Preparing for Pandemic Influenza: Should Hospitals Stockpile Oseltamivir? • Author(s): Sandro Cinti , MD; Carol Chenoweth , MD; Arnold S. Monto , MDSource: Infection Control and Hospital Epidemiology, Vol. 26, No. 11 (November 2005), pp.852-854Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiologyof AmericaStable URL: http://www.jstor.org/stable/10.1086/502507 .

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852 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY November 2005

Drs. Cinti and Chenoweth are from the Division of Infectious Diseases; and Dr. Chenoweth is also from the Department of Infection Control and Epidemiology, University of Michigan Health System, Ann Arbor, Michigan. Dr. Cinti is also from Ann Arbor VA Health Systems, Ann Arbor, Michigan. Drs. Chenoweth and Monto are from the University of Michigan School of Public Health, Ann Arbor, Michigan.

Address reprint requests to Sandro Cinti, MD, Clinical Assistant Professor, Infectious Diseases, University of Michigan Hospitals/Ann Arbor VA Health Systems, 2215 Fuller Rd., Ann Arbor, MI 48105. scinti@umich.edu

The authors thank Curt Collins for providing pharmacy cost data.Drs. Cinti and Chenoweth have no proprietary interests. Dr. Monto reports having received consultation fees and grant support from Roche.

PREPARING FOR PANDEMIC INFLUENZA: SHOULD HOSPITALS STOCKPILE OSELTAMIVIR?

Sandro Cinti, MD; Carol Chenoweth, MD; Arnold S. Monto, MD

The outbreak of H5N1 avian influenza in Asia has reig-nited concerns about an influenza pandemic. It is clear that influenza vaccine will be in short supply (or nonexistent) early in an influenza pandemic. Without vaccine, the role of antiviral agents, especially oseltamivir, in treatment and prophylaxis is of paramount importance. Unfortunately, the government can-

not possibly stockpile enough oseltamivir to provide long-term prophylaxis or treatment for every healthcare worker in the United States. We think that hospitals should consider stock-piling oseltamivir, and we provide a strategy for doing so at a reasonable cost (Infect Control Hosp Epidemiol 2005;26:852-854).

ABSTRACT

The influenza pandemic of 1918 claimed 40 mil-lion lives, 500,000 of those in the United States.1 The current ongoing outbreak of avian influenza (H5N1) in Southeast Asia claimed 54 lives from January 28, 2004, to June 17, 2005,2 and has raised the specter of a pan-demic that could claim up to 100 million lives worldwide if human-to-human transmission becomes ef ficient.3 The monetary costs of pandemic influenza to the United States alone, based on a conservative estimate, would be between $71 and $167 billion.4 Healthcare workers would be at the highest risk of exposure as they care for infected patients.

The traditional public health approach to annual influenza epidemics has three components: vaccination of high-risk populations, chemoprophylaxis of exposed high-risk populations, and treatment of populations at high risk for complications of influenza.5 However, the public health response to an influenza pandemic is dif-ferent. First, it is unlikely that enough (or any) vaccine will be available quickly enough to prevent significant morbidity and mortality. Second, the population at high risk for complications may expand tremendously. Finally, containing illness among healthcare workers during an influenza pandemic will be challenging even if excellent infection control practices are followed. Therefore, the initially specific protection of healthcare workers will de-

pend more on available antiviral agents for chemoprophy-laxis and treatment than on vaccination. We think that it is prudent for hospitals to stockpile oseltamivir (Tamiflu, Roche Pharmaceuticals, Nutley, NJ), an antiviral agent, to provide treatment or chemoprophylaxis for their em-ployees and patients during an influenza pandemic. Our rationale is outlined below.

1. DURING A PANDEMIC, VACCINE WILL NOT BE AVAILABLE.

It should be assumed that at the beginning of a pandemic, little or no vaccine will be available.6,7 Produc-tion of a pandemic vaccine involves identification of a rel-evant strain, development of a strain that grows in eggs by either reassortment or reverse genetics, inoculation or incubation of eggs (assuming availability), harvest-ing allantoic fluids, purification and inactivation of virus, potency testing, and clinical testing or trials. Even under the most optimal conditions, and even if virus was grown in a cell culture instead of eggs, this process requires 6 to 8 months.7 A pandemic influenza strain could spread around the world in half that time.8 It is unlikely that a rapid method for producing reassortants (eg, reverse ge-netics) will be widely available before the next pandemic occurs. Currently, there is no commercially available vac-cine for H5N1 avian influenza.

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Vol. 26 No. 11 PREPARING FOR PANDEMIC INFLUENZA 853

2. THE POPULATION AT HIGH RISK FOR INFLUENZA COMPLICATIONS WILL EXPAND DURING A PANDEMIC.

During annual influenza epidemics, the following groups are at increased risk of complications from influen-za5: adults older than 50 years; residents of nursing homes; adults and children with chronic pulmonary and cardiovas-cular disorders; adults and children with diabetes, renal dysfunction, hemoglobinopathies, or immunosuppression; children and adolescents receiving long-term aspirin ther-apy due to the risk of Reye’s syndrome; pregnant women; and children 6 to 23 months of age. In 2000, these high-risk groups represented approximately 73 million individuals in the United States.

During a pandemic influenza outbreak, the high-risk population might be two to three times greater. During the influenza pandemic of 1918, in addition to the high mortality rates among the very young and the elderly, especially high rates of death occurred among young adults between the ages of 15 and 35 years.9 Thus, a large part of the healthcare work force would be at high risk of influenza complications. Without vaccine to offer protection, healthcare workers would be left to rely on antiviral agents and infection con-trol practices.

3. INFECTION CONTROL PRECAUTIONS MAY NOT BE ADEQUATE TO CONTAIN AN INFLUENZA PANDEMIC.

Infection control precautions may not be adequate to prevent transmission of a pandemic influenza virus to healthcare workers. Although there is some evidence for airborne transmission,10 influenza is generally spread through respiratory droplets and droplet precautions are recommended to control spread of the virus in a healthcare setting.11 The addition of airborne and con-tact isolation has been recommended for avian influenza. Unfortunately, healthcare worker attack rates during outbreaks are as high as 59%.11 Even with excellent infec-tion control practices, attack rates of greater than 10% are likely to occur among healthcare workers in the ab-sence of vaccine.11 Viral shedding of influenza occurs 1 to 2 days before symptoms and can continue for 7 days after symptoms begin. Infants and immunocompromised individuals may shed for weeks.11 This makes transmis-sion of influenza even more difficult to control in both the hospital and the community. In contrast, coronavirus shedding in severe acute respiratory syndrome peaks at 7 to 10 days after symptoms begin,12 making this dis-ease more easily contained with current infection control practices.13

A STRATEGY FOR STOCKPILING OSELTAMIVIR

If the mortality rate for the next pandemic approach-es that seen in the current avian influenza (H5N1) outbreak in Southeast Asia (50%),14,15 it may be difficult to convince a concerned healthcare work force to care for sick patients. Without a vaccine and with imperfect protection afforded

by sound infection control practices, the role of antiviral agents becomes paramount. The World Health Organiza-tion has suggested that, in the absence of vaccine, advanced stockpiling of antiviral drugs may be an alternative tool to manage an influenza pandemic.6

Unfortunately, future pandemic influenza strains are likely to be resistant to the less-expensive adamantanes, rimantadine and amantadine,16 and the use of these drugs in nursing home outbreaks has sometimes resulted in rapid development of resistance.17 Human isolates of H5N1 since 2003 have been resistant to the adamantanes, but avian strains have been variable in susceptibility.15 This leaves the neuraminidase inhibitors, oseltamivir and zanamavir, as the antiviral drugs of choice for stockpiling. Although it may have some role in a stockpile to treat oseltamivir-resistant influenza strains, zanamavir is not widely available and it must be administered as an inhaled powder. Therefore, the U.S. government has added oseltamivir to its Strategic Na-tional Stockpile.18 Oseltamivir is expensive ($35 to $40 per 5-day treatment course; University of Michigan Health Sys-tem pharmacy, unpublished data, May 3, 2005) and it is un-likely that enough medication can be stockpiled to provide long-term prophylaxis for all healthcare workers in a timely fashion. Many hospitals have the resources to stockpile and efficiently disseminate antiviral drugs to healthcare work-ers and high-risk groups within the general population.

There are four potential strategies for using antiviral agents during an influenza outbreak6,19: chemoprophylaxis for the entire influenza outbreak and season (or until vac-cine is available), postexposure chemoprophylaxis, treat-ment of ill patients, and a combination of chemoprophylaxis and treatment.

Chemoprophylaxis has been used to prevent spread of influenza in limited populations.19 Several studies of in-fluenza prevention in nursing homes support the use of prophylactic antiviral agents.20-23 In a model of the influenza pandemic (H2N2) of 1957–1958, targeted antiviral prophy-laxis of close contacts of influenza case-patients for 8 weeks would have reduced the attack rate from 33% to 2%.24 How-ever, this strategy is prohibitively expensive for most hospi-tals. During a pandemic, targeted prophylaxis of healthcare workers and patients would likely mean giving 6 to 8 weeks of prophylaxis (75 mg/d of oseltamivir) to all vulnerable groups. The cost to our hospital (the University of Michi-gan Health System) would be $1 to $2 million to cover 5,000 to 10,000 workers (University of Michigan Health System pharmacy, unpublished data, May 3, 2005). This cost would be incurred every 5 years as the medication expires.

We believe that a strategy that focuses primarily on the treatment of ill healthcare workers with some targeted chemoprophylaxis of heavily exposed workers (eg, respi-ratory therapists, those intubating influenza patients, and emergency department personnel) is financially feasible and offers treatment for healthcare workers caring for patients infected with influenza during a pandemic outbreak. Recent studies have demonstrated that neuraminidase inhibitors ad-ministered as treatment (75 mg twice a day for 5 days) within 48 hours of symptoms decrease not only the duration of ill-

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854 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY November 2005

ness but also the incidence of hospitalization, antibiotic use, and mortality.23,25,26 Bowles et al. demonstrated a significant decrease in antibiotic use (20% vs 65%), hospitalization (0% vs 22%), and death (2% vs 22%) among nursing home patients treated with oseltamivir within 48 hours of influenza symp-toms compared with patients who received no therapy.23 Kai-ser et al., in a review of 10 double-blind, placebo-controlled studies investigating the safety and efficacy of oseltamivir treatment, found that oseltamivir treatment reduced antibi-otic use by 27%, the incidence of influenza-related lower re-spiratory tract complications resulting in antibiotic therapy by 55%, and hospitalizations by 59%.25

Healthcare workers are easily tracked and could be monitored for symptoms (eg, fevers and myalgias) of influen-za. It seems feasible that such monitoring would identify most of the ill workers and thus allow timely administration of anti-viral therapy. We estimate that, with optimal infection control practices, we could expect 15% to 35% of our hospital workers to become ill during an influenza pandemic. Thus, at our hos-pital, we would expect to treat approximately 1,500 to 3,500 individuals with a 5-day course of oseltamivir (10 pills). The total cost to stockpile enough Tamiflu for this strategy would be between $60,000 and $140,000 (University of Michigan Health System pharmacy, unpublished data, May 3, 2005). Ad-ditional stockpiling for limited treatment of patients and high-risk contacts could be expected to add another $20,000. Given the current shelf-life of oseltamivir, a hospital could rotate the drug supply every 5 years to reduce these costs even further.27 Costs to smaller hospitals would be considerably less.

We think that hospitals should take on some of the burden of stockpiling oseltamivir. Other international influ-enza experts have also proposed institutional stockpiling of neuraminidase inhibitors as a way of preparing for the next influenza pandemic.27 When the next influenza pandemic occurs, there will almost certainly not be enough vaccine available to protect the citizenry and, if mortality rates are high, it may be difficult for healthcare workers to risk con-tracting potentially fatal influenza while caring for patients with influenza. Although excellent infection control prac-tices will provide some protection for employees, the avail-ability of these drugs will be essential for treatment in the event of infection. It is unlikely that the Centers for Disease Control and Prevention will be able to stockpile and quickly disseminate enough oseltamivir in the early stages of the next influenza pandemic. The demand for this drug will be too great, too diffuse, and too immediate. Hospitals with resources should consider stockpiling enough oseltamivir to offer a combination of treatment and chemoprophylaxis to employees and patients. These institutional stockpiles will allow local control, rapid access, and, possibly, use in large, non-pandemic influenza outbreaks. The cost, which will largely be incurred by hospitals, is both reasonable and justifiable when one considers the inevitability of future in-fluenza pandemics.

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