimicrobial resistance thet seem overly opti- mistic today (8). For instance, in 1952, a famous French, microbiologist anticipated pneumococci, gonococei, and 708 meningococci would not change their enfimicrobial sus. ceplibility profile in the future (‘Pour une espéce qui au dépast etait entiérement sensible, 'espéce sera toujours aussi sensible. C’est le cas des geimes trés sensbles a la pénicilline: gonocoques, pneumocoques, méningoco- ques’) (9). Yet exactly 40 years later, we were rapidly progressing towards a “post-antimicrobiel era” in which, doctors may become helpless against even common infec- tions (40). In the last past of this article, we contemplate the possi- ble status of antimicrobiel resistance in 2025. Although the itection of a few major trends seems relatively easy, other Factors that drive uncesteinty present tremendous farecast- ing challenges. Therefore, we have developed? alternative scenarios about the future dissemination end control of antimicrobial resistance. These were extrapolated from the key determinants discussed easlier. The informed reader of 2025 may apologize for ow lack of imaganetion. ‘What Will Be the Status of Antimicrobial Resistance in 20 Years? The Bright Scenario Te will observe a change inprescribing habits and atti- udes toward outpatient antimicrobial use, especially for respiratory infections. Policies and bebavier change inter- ‘ventions contribute to a massive change in social nosms sound entimicrobiel deug use, similar to whet hes hap- pened with tobacco control. Intensive educational cam- paigns, aimed at optimizing entimicrobial drug use, combined with immunizetion programs for infants end children will lead to reduced spread end clinical impact of antimicrobiel-resistent pneumococci, Tools from information technology and progress in microbiology will reduce diagnostic uncertainty and improve antimicrobial dosing selection, and treatment dhvation Use of antimicrobial agents will, therefore, con tinue to decrease, not only in the outpatient setting, but also in the inpatient setting Naw therapies will be developed based on probiotic principles, Technologic advances will enhance the identi- ficstion and characterization of the vast microbial “Table 3. Proportions of appropriate perioperative antimicrobial «rug prophylaxis in Belgian hospitals ater change inthe reimoursement system™ 1886.(%) 1886 (6) Correct timing 53 70 Correct incication 2 7 Duration >48 h 50 8 Choice of agent First-generation cephalosporin 28 cy ‘Second-generation 7 23 cephalosporin "Source: Goossons ak al Emerging infectious Diseases - wwwn.cde.gov/eid» Vol. 11, No. 8, June 2005diversity colonizing the humen body (commensels end, pathogens), which may lead to new probiotic strategies to prevent infections and reduce antimicrobial selection pressure Data sharing and increased international cooperation will lead to consistent conivol measures across different continents. Asien countries, users of lerge amounts of entimicrobiel egents and important dkivers of resistance until recently, will change paradigms and introduce mod- ern infection contsol concepts and public health policies thet will decrease overuse of entimicrobiel agents. Antimicrobial resistance among important pathogens will be slowly reversible. Trends in entimicsobiel resist ence follow en S-shaped curve with a quick ascent, ¢ plateau end, sometimes, a slow decline, Antimicrobial resistence in high prevalence counties will be slowly reduced, especially for several gram-positive microorgan- isms (1) Antimicrobial resistance will not have a major impact on life expectancy in the indusrialized world Deaths from pensesistant infections without eny treatment option will semein rare complications in high-income countries, since now entimicrobial agents and better use of currently aveil- able antimicrobial drugs will become standard policy. The Dark Scenario Now resistence mecharaisms will emerge and cissemi- nate, Multiesistent group A streptococci will render per cillin and macrolides useless in the treatment of pharyngitis Salmonella spp. infections cen no longer be treated with advanced cephalosporins, uorquinolones, or cerbepenems, We will observe raxsing resistence rates for most pathogens. Muliresistent Acinetobacter spp, enterococci, ‘nd stephylococe will ceuse substantial illness and increased treatment costs in those pasts ofthe world that have not installed stringent contol measures. Healthcare. associated infections due to vencomycin-renstententero- cocci will become endemic in many countries “Antibacterial resistant § caves will Become a mazsive public health problem. The scope of staphylococcal ‘mtimicrobiel resistance will extend not only to new sntimicrobiel agents, but eso to more settings. Although hospitals were once the sole province of methucillin reat ant § aires (MRSA), more and more community ou tress of MRSA will ocew in those persons who lack traditional ssc factors for camiage of MRSA. The preva lence of MRSAin the US comatenty will reach 25% witty in the nect decade, with cetes3 ines as high in hostels @p Technological development will not fulfill its promise. No new entimicrobiel classes o testament strategies have been developed for gram-negative bacteria, and vaccines Emerging Infectious Diseases - wwwn.cde.govleid» Vol. 1, No. 8, June 2005 ‘Antimicrobial Resistance Determinants and Future Control hhave not been widely effective. Serotype replacement in. pneumococci allowed thet organism to escape control Fluoroquinalones are no longer effective against a wide ‘ray of infections end have not been replaced by eny new class of orally aveileble antimicrobial agents. New entimi- crobiel drugs with novel mechanisms of action (e.g, bac- teriophages) have failed in lexge phase III tials, Anthrax and pandemic influenca theeats have led to ‘mass prophylaxis, with disastrous consequences in terms of resistance. Severel disasters end pandemics will increase the use of antimicrobial drugs on a global scale, leading to emergence and dissemination of resistance Acontimang flood of consensus conference statements ‘position papers, and staveillance network reports will be issued about the problem of antimicrobial resistance, with- ‘out ary measurable and sustained effect on containment Heeltheare policy will not introduce stringent control ‘measures because of alack of precise estimates of the pub- ic heslth impact of antimicrobiel resistence and the pricr- ity of other more pressing infectious disease problems such, asHIV, tuberculosis, and malaria. Conclusion ‘The high levels of uncertainty and complexity regard ing antimicrobial resistance mandate thet we build the capabilities to prepare not only for 1 specific future (Fol- owing the pessimistic viewpoint of antimicrobial therapy: ‘use it and lose i), but also across a sange of altemative sce- rnasios that may be less pessimistic ‘Whether the cusent epidemic of antimicrobial resist. ance is sustainable or will succumb to current efforts to limit its spread will be decided by en interaction of factors elated to microorgenisms, host, use pattems of antimicro- ‘bial drugs, and the impact of infection contral measwes and technologic development (5). We hope that adding infection control and prudent use of antimicrobial agents to new drug development will avert the realization of pes- simistic predictions about the future of antimicrobial resistence ‘Acknowledgments ‘We thank Tim Lahey, Dennis Ross-Degnen, Angela Cebello ‘Munoz, Roxane Salvatienma Gonzalez, Herman Goossens, and ‘Winfiied Kem for help in preparing this manuscript ‘Matthew H. Samore was supported by Centes for Disease CContol and Prevention grant no. RS1 CCRS20631 Dr. Haxbarth is associate hospital epidemiologist at the University of Geneva Hospitals in Switzerland. His research interests include the prevention of healtheate-ecquized infections and the epidemiology of antimicrobial drug-resistant pathogensPERSPECTIVE Dr. Samore is professor of intemal medicine at the University of Utah and chief of the Division of Clinical Epidemiology. He is also diector of the Salt Lake Informatics, Decision, Enhancement, and Surveillance Center. 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Ot, Univasty of Geneva Hoptals, 1211 Geneva 4, Srtzeind, sstenirobalers, Seiece. 1092,257-1050-5 fue 41-22:3723987; email: stephan harbarth @heage ch Treat colds and flu with care. Talk to your doctor. Emerging Infectious Diseases - wwwn.cde.govleid» Vol. 1, No. 8, June 2005 01