Should Tamiflu™ Be Stockpiled Locally?

JEM Should Tamiflu™ be stockpiled locally?

Sandro Cinti, MD Gerald Blackburn, DO

AbstrAct to medications, vaccines, and personal protective The outbreak of H5N1 avian influenza in Asia equipment (PPE). The response to Hurricane Katrina raises serious concerns about an influenza pandemic demonstrates that, even with advance notice, the fed- of the kind seen in 1918. In addition, the recent feder- eral government is not capable of intervening quickly al response to Hurricane Katrina highlights the need enough to provide adequate protection for first for advanced local preparation for biological disas- responders.5 It is therefore incumbent upon local gov- ters. It is clear that there will not be enough vaccine ernments and hospitals to provide such protection in early in an influenza pandemic. Without vaccine, the the event of a pandemic influenza outbreak. Because role of antivirals, especially oseltamivir (Tamiflu™), vaccine will not be available early in a pandemic, and in treatment and prophylaxis becomes of paramount PPE and infection control practices will not be ade- importance. It is unlikely that the Centers for Disease quate to contain influenza, local governments and Control and Prevention (CDC) will be able to stockpile hospitals should consider stockpiling the antiviral enough oseltamivir to protect every first responder in oseltamivir (Tamiflu™). The rationale for this recom- the United States. Thus, it is important that local mendation is outlined below. governments and hospitals consider stockpiling oseltamivir for the treatment and/or prophylaxis of concerns local first responders. Key words: pandemic, influenza, oseltamivir, Vaccine will not be available early in a pandemic Tamiflu™, antivirals, first responders According to the World Health Organization (WHO), influenza vaccine will be in limited supply IntroductIon during the first part of a pandemic and may not be It is estimated that the 1918 influenza pandemic available at all.6 The mass production of vaccine claimed 40 to 50 million lives, 500,000 of those in the using current techniques cannot be accomplished in United States.1 The ongoing outbreak of avian fewer than six to eight months, even under the most influenza (H5N1) in Southeast Asia claimed 60 lives optimal conditions.7 A pandemic influenza strain between January 28, 2004, and September 29, 2005,2 could spread around the world in half that time.8 and has posed the possibility of a pandemic that could More rapid vaccine production methods (e.g., reverse claim up to 150 million lives worldwide if human-to- genetics) are unlikely to be widely available before human transmission were to become efficient.3 A the next pandemic occurs. At present, there is no recent model suggests that such a pandemic could commercially available vaccine for H5N1 avian cost the United States between $71 and $167 billion.4 influenza. First responders, including healthcare personnel, police, and emergency management personnel, will Pandemic influenza will be deadlier over a wider be at the highest risk of exposure during their care of range of the population infected patients. This group will require rapid access The groups at increased risk of complications

Journal of Emergency Management 21 Vol. 4, No. 3, May/June 2006 from influenza during typical yearly outbreaks are very the benefIts of stockpIlIng oseltAmIvIr locAlly predictable and are the basis for yearly vaccination If the mortality rate for the next pandemic recommendations by the Centers for Disease Control approaches that seen in the current avian influenza and Prevention (CDC). These groups, which make up (H5N1) outbreak in Southeast Asia (52 percent),2,15,16 it approximately 30 percent of the population, include the may be difficult to persuade frightened first responders elderly, young children, and the immunocompromised to care for sick patients. In this setting, the role of population. Although many first responders are tar- antivirals becomes very important, especially if vaccine geted for yearly vaccination, this group (usually aged is unavailable. The WHO and, more recently, the CDC 24 to 50) is generally at low risk for serious compli- have suggested that, in the absence of vaccine, stockpil- cations from influenza.9 Yearly influenza epidemics ing of antiviral drugs may be an alternative strategy for may lead to a few sick days, but death and debility managing the next influenza pandemic.6,17 are rare and unexpected among first responders. Unfortunately, the H5N1 avian strain is resistant A pandemic influenza outbreak, however, will to the relatively cheap adamantanes rimantadine result in much higher rates of morbidity and mortal- and amantadine, and future pandemic influenza ity across a wider range of the population. In fact, strains are likely to be resistant as well.18,19 This during the 1918 influenza pandemic, the highest mor- leaves the neuraminidase inhibitors oseltamivir and tality rates occurred among young adults between the zanamavir as the antiviral drugs of choice for stock- ages of 15 and 35.10 Thus, a large part of the first piling. Zanamavir is difficult to administer (inhaled responder workforce will be at high risk for influenza powder) and is not widely available. Therefore, the complications. Without vaccine, first responders will CDC, the WHO, and several countries have chosen to be left to rely on antiviral medications and effective stockpile oseltamivir.17 Unfortunately, these central- infection control practices. ly located stockpiles may be useless if pandemic influenza simultaneously descends upon many US Standard infection control practices may not provide cities, in which case antivirals will not arrive prompt- adequate protection during a pandemic ly enough to protect first responders. On the other Influenza is generally transmitted through res- hand, local stockpiles created by hospitals and city piratory droplets, and droplet precautions are rec- governments could be quickly and efficiently dissem- ommended to control spread of the virus in a inated based on the needs of local responders. healthcare setting.11 Even with such precautions in There are four potential strategies for using place, healthcare worker attack rates during antivirals during an influenza outbreak6,20: 1) chemo- influenza outbreaks are as high as 59 percent.12 prophylaxis for the entire influenza outbreak/season Furthermore, first responders will be at high risk of (or until vaccine is available), 2) post-exposure acquiring influenza in the community, where infec- chemoprophylaxis, 3) treatment of infected patients, tion rates as high as 15 to 25 percent can be expect- and 4) a combination of chemoprophylaxis and treat- ed in an unimmunized population.4 Viral shedding ment. Chemoprophylaxis is the best strategy to pre- of influenza occurs one to two days before symptoms vent the spread of influenza.20 Several nursing home and can continue for seven days after symptoms studies of influenza prevention support the use of begin. Infants and immunocompromised individu- prophylactic antivirals.21-24 In a model of the 1957 to als may shed for weeks.12 Thus, containment of pan- 1958 influenza pandemic (H2N2), targeted antiviral demic influenza will be almost impossible. In con- prophylaxis of close contacts of influenza cases for trast, the Severe Acute Respiratory Syndrome eight weeks reduced the attack rate from 33 percent (SARS) coronavirus shedding peaks seven to 10 to 2 percent.25 However, this strategy is prohibitively days after symptoms begin,13 making this disease expensive for most hospitals and local governments. more easily contained with current infection control For instance, the cost of administering prophylactic practices.14 oseltamivir (75 mg/day) for six to eight weeks (the

22 Journal of Emergency Management Vol. 4, No. 3, May/June 2006 average length of a pandemic outbreak in a commu- become ill during an influenza pandemic. Using a 600- nity) to up to 10,000 hospital workers in a 600-bed bed hospital with 10,000 employees as an ex ample, hospital would range between $1 to $2 million (phar- between 2,500 and 3,000 people would require treat- macy data). This stockpiling cost would be incurred ment with a five-day course of oseltamivir (10 pills). every five years as the expiration date approached.26 The total cost to stockpile enough oseltamivir using this The most reasonable strategy is one that focuses strategy would be $100,000 to $120,000 (pharmacy primarily on treatment of ill first responders with data). Additional stockpiling for limited chemoprophy- additional targeted chemoprophylaxis of heavily laxis and treatment of patients and high-risk contacts exposed workers (e.g., respiratory therapists, those could be expected to add another $20,000 to $40,000. intubating influenza patients). This is financially fea- Given the five-year expiration date on capsulated sible and offers adequate protection to first respon- oseltamivir,26 the cost per year for a 600-bed hospital ders caring for influenza-infected patients during a would be $24,000 to $32,000. Costs to smaller hospitals pandemic outbreak. Recent studies have demonstrated would be considerably less. Local governments could that neuraminidase inhibitors administered as treat- stockpile for nonhospital first responders with econom- ment (75 mg twice a day for five days) within 48 hours of ic support from the state and federal governments. The symptoms not only decrease the duration of illness but federal government currently has plans to stockpile also decrease the incidences of hospitalization, antibiotic enough oseltamivir for 81 million people.29 Much of this use, and mortality.24,27,28 First responders could easi- stockpile could be stored locally, where it would be ly be monitored for symptoms (e.g., fevers, myalgias) immediately accessible to first responders. of influenza. It is likely that such monitoring would identify the majority of ill workers and thus allow conclusIon timely administration of antiviral therapy. In summary, hospitals and local governments Even with optimal infection control practices, should take on some of the burden of stockpiling approximately 25 to 30 percent of first responders will oseltamivir. When the next influenza pandemic

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Journal of Emergency Management 23 Vol. 4, No. 3, May/June 2006 occurs, there will almost certainly not be enough vac- 9. Centers for Disease Control and Prevention. Prevention and con- cine available to protect the citizenry and, if mortali- trol of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep. 2003; ty rates are high, it may be difficult to convince first 52(RR-08): 1-50. responders to continue to care for patients with 10. Taubenberger JK, Reid AH, Fanning TG: Capturing a killer flu virus. Sci Am. 2005; 292: 48-57. influenza. The availability of antivirals, especially 11. Moser MR, Bender TR, Margolis HS, et al.: An outbreak of in- oseltamivir, will be of paramount importance, as they fluenza aboard a commercial airliner. Am J Epidemiol. 1979; 110: 1-6. offer the possibility of both chemoprophylaxis and 12. Salgado CD, Farr BM, Hall KK, et al.: Influenza in the acute hospital setting. Lancet Infect Dis. 2002; 2: 145-155. treatment. Even if the CDC maintains a large stock- 13. Peiris JSM, Chu CM, Cheng VCC, et al.: Clinical progression and pile of antivirals, it is unlikely that this cache will be viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. 2003; 361: 1519-1520. efficiently distributed in the early stages of a rapidly 14. Gopalakrishna G, Choo P, Leo YS, et al.: SARS transmission spreading influenza pandemic. The demand for this and hospital containment. Emerg Infect Dis. 2004; 10: 395-400. drug will be too great, too diffuse, and too immediate. 15. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al.: Human disease from influenza A (H5N1), Thailand, 2004. Hospitals should consider stockpiling enough Emerg Infect Dis. 2005; 11: 201-208. oseltamivir to offer a combination of treatment and 16. Hien TT, Liem NT, Dung NT, et al.: Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004; 350: 1179-1188. chemoprophylaxis to employees and patients. 17. CDC Guidelines and Recommendations: Influenza antiviral Furthermore, the CDC should help local governments medications; 2005-2006 chemoprophylaxis (prevention) and treat- establish their own stockpiles for nonhospital first ment guidelines. 18. Wainright PO, Perdue ML, Brugh M, et al.: Amantadine resist- responders. The cost is both reasonable and justifi- ance among hemagglutinin subtype 5 strains of avian influenza able when one considers the inevitability of future virus. Avian Dis. 1991; 35: 31-39. 19. Saito R, Oshitani H, Masuda H, et al.: Detection of amanta- influenza pandemics. dine-resistant influenza A virus strains in nursing homes by PCR-restriction fragment length polymorphism analysis with Sandro Cinti, MD, Clinical Assistant Professor, Infectious Diseases, nasopharyngeal swabs. J Clin Microbiol. 2002; 40: 84-88. University of Michigan Hospitals/Ann Arbor VA Health Systems, Ann 20. Ward P, Smith I, Small J, et al.: Oseltamivir (Tamiflu™) and Arbor, Michigan; National Center for Critical Incident Analysis (NCCIA), its potential for use in the event of an influenza pandemic. J National Defense University, Washington DC. Antimicrob Chemother. 2005; 55 (suppl. S1): i5-i21. 21. Brady MT, Sears SD, Pacini DL, et al.: Safety and prophylac- Gerald Blackburn, DO, Botsford Hospital, Farmington Hills; Michigan tic efficacy of low-dose rimantidine in adults during an influen- State University College of Osteopathic Medicine, Michigan. za A epidemic. Antimicrob Agents Chemother. 1990; 34: 1633- 1636. 22. Shilling M, Povinelli L, Krause P, et al.: Efficacy of zanamivir references for chemoprophylaxis of nursing home influenza outbreaks. 1. Crosby A: America’s Forgotten Pandemic. Cambridge: Vaccine. 1998; 16: 1771-1774. Cambridge University Press, 1989. 23. Hayden FG, Altmar RL, Schilling M, et al.: Use of the selective 2. World Health Organization: Cumulative number of confirmed neuraminidase inhibitor oseltamivir to prevent influenza. New human cases of avian influenza A (H5N1) since 28 January 2004. Engl J Med. 1999; 341: 1336-1343. World Health Organization Web site. Available at http:// 24. Bowles SK, Lee W, Simor AE, et al.: Use of oseltamivir during www.who.int/csr/disease/avian_influenza/country/cases_table_2 influenza outbreaks in Ontario nursing homes, 1999-2000. J Am 005_09_29/en/index.html. Accessed April 12, 2006. Geriatr Soc. 2002; 50: 608-616. 3. Schoch-Spana M: Implications of pandemic influenza for bioter- 25. Longini IM, Halloran ME, Nizam A: Containing pandemic rorism response. Clin Infect Dis. 2000; 31: 1409-1413. influenza with antiviral agents. Am J Epidemiol. 2004; 159: 623- 4. Meltzer ML, Cox NJ, Fukuda K: The economic impact of pandemic influenza in the United States: Priorities for intervention. 633. Emerg Infect Dis. 1999; 5: 659-672. 26. Hayden FG: Pandemic influenza: Is an antiviral response real- 5. Hsu S: Brown defends FEMA’s efforts. The Washington Post. istic? Pediatr Infect Dis J. 2004; 23: S262-S269. September 28, 2005; A01. 27. Kaiser L, Wat C, Mills T, et al.: Impact of oseltamivir treatment 6. The World Health Organization. WHO guidelines on the use of on influenza-related lower respiratory tract complications and hos- vaccines and antivirals during influenza pandemics. Global Health pitalizations. Arch Intern Med. 2003; 163: 1667-1672. Security: Epidemic Alert and Response. 2004:1-11. 28. Whitley RJ, Hayden FG, Reisinger KS, et al.: Oral oseltamivir 7. Patriarca PA, Cox NJ: Influenza pandemic preparedness plan treatment of influenza in children. Pediatr Infect Dis J. 2001; 20: for the United States. J Infect Dis. 1997; 176(suppl. 1): S4-S7. 127-133. 8. Stohr K, Esveld M: Public Health: Enhanced: Will vaccines be 29. HHS Pandemic Flu Plan, November 2005. United States available for the next influenza pandemic? Science. 2004; 306: Department of Health and Human Services Web site. Available at 2195-2196. http://www.hhs.gov/pandemicflu/plan/. Accessed April 12, 2006.

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