- Email: [email protected]
Postexposure Prophylaxis of H1N1 With Oseltamivir in a Newly Transplanted Kidney Recipient Receiving Intense Immunosuppressive Therapy
Postexposure Prophylaxis of H1N1 With Oseltamivir in a Newly Transplanted Kidney Recipient Receiving Intense Immunosuppressive Therapy K. Marfo, J. Chapochnick-Friedmann, E. Akalin, and A. Lu ABSTRACT Solid organ transplant recipients undergoing immunosuppressive therapy are considered to be at high risk for serious infectious complications. Recently in the United States, a pandemic of H1N1 flu infection has been reported with serious complications. We describe H1N1 infection in a living kidney donor and the 42-year-old kidney transplant recipient exposed to this kidney donor and undergoing intense immunosuppressive therapy. Postexposure prophylaxis with oseltamivir was effective to prevent H1N1 influenza A virus in a donor and a recipient. CCORDING TO THE World Health Organization, 94,500 laboratory-confirmed cases of the human swine flu (H1N1) have been reported in 100 countries.1 In the United States, cases have been identified in all 50 states. In the H1N1 pandemic, individuals at risk for complications include those younger than 2 or over 65 years; pregnant; or with a weakened immune system such as solid organ transplant recipients.2 To our knowledge, there has not been a documented H1N1 illness contracted through blood or solid organ transmission. While the organ transplant recipient is at risk for H1N1 infection, currently the impact of the H1N1 outbreak on organ donation is unknown. Herein we have reported a kidney transplant recipient undergoing intense immunosuppressive therapy whose living donor experienced influenza A confirmed to be H1N1.
A
CASE REPORT Donor The donor was a 31-year-old Hispanic woman, who was admitted for donor nephrectomy to her sibling. Her past medical history was not significant. She had a previous surgical history of a laparoscopic cholecystectomy, abdominoplasty, and breast implantation. On the day of surgery, the donor reported no symptoms. Her physical examination was within normal limits with no abnormal findings. The surgical procedure was uneventful. Her immediate postoperative course was without any complaints; however, on postoperative day 1 she developed a temperature of 102.9°F with subsequent elevations throughout the day. She also complained of cough, chills, and nasal congestion. Fever evaluation consisted of blood tests, urinalysis, urine culture, and blood cultures. All laboratory tests were within normal limits. Given the symptoms, we sent a viral culture and rapid nasal swab test for influenza A/B, which was returned as positive for influenza A. As per our institution’s
protocol, her viral culture sent for testing to New York City Department of Health was confirmed to be the specific H1N1 strain. Treatment for influenza A was initiated with oseltamivir (75 mg twice daily) for 5 days. The patient became afebrile and was discharged home on postoperative day 2 to complete the 5-day course of oseltamivir treatment for influenza A. At follow-up on postoperative day 5, her symptoms had resolved and she was clinically well without any complications.
Recipient A 42-year-old Hispanic woman with history of end-stage renal disease related to polycystic kidney disease who had been on hemodialysis for 1 month was admitted to receive a living related renal transplant from her sister. The patient’s past medical history was significant for hypertension. Her surgical history included a hernia repair and three childbirths by Cesarean section. Her procedure was uneventful. In the operating room, she received induction therapy with methylprednisolone and anti-thymocyte globulin. Intravenous immunoglobulin (IVIG) was also given secondary to detection of a donor-specific antibody. During the perioperative period, we administered four doses of anti-thymocyte globulin and three doses of IVIG. For maintenance immunosuppressive therapy, she received tacrolimus, mycophenolate mofetil, and prednisone (20 mg daily). She displayed immediate graft function. Her immediate posttransplant course was complicated by From the Department of Pharmacy (K.M.) Montefiore Medical Center, Bronx; Department of Surgery (J.C.-F., A.L.), Abdominal Organ Transplant Program, Montefiore Medical Center; and Department of Nephrology (E.A.), Montefiore Medical Center, Bronx, New York, New York, USA. Address reprint requests to Dr Amy Lu, Montefiore Medical Center, 111 East 210th Street, Bronx, New York, NY 10467. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.09.052
Transplantation Proceedings, 41, 4411– 4413 (2009)
4411
4412
MARFO, CHAPOCHNICK-FRIEDMANN, AKALIN ET AL
close contact with her donor who had begun to exhibit a cough and fever on the first postoperative day. Given the recipient’s significant exposure to the donor and her immunosuppression, oseltamivir (75 mg once daily) was initiated for 5 days. The immunosuppressive therapy was not reduced. The remainder of her posttransplant course was uneventful; she was discharged on posttransplant day 4 with no fever and with continued excellent graft function. On posttransplant day 10, at a routine clinic visit, her serum creatinine had increased from a baseline of 0.8 to 1.3 mg/dL. She was admitted for a renal biopsy, which was significant for changes consistent with acute antibody-mediated rejection (Banff class II). She was treated with a 3-day course of methylprednisolone, a 5-day course of IVIG and plasmapheresis, and a single dose of rituximab. She responded to treatment and her serum creatinine at posttransplant day 30 decreased to 0.8 mg/dL. Throughout her course, she did not manifest any signs or symptoms of influenza-like illness: fever temperature greater than 100.4°F or 37.8°C, cough, fatigue, chills, diarrhea, sore throat, headache or body aches, and stuffy or runny nose.
DISCUSSION
While solid organ transplant recipients under immunosuppressive therapy may be at higher risk for H1N1 complications when exposed to close contacts, our report suggested a benefit of oseltamivir prophylaxis. Neither did our patient develop manifestations of a flulike illness or adverse effects from the 5-day course of oseltamivir. Currently available antiinfluenza agents include amantadine, rimantadine, oseltamivir, and zanamivir (Table 1). Amantadine and rimantidine are effective only for the prevention and treatment of influenza A virus infections.3 Most of the strains of H1N1 influenza A virus appear sensitive in vitro to neuraminidase inhibitors (oseltamivir and zanamivir), but all current H1N1 strains tested have been resistant to amantadine and rimantadine.4 – 6 This has led to a statement by the US Centers for Disease Control and Prevention that H1N1 is susceptible to the neuraminidase-inhibitor antiviral medications oseltamivir and zanamivir, which target the early phase of the influenza infection, but that this influenza strain is resistant to amantadine, rimantadine, and other adamantanes. Therapy with neuraminidase inhibitors is usually initiated in patients who are suspected to have or have been exposed to H1N1 even though there are no reported studies on the clinical benefits
of antiviral therapy either for treatment or prophylaxis against H1N1. Oseltamivir and zanamivir are potent selective inhibitors of influenza A and B virus neuraminidases, hence the therapeutic category neuraminidase inhibitors.7 They also have activity in inhibiting amantadine- and rimantadineresistant influenza A viruses. The major difference between the two agents is the route of administration. Oral oseltamivir has a bioavailability of 80% while the oral availability of zanamivir is ⬍5%, and the commercial form is delivered by (oral inhalation) of dry powder.8,9 Oral oseltamivir is effective in the treatment and prevention of influenza A and B virus infections, as opposed to amantadine and rimantadine, which have activity against influenza A only. Treatment of previously healthy adults with acute influenza at a dose of 75 mg twice daily for 5 days decreases the duration of illness by about 1 to 2 days, speeds functional recovery, and reduces the risk of complications leading to antibiotic use by 40% to 50%.10,11 Oseltamivir treatment should be started within 48 hours of the onset of flu symptoms. When used for prophylaxis during the influenza season at a dose of 75 mg once daily, oseltamivir is effective to decrease the likelihood of influenza illness in both non-immunized working adults and in immunized nursing home residents. Furthermore, short-term use for 7 to 10 days protects against influenza in household contacts.12 Besides these therapeutic benefits, unwanted adverse events such as nausea, abdominal discomfort, and, less often, emesis may occur with treatment. Such gastrointestinal complaints are usually mild to moderate in intensity, typically resolve in 1 to 2 days despite continuing therapy, and are preventable by administration with food. Zanamivir, however, must be administered topically, by inhalation, or parenterally (intravenously), to be effective13,14; only the inhaled product is commercially available. Inhaled zanamivir is also effective for the prevention and treatment of influenza A and B virus infections. Early zanamivir treatment at a dose of 10 mg twice daily for 5 days of febrile influenza in ambulatory adults shortens the time of illness resolution by 1 to 3 days and reduces the risk of lower respiratory tract complications leading to antibiotic use by 40%.10,15 For prophylaxis, once-daily inhaled zana-
Table 1. Therapeutic Characteristics of Antivirals for Influenza and Human Swine Flu H1N1
Spectrum of activity Route Bioavailability Half-life Dosing (prophylaxis) (mg/d) Dosing (treatment) (mg/d) Dose adjustments Common side effects
Amantadine
Rimantadine
Zanamivir
Oseltamivir
Influenza A Oral ⬎90% 12–18 200 200 Clcr ⱕ 50 Light-headedness Loss of appetite
Influenza A Oral ⬎90% 24–36 200 200 Clcr ⱕ 50 Light-headedness Loss of appetite
Influenza A, B, H1N1* Inhaled/intravenous† ⬍5% 2.5–5 10 20 None Wheezing Bronchospasm
Influenza A, B, H1N1* Oral ⬃80% 6–10 75 150 Clcr ⱕ 30 Nausea Abdominal discomfort
H1N1, human swine flu; Clcr, creatinine clearance. *Appear sensitive. † Not commercially available.
POSTEXPOSURE PROPHYLAXIS OF H1N1
mivir is highly protective against community-acquired influenza illness and when given for 10 days, it protects against household transmission. The main disadvantage of zanamivir administration is reported incidences of wheezing and bronchospam in patients without a history of airway disease. Acute deteriorations in lung function, including fatal outcomes, have occurred in patients with underlying airway diseases such as asthma and chronic obstructive airway disease. Zanamivir is not generally recommended for treatment of patients with underlying airway disease because of serious adverse events. Recently, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus. Although there are ongoing clinical studies to demonstrate the efficacy of these vaccines, the preliminary data from healthy adult volunteers has been promising. The vaccines are available as live, attenuated intranasal and inactivated injectable. Since annual influenza vaccination is the most effective method for preventing influenza virus and its complications, such may also be the benefit from the H1N1 vaccine. Transplant recipients and candidates should receive the annual trivalent inactivated influenza vaccine in addition to inactivated injectable H1N1 vaccine as per recommendations from the American Society of Transplantation guidance on novel influenza A/H1N1*. If a transplant recipient has already received vaccine pretransplant, there is no need to give a repeat dose posttransplant. However, in the immediate posttransplant period, it seems reasonable to delay influenza vaccination for weeks before the suspected start of the influenza season in patients receiving intense immunosuppressive therapy. This case illustrated that there is a potential that H1N1 transmission can occur from living donors to recipients even with the usual precautions. REFERENCES 1. World Health Organization: Pandemic (H1N1) 2009 — update 58, July 6, 2009. Available at: http://www.who.int/csr/don/ 2009_07_06/en/index.html. Accessed July 14, 2009
4413 2. US Centers for Disease Control and Prevention: Interim Guidance on Antiviral Recommendations for Patients with Novel Influenza A (H1N1) Virus Infection and Their Close Contacts. May 6, 2009. Available at: http://www.cdc.gov/h1n1flu/recommendations.htm. Accessed July 12, 2009 3. Hayden F, Aoki F: Amantadine, rimantadine, and related agents. In Yu V, Merigan T, White N, et al (eds): Antimicrobial Therapt and Vaccines. Williams Baltimore; Williams & Wilkins; 1999, p 1344 4. Garcia J, Sovero M, Torres Al, et al: Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markets. Influenza Other Respi Viruses 3:69, 2009 5. Rungrotmongkol T, Intharathep P, Malaisree M, et al: Susceptibility of antiviral drugs against 2009 influenza A (H1N1) virus. Biochem Biophys Res Commun 385:390, 2009 6. Laplante JM, Marshall SA, Shudt M, et al: Influenza antiviral resistance testing in New York and Wisconsin, 2006 to 2008: methodology and surveillance data. J Clin Microbiol 47:1372, 2009 7. Gubareva L, Hayden F, Kaiser L: Influenza virus neuraminidase inhibitors. Lancet 355:827, 2000 8. He G, Massarella J, Ward P: Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 37:471, 1999 9. Cass L, Efthymiopoulos C, Bye A: Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 36:1, 1999 10. Cooper N, Sutton A, Abrams K: Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta- analyses of randomized, controlled trials. Br Med J 326:1235, 2003 11. Whitley RJ, Hayden FG, Reisinger K: Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127, 2001 12. Hayden F, Belshe R, Villaneuva C: Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without post-exposure prophylaxis. J Infect Dis 189:440, 2004 13. Calfee DP, Peng AW, Cass LM: Protective efficacy of intravenous zanamivir in experimental human influenza A virus infection. Antimicrob Agents Chemother 43:1616, 1999 14. Hayden FG, Osterhaus AD, Treanor JUJ: Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GC 167 influenza Study Group. N Engl J Med 337:874, 1997 15. Hedrick J, Barzilai A, Behre U: Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized, controlled trial. Pediatr Infect Dis J 19:410, 2000
A
CASE REPORT Donor The donor was a 31-year-old Hispanic woman, who was admitted for donor nephrectomy to her sibling. Her past medical history was not significant. She had a previous surgical history of a laparoscopic cholecystectomy, abdominoplasty, and breast implantation. On the day of surgery, the donor reported no symptoms. Her physical examination was within normal limits with no abnormal findings. The surgical procedure was uneventful. Her immediate postoperative course was without any complaints; however, on postoperative day 1 she developed a temperature of 102.9°F with subsequent elevations throughout the day. She also complained of cough, chills, and nasal congestion. Fever evaluation consisted of blood tests, urinalysis, urine culture, and blood cultures. All laboratory tests were within normal limits. Given the symptoms, we sent a viral culture and rapid nasal swab test for influenza A/B, which was returned as positive for influenza A. As per our institution’s
protocol, her viral culture sent for testing to New York City Department of Health was confirmed to be the specific H1N1 strain. Treatment for influenza A was initiated with oseltamivir (75 mg twice daily) for 5 days. The patient became afebrile and was discharged home on postoperative day 2 to complete the 5-day course of oseltamivir treatment for influenza A. At follow-up on postoperative day 5, her symptoms had resolved and she was clinically well without any complications.
Recipient A 42-year-old Hispanic woman with history of end-stage renal disease related to polycystic kidney disease who had been on hemodialysis for 1 month was admitted to receive a living related renal transplant from her sister. The patient’s past medical history was significant for hypertension. Her surgical history included a hernia repair and three childbirths by Cesarean section. Her procedure was uneventful. In the operating room, she received induction therapy with methylprednisolone and anti-thymocyte globulin. Intravenous immunoglobulin (IVIG) was also given secondary to detection of a donor-specific antibody. During the perioperative period, we administered four doses of anti-thymocyte globulin and three doses of IVIG. For maintenance immunosuppressive therapy, she received tacrolimus, mycophenolate mofetil, and prednisone (20 mg daily). She displayed immediate graft function. Her immediate posttransplant course was complicated by From the Department of Pharmacy (K.M.) Montefiore Medical Center, Bronx; Department of Surgery (J.C.-F., A.L.), Abdominal Organ Transplant Program, Montefiore Medical Center; and Department of Nephrology (E.A.), Montefiore Medical Center, Bronx, New York, New York, USA. Address reprint requests to Dr Amy Lu, Montefiore Medical Center, 111 East 210th Street, Bronx, New York, NY 10467. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.09.052
Transplantation Proceedings, 41, 4411– 4413 (2009)
4411
4412
MARFO, CHAPOCHNICK-FRIEDMANN, AKALIN ET AL
close contact with her donor who had begun to exhibit a cough and fever on the first postoperative day. Given the recipient’s significant exposure to the donor and her immunosuppression, oseltamivir (75 mg once daily) was initiated for 5 days. The immunosuppressive therapy was not reduced. The remainder of her posttransplant course was uneventful; she was discharged on posttransplant day 4 with no fever and with continued excellent graft function. On posttransplant day 10, at a routine clinic visit, her serum creatinine had increased from a baseline of 0.8 to 1.3 mg/dL. She was admitted for a renal biopsy, which was significant for changes consistent with acute antibody-mediated rejection (Banff class II). She was treated with a 3-day course of methylprednisolone, a 5-day course of IVIG and plasmapheresis, and a single dose of rituximab. She responded to treatment and her serum creatinine at posttransplant day 30 decreased to 0.8 mg/dL. Throughout her course, she did not manifest any signs or symptoms of influenza-like illness: fever temperature greater than 100.4°F or 37.8°C, cough, fatigue, chills, diarrhea, sore throat, headache or body aches, and stuffy or runny nose.
DISCUSSION
While solid organ transplant recipients under immunosuppressive therapy may be at higher risk for H1N1 complications when exposed to close contacts, our report suggested a benefit of oseltamivir prophylaxis. Neither did our patient develop manifestations of a flulike illness or adverse effects from the 5-day course of oseltamivir. Currently available antiinfluenza agents include amantadine, rimantadine, oseltamivir, and zanamivir (Table 1). Amantadine and rimantidine are effective only for the prevention and treatment of influenza A virus infections.3 Most of the strains of H1N1 influenza A virus appear sensitive in vitro to neuraminidase inhibitors (oseltamivir and zanamivir), but all current H1N1 strains tested have been resistant to amantadine and rimantadine.4 – 6 This has led to a statement by the US Centers for Disease Control and Prevention that H1N1 is susceptible to the neuraminidase-inhibitor antiviral medications oseltamivir and zanamivir, which target the early phase of the influenza infection, but that this influenza strain is resistant to amantadine, rimantadine, and other adamantanes. Therapy with neuraminidase inhibitors is usually initiated in patients who are suspected to have or have been exposed to H1N1 even though there are no reported studies on the clinical benefits
of antiviral therapy either for treatment or prophylaxis against H1N1. Oseltamivir and zanamivir are potent selective inhibitors of influenza A and B virus neuraminidases, hence the therapeutic category neuraminidase inhibitors.7 They also have activity in inhibiting amantadine- and rimantadineresistant influenza A viruses. The major difference between the two agents is the route of administration. Oral oseltamivir has a bioavailability of 80% while the oral availability of zanamivir is ⬍5%, and the commercial form is delivered by (oral inhalation) of dry powder.8,9 Oral oseltamivir is effective in the treatment and prevention of influenza A and B virus infections, as opposed to amantadine and rimantadine, which have activity against influenza A only. Treatment of previously healthy adults with acute influenza at a dose of 75 mg twice daily for 5 days decreases the duration of illness by about 1 to 2 days, speeds functional recovery, and reduces the risk of complications leading to antibiotic use by 40% to 50%.10,11 Oseltamivir treatment should be started within 48 hours of the onset of flu symptoms. When used for prophylaxis during the influenza season at a dose of 75 mg once daily, oseltamivir is effective to decrease the likelihood of influenza illness in both non-immunized working adults and in immunized nursing home residents. Furthermore, short-term use for 7 to 10 days protects against influenza in household contacts.12 Besides these therapeutic benefits, unwanted adverse events such as nausea, abdominal discomfort, and, less often, emesis may occur with treatment. Such gastrointestinal complaints are usually mild to moderate in intensity, typically resolve in 1 to 2 days despite continuing therapy, and are preventable by administration with food. Zanamivir, however, must be administered topically, by inhalation, or parenterally (intravenously), to be effective13,14; only the inhaled product is commercially available. Inhaled zanamivir is also effective for the prevention and treatment of influenza A and B virus infections. Early zanamivir treatment at a dose of 10 mg twice daily for 5 days of febrile influenza in ambulatory adults shortens the time of illness resolution by 1 to 3 days and reduces the risk of lower respiratory tract complications leading to antibiotic use by 40%.10,15 For prophylaxis, once-daily inhaled zana-
Table 1. Therapeutic Characteristics of Antivirals for Influenza and Human Swine Flu H1N1
Spectrum of activity Route Bioavailability Half-life Dosing (prophylaxis) (mg/d) Dosing (treatment) (mg/d) Dose adjustments Common side effects
Amantadine
Rimantadine
Zanamivir
Oseltamivir
Influenza A Oral ⬎90% 12–18 200 200 Clcr ⱕ 50 Light-headedness Loss of appetite
Influenza A Oral ⬎90% 24–36 200 200 Clcr ⱕ 50 Light-headedness Loss of appetite
Influenza A, B, H1N1* Inhaled/intravenous† ⬍5% 2.5–5 10 20 None Wheezing Bronchospasm
Influenza A, B, H1N1* Oral ⬃80% 6–10 75 150 Clcr ⱕ 30 Nausea Abdominal discomfort
H1N1, human swine flu; Clcr, creatinine clearance. *Appear sensitive. † Not commercially available.
POSTEXPOSURE PROPHYLAXIS OF H1N1
mivir is highly protective against community-acquired influenza illness and when given for 10 days, it protects against household transmission. The main disadvantage of zanamivir administration is reported incidences of wheezing and bronchospam in patients without a history of airway disease. Acute deteriorations in lung function, including fatal outcomes, have occurred in patients with underlying airway diseases such as asthma and chronic obstructive airway disease. Zanamivir is not generally recommended for treatment of patients with underlying airway disease because of serious adverse events. Recently, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus. Although there are ongoing clinical studies to demonstrate the efficacy of these vaccines, the preliminary data from healthy adult volunteers has been promising. The vaccines are available as live, attenuated intranasal and inactivated injectable. Since annual influenza vaccination is the most effective method for preventing influenza virus and its complications, such may also be the benefit from the H1N1 vaccine. Transplant recipients and candidates should receive the annual trivalent inactivated influenza vaccine in addition to inactivated injectable H1N1 vaccine as per recommendations from the American Society of Transplantation guidance on novel influenza A/H1N1*. If a transplant recipient has already received vaccine pretransplant, there is no need to give a repeat dose posttransplant. However, in the immediate posttransplant period, it seems reasonable to delay influenza vaccination for weeks before the suspected start of the influenza season in patients receiving intense immunosuppressive therapy. This case illustrated that there is a potential that H1N1 transmission can occur from living donors to recipients even with the usual precautions. REFERENCES 1. World Health Organization: Pandemic (H1N1) 2009 — update 58, July 6, 2009. Available at: http://www.who.int/csr/don/ 2009_07_06/en/index.html. Accessed July 14, 2009
4413 2. US Centers for Disease Control and Prevention: Interim Guidance on Antiviral Recommendations for Patients with Novel Influenza A (H1N1) Virus Infection and Their Close Contacts. May 6, 2009. Available at: http://www.cdc.gov/h1n1flu/recommendations.htm. Accessed July 12, 2009 3. Hayden F, Aoki F: Amantadine, rimantadine, and related agents. In Yu V, Merigan T, White N, et al (eds): Antimicrobial Therapt and Vaccines. Williams Baltimore; Williams & Wilkins; 1999, p 1344 4. Garcia J, Sovero M, Torres Al, et al: Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markets. Influenza Other Respi Viruses 3:69, 2009 5. Rungrotmongkol T, Intharathep P, Malaisree M, et al: Susceptibility of antiviral drugs against 2009 influenza A (H1N1) virus. Biochem Biophys Res Commun 385:390, 2009 6. Laplante JM, Marshall SA, Shudt M, et al: Influenza antiviral resistance testing in New York and Wisconsin, 2006 to 2008: methodology and surveillance data. J Clin Microbiol 47:1372, 2009 7. Gubareva L, Hayden F, Kaiser L: Influenza virus neuraminidase inhibitors. Lancet 355:827, 2000 8. He G, Massarella J, Ward P: Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 37:471, 1999 9. Cass L, Efthymiopoulos C, Bye A: Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 36:1, 1999 10. Cooper N, Sutton A, Abrams K: Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta- analyses of randomized, controlled trials. Br Med J 326:1235, 2003 11. Whitley RJ, Hayden FG, Reisinger K: Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127, 2001 12. Hayden F, Belshe R, Villaneuva C: Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without post-exposure prophylaxis. J Infect Dis 189:440, 2004 13. Calfee DP, Peng AW, Cass LM: Protective efficacy of intravenous zanamivir in experimental human influenza A virus infection. Antimicrob Agents Chemother 43:1616, 1999 14. Hayden FG, Osterhaus AD, Treanor JUJ: Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GC 167 influenza Study Group. N Engl J Med 337:874, 1997 15. Hedrick J, Barzilai A, Behre U: Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized, controlled trial. Pediatr Infect Dis J 19:410, 2000