Perspective
Oseltamivir Resistance — Disabling Our Influenza Defenses
N Engl J Med 2005; 353:2633-2636December 22, 2005
- Article
Audio Interview
Interview with Dr. Anne Moscona on the clinical implications of oseltamivir resistance (7:03)
Animation
Mechanism of Resistance to Oseltamivir.
As the potential for an influenza pandemic has galvanized the medical community and the public into action, physicians and patients alike have been heartened by the availability of effective antiviral drugs. The neuraminidase inhibitors provide valuable defenses against pandemic and seasonal influenza, and physicians have been flooded with requests from patients for personal supplies of oseltamivir (Tamiflu). A benefit of having oseltamivir at home is that the sooner the drug is taken after the onset of symptoms, the better its clinical efficacy.1 And certainly, enabling ill people to stay home and out of waiting rooms and pharmacies should limit the spread of influenza. So it is not surprising that many believe there should be a supply of oseltamivir in every medicine cabinet. This scenario, however, is potentially dangerous. Misuse of the drug could rob us of the advantages that neuraminidase inhibitors provide, by favoring the emergence of oseltamivir-resistant influenza virus. The potentially serious consequences of oseltamivir resistance in patients with influenza A (H5N1) virus infections is alarmingly underscored by the report by de Jong and colleagues in this issue of the Journal (pages 2667–2672).
One strength of the neuraminidase inhibitors oseltamivir and zanamivir (Relenza) over the older adamantanes is that they are less prone to selecting for resistant influenza viruses.2 Indeed, no virus resistant to zanamivir, which is currently available only in an inhaled form, has yet been isolated from immunocompetent patients after treatment. The recent emergence of oseltamivir-resistant variants is therefore a matter of immediate concern.
Why is resistance developing to oseltamivir? Several years ago, structural analysis3 predicted that aspects of the chemical structure of oseltamivir (not present in zanamivir) could facilitate the development of resistance mutations that would permit neuraminidase to function, allowing drug-resistant virus to survive and propagate. This prediction is now being validated by clinical data.
The mechanism of the development of resistance is illustrated in the diagram
Mechanism of Resistance to Oseltamivir.. The influenza neuraminidase releases newly formed viruses from infected cells, allowing them to spread from cell to cell. The inhibitor molecules mimic the natural substrate of the influenza neuraminidase (the sialic acid receptors) and bind to the active site, preventing neuraminidase from cleaving host-cell receptors and releasing new virus. All the resistant variants thus far have contained specific mutations in the neuraminidase molecule; but since neuraminidase serves an essential purpose, mutations that allow the virus to survive must not inactivate the enzyme.To accommodate the bulky side chain of oseltamivir in the active site, the neuraminidase molecule must undergo rearrangement to create a pocket (Panel A). Zanamivir, by contrast, binds to the active site without any rearrangement of the molecule. Several mutations that limit the necessary molecular rearrangement may diminish the binding of oseltamivir (Panel B). Molecular-level analysis (Panel C) shows that the amino acid termed E276 must rotate and bond with R224 to form a pocket for the side chain of oseltamivir. The mutations R292K, N294S, and H274Y inhibit this rotation and prevent the pocket from forming, resulting in resistance to oseltamivir. The mutations nonetheless allow the binding of natural sialic acid substrate, so mutated virus can survive and propagate. In contrast, the binding of zanamivir does not require any reorientation of amino acids, so these mutated viruses remain sensitive to that drug. An E119V mutation also interferes only with oseltamivir binding, possibly because a water molecule can fit between oseltamivir and valine at the active site but cannot insinuate itself between zanamivir and valine at residue 119.
These mechanisms have clinical implications. The mutations identified in the resistant viruses have thus far all been in the amino acids mentioned above. A 2004 study in Japan found that 9 of 50 children with influenza A (H3N2) virus infection who had been treated with oseltamivir (18 percent) had a virus with a drug-resistance mutation in the neuraminidase gene (R292K, N294S, or E119V).1 A 2000–2001 Japanese study also revealed resistant influenza A (H1N1) viruses with the H274Y mutation in 7 of 43 oseltamivir-treated children (16 percent).4
The surprisingly high rate of emerging resistance in the Japanese studies may have been due to the use of insufficient doses of the drug and resultant failure to eradicate the virus. In both studies, the children were given 2 mg of oseltamivir per kilogram of body weight, and many were very young (75 percent were one to three years of age in the 2004 study, as were 43 percent of those in the 2000–2001 study). Of 147 children in a U.S. trial (including 26 younger than five years) who received the age- and weight-tailored (and therefore sometimes substantially higher) doses that have been approved outside of Japan, none shed resistant virus.1
It is therefore worrisome that personal stockpiling of oseltamivir is likely to lead to the use of insufficient doses or inadequate courses of therapy. Shortages during a pandemic would inspire sharing of personal supplies, resulting in inadequate treatment. Such undertreatment is of particular concern in children — the main source for the dissemination of influenza within the community, since they usually have higher viral loads than adults and excrete infectious virus for longer periods. The habit of stopping treatment prematurely when symptoms resolve (a well-established tendency with antibiotic therapy) could also lead to suboptimal treatment of influenza and promote the development of drug resistance.
Could drug-resistant viruses then spread? Although many oseltamivir-resistant (non-H5N1) viruses that have been studied in animals have compromised biologic fitness, some resistant variants have been transmitted among ferrets, arousing concern about transmissibility among humans.5 In fact, according to recent data collected in Japan by the Neuraminidase Inhibitor Susceptibility Network, 3 of 1200 isolates from ill patients without known exposure to neuraminidase inhibitors contained resistance mutations, suggesting that these resistant viruses are transmitted at least at a low level in humans and are not severely biologically compromised.
There have now been several reports that oseltamivir-resistant influenza A (H5N1) viruses with the H274Y mutation have been isolated from humans with avian influenza infection who were treated with oseltamivir.4 The cases described by de Jong et al. raise the worrisome prospect that even with therapeutic doses, oseltamivir resistance may develop during the course of illness and may affect clinical outcomes. Nothing is yet known about the transmissibility of oseltamivir-resistant influenza A (H5N1) viruses in humans, and it will be important to study these isolates in animals to determine how the H274Y mutation affects virulence, pathogenicity, and transmissibility.
There is much to be learned about the clinical and virologic course of H5N1 infection in humans, as well as the response to therapy and the development of resistance. We know that the virus may have a longer incubation period than other influenza viruses, potentially increasing the period of transmissibility before symptoms appear, and that the virus frequently leads to fulminant lower respiratory tract infection.4 Interventions of any kind have failed when initiated late in the course of illness, but early therapy with neuraminidase inhibitors is probably beneficial; the cases reported by de Jong et al. suggest that even therapy initiated later in the illness may limit ongoing viral replication. H5N1 virus infections may require higher doses of oseltamivir for longer periods than do other types of influenza.5 Indeed, it is becoming clear that more medication than the currently recommended doses may be required for adequate treatment. If so, treatment with the current doses could not only fail but also select for resistant influenza A (H5N1) viruses.
Like any successful infectious agent, influenza virus will most likely evolve to evade any single drug. By targeting several points in the viral life cycle simultaneously with different drugs, we are more likely to discourage the emergence of viruses that can resist all drugs at once. But we currently rely solely on the neuraminidase inhibitors — and solely on oseltamivir in many situations, such as in patients who cannot use inhaled medication or in patients infected with H5N1 virus, in whom systemic drug levels may be important. We must not abrogate the usefulness of these drugs by exposing circulating influenza to them in such a way as to facilitate the selection of resistant viruses. The study by de Jong et al. confirms that oseltamivir-resistant H5N1 virus is now a reality. The need to learn more about how and when resistance to the neuraminidase inhibitors develops, while we focus on the development of new antiviral drugs, is pressing. This frightening report should inspire us to devise pandemic strategies that do not favor the development of oseltamivir-resistant strains. Improper use of personal stockpiles of oseltamivir may promote resistance, thereby lessening the usefulness of our frontline defense against influenza, and should be strongly discouraged.
An interview with Dr. Moscona can be heard at www.nejm.org.
Source Information
Dr. Moscona is a professor in the Departments of Pediatrics and Microbiology and Immunology at Weill Medical College of Cornell University, New York.
- References
References
1
Moscona A . Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363-1373
Full Text | Web of Science | Medline2
Bright RA ,Medina MJ ,Xu X , et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005;366:1175-1181
CrossRef | Web of Science | Medline3
Varghese JN ,Smith PW ,Sollis SL , et al. Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure 1998;6:735-746
CrossRef | Web of Science | Medline4
The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5
Full Text | Web of Science | Medline5
McKimm-Breschkin JL . Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance. Treat Respir Med 2005;4:107-116
CrossRef | Medline
- Citing Articles (66)
Citing Articles
1
Georgiana Surpateanu, Jean-François Soulé, Jean-Marie Beau, Stéphanie Norsikian, Bogdan I. Iorga. (2012) Conformational Study of Glycal-Type Neuraminidase Inhibitors. Journal of Carbohydrate Chemistry 31:2, 114-129
CrossRef2
Sergey A. Tarasov, Vladimir V. Zarubaev, Evgeniy A. Gorbunov, Svetlana A. Sergeeva, Oleg I. Epstein. (2011) Activity of ultra-low doses of antibodies to gamma-interferon against lethal influenza A(H1N1)2009 virus infection in mice. Antiviral Research
CrossRef3
O.P. Zhirnov, H.D. Klenk, P.F. Wright. (2011) Aprotinin and similar protease inhibitors as drugs against influenza. Antiviral Research 92:1, 27-36
CrossRef4
Ross Vlahos, John Stambas, Stavros Selemidis. (2011) Suppressing production of reactive oxygen species (ROS) for influenza A virus therapy. Trends in Pharmacological Sciences
CrossRef5
S. W. Gerritz, C. Cianci, S. Kim, B. C. Pearce, C. Deminie, L. Discotto, B. McAuliffe, B. F. Minassian, S. Shi, S. Zhu, W. Zhai, A. Pendri, G. Li, M. A. Poss, S. Edavettal, P. A. McDonnell, H. A. Lewis, K. Maskos, M. Mortl, R. Kiefersauer, S. Steinbacher, E. T. Baldwin, W. Metzler, J. Bryson, M. D. Healy, T. Philip, M. Zoeckler, R. Schartman, M. Sinz, V. H. Leyva-Grado, H.-H. Hoffmann, D. R. Langley, N. A. Meanwell, M. Krystal. (2011) Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers. Proceedings of the National Academy of Sciences 108:37, 15366-15371
CrossRef6
Yogesh Chander, Naresh Jindal, Srinand Sreevatsan, Sagar M. Goyal. (2011) Sequence analysis of the neuraminidase genes of avian influenza A viruses isolated from live bird markets in the United States. Virus Genes 43:1, 60-65
CrossRef7
C. Uhlenhaut, J.I. Cohen, S. Pavletic, G. Illei, J.C. Gea-Banacloche, M. Abu-Asab, T. Krogmann, L. Gubareva, S. McClenahan, P.R. Krause. (2011) Use of a novel virus detection assay to identify coronavirus HKU1 in the lungs of a hematopoietic stem cell transplant recipient with fatal pneumonia. Transplant Infectious Diseaseno-no
CrossRef8
Qi-Shi Du, Hang Wei, Ri-Bo Huang, Kuo-Chen Chou. (2011) Progress in structure-based drug design against influenza A virus. Expert Opinion on Drug Discovery 6:6, 619-631
CrossRef9
Willard Lew, Michael Z. Wang, Xiaowu Chen, James F. Rooney, Choung Kim. 2011. Neuraminidase Inhibitors as Anti-Influenza Agents. , 351-376.
CrossRef10
Alisha K. Weight, Jayanta Haldar, Luis Álvarez de Cienfuegos, Larisa V. Gubareva, Terrence M. Tumpey, Jianzhu Chen, Alexander M. Klibanov. (2011) Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus. Journal of Pharmaceutical Sciences 100:3, 831-835
CrossRef11
Mao Shu, Zhihua Lin, Yunru Zhang, Yuqian Wu, Hu Mei, Yongjun Jiang. (2011) Molecular dynamics simulation of oseltamivir resistance in neuraminidase of avian influenza H5N1 virus. Journal of Molecular Modeling 17:3, 587-592
CrossRef12
E. Ghedin, J. Laplante, J. DePasse, D. E. Wentworth, R. P. Santos, M. L. Lepow, J. Porter, K. Stellrecht, X. Lin, D. Operario, S. Griesemer, A. Fitch, R. A. Halpin, T. B. Stockwell, D. J. Spiro, E. C. Holmes, K. S. George. (2011) Deep Sequencing Reveals Mixed Infection with 2009 Pandemic Influenza A (H1N1) Virus Strains and the Emergence of Oseltamivir Resistance. Journal of Infectious Diseases 203:2, 168-174
CrossRef13
Donna M. Tscherne, Adolfo García-Sastre. (2011) Virulence determinants of pandemic influenza viruses. Journal of Clinical Investigation 121:1, 6-13
CrossRef14
Ambarnil Ghosh, Ashesh Nandy. 2011. Graphical representation and mathematical characterization of protein sequences and applications to viral proteins. , 1-42.
CrossRef15
G. B. Triana-Baltzer, R. L. Sanders, M. Hedlund, K. A. Jensen, L. M. Aschenbrenner, J. L. Larson, F. Fang. (2011) Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181. Journal of Antimicrobial Chemotherapy 66:1, 15-28
CrossRef16
C. Renaud, J. Kuypers, L. Corey. (2010) Diagnostic accuracy of an allele-specific reverse transcriptase-PCR assay targeting the H275Y oseltamivir resistant mutation in 2009 pandemic influenza A/H1N1 virus. Journal of Clinical Virology 49:1, 21-25
CrossRef17
R. B. Moss, R. T. Davey, R. T. Steigbigel, F. Fang. (2010) Targeting pandemic influenza: a primer on influenza antivirals and drug resistance. Journal of Antimicrobial Chemotherapy 65:6, 1086-1093
CrossRef18
Kalyan Das, James M Aramini, Li-Chung Ma, Robert M Krug, Eddy Arnold. (2010) Structures of influenza A proteins and insights into antiviral drug targets. Nature Structural & Molecular Biology 17:5, 530-538
CrossRef19
Neetu Singh, Aseem Pandey, Suresh K. Mittal. (2010) Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target. Expert Reviews in Molecular Medicine 12,
CrossRef20
Adam Gordon, Victoria Ewan. (2010) Pneumonia and influenza – specific considerations in care homes. Reviews in Clinical Gerontology 20:01, 69
CrossRef21
Margaret Okomo-Adhiambo, Ha T. Nguyen, Katrina Sleeman, Tiffany G. Sheu, Varough M. Deyde, Rebecca J. Garten, Xiyan Xu, Michael W. Shaw, Alexander I. Klimov, Larisa V. Gubareva. (2010) Host cell selection of influenza neuraminidase variants: Implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Research 85:2, 381-388
CrossRef22
Kh. Dhanachandra Singh, Karthikeyan Muthusamy. (2009) In silico genome analysis and drug efficacy test of influenza A virus (H1N1) 2009. Indian Journal of Microbiology 49:4, 358-364
CrossRef23
Mehran Haidari, Muzammil Ali, Samuel Ward Casscells, Mohammad Madjid. (2009) Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir. Phytomedicine 16:12, 1127-1136
CrossRef24
Thanyada Rungrotmongkol, Thanyarat Udommaneethanakit, Maturos Malaisree, Nadtanet Nunthaboot, Pathumwadee Intharathep, Pornthep Sompornpisut, Supot Hannongbua. (2009) How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?. Biophysical Chemistry 145:1, 29-36
CrossRef25
James Fung. (2009) Current challenges in viral hepatitis, antimicrobial resistance and the influenza pandemic. Expert Review of Anti-infective Therapy 7:8, 945-949
CrossRef26
Maturos Malaisree, Thanyada Rungrotmongkol, Nadtanet Nunthaboot, Ornjira Aruksakunwong, Pathumwadee Intharathep, Panita Decha, Pornthep Sompornpisut, Supot Hannongbua. (2009) Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation. Amino Acids 37:4, 725-732
CrossRef27
Charlotte D'Souza, Meena Kanyalkar, Mamata Joshi, Evans Coutinho, Sudha Srivastava. (2009) Search for novel neuraminidase inhibitors: Design, synthesis and interaction of oseltamivir derivatives with model membrane using docking, NMR and DSC methods. Biochimica et Biophysica Acta (BBA) - Biomembranes 1788:9, 1740-1751
CrossRef28
N. Dogan, B. Ozkan, I. Boga, M. Kizilkaya, H. Altindag. (2009) A Succesful Treatment of Avian Influenza Infection in Turkey. Journal of Tropical Pediatrics 55:4, 268-271
CrossRef29
Marguerite Pappaioanou. (2009) Highly pathogenic H5N1 avian influenza virus: Cause of the next pandemic?. Comparative Immunology, Microbiology and Infectious Diseases 32:4, 287-300
CrossRef30
Murray E. Alexander, Sarah M. Dietrich, Yi Hua, Seyed M. Moghadas. (2009) A comparative evaluation of modelling strategies for the effect of treatment and host interactions on the spread of drug resistance. Journal of Theoretical Biology 259:2, 253-263
CrossRef31
C. Fraser, C. A. Donnelly, S. Cauchemez, W. P. Hanage, M. D. Van Kerkhove, T. D. Hollingsworth, J. Griffin, R. F. Baggaley, H. E. Jenkins, E. J. Lyons, T. Jombart, W. R. Hinsley, N. C. Grassly, F. Balloux, A. C. Ghani, N. M. Ferguson, A. Rambaut, O. G. Pybus, H. Lopez-Gatell, C. M. Alpuche-Aranda, I. B. Chapela, E. P. Zavala, D. Ma. E. Guevara, F. Checchi, E. Garcia, S. Hugonnet, C. Roth, . (2009) Pandemic Potential of a Strain of Influenza A (H1N1): Early Findings. Science 324:5934, 1557-1561
CrossRef32
Michel Weïwer, Chi-Chang Chen, Melissa M. Kemp, Robert J. Linhardt. (2009) Synthesis and Biological Evaluation of Non-Hydrolyzable 1,2,3-Triazole-Linked Sialic Acid Derivatives as Neuraminidase Inhibitors. European Journal of Organic Chemistry 2009:16, 2611-2620
CrossRef33
Marcel Verweij. (2009) Moral Principles for Allocating Scarce Medical Resources in an Influenza Pandemic. Journal of Bioethical Inquiry 6:2, 159-169
CrossRef34
S. Bolotin, A.V. Robertson, A. Eshaghi, C. De Lima, E. Lombos, E. Chong-King, L. Burton, T. Mazzulli, S.J. Drews. (2009) Development of a novel real-time reverse-transcriptase PCR method for the detection of H275Y positive influenza A H1N1 isolates. Journal of Virological Methods 158:1-2, 190-194
CrossRef35
Lizheng Guo, Rebecca J. Garten, Angie S. Foust, Wendy M. Sessions, Margaret Okomo-Adhiambo, Larisa V. Gubareva, Alexander I. Klimov, Xiyan Xu. (2009) Rapid identification of oseltamivir-resistant influenza A(H1N1) viruses with H274Y mutation by RT-PCR/restriction fragment length polymorphism assay. Antiviral Research 82:1, 29-33
CrossRef36
Thanyada Rungrotmongkol, Vladimir Frecer, Wanchai De-Eknamkul, Supot Hannongbua, Stanislav Miertus. (2009) Design of oseltamivir analogs inhibiting neuraminidase of avian influenza virus H5N1. Antiviral Research 82:1, 51-58
CrossRef37
Anja Leppin, Arja R. Aro. (2009) Risk Perceptions Related to SARS and Avian Influenza: Theoretical Foundations of Current Empirical Research. International Journal of Behavioral Medicine 16:1, 7-29
CrossRef38
S. Yongkiettrakul, K. Boonyapakron, A. Jongkaewwattana, A. Wanitchang, U. Leartsakulpanich, P. Chitnumsub, L. Eurwilaichitr, Y. Yuthavong. (2009) Avian influenza A/H5N1 neuraminidase expressed in yeast with a functional head domain. Journal of Virological Methods 156:1-2, 44-51
CrossRef39
Maturos Malaisree, Thanyada Rungrotmongkol, Panita Decha, Pathumwadee Intharathep, Ornjira Aruksakunwong, Supot Hannongbua. (2008) Understanding of known drug-target interactions in the catalytic pocket of neuraminidase subtype N1. Proteins: Structure, Function, and Bioinformatics 71:4, 1908-1918
CrossRef40
S. M Moghadas. (2008) Management of drug resistance in the population: influenza as a case study. Proceedings of the Royal Society B: Biological Sciences 275:1639, 1163-1169
CrossRef41
John Beigel, Mike Bray. (2008) Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Research 78:1, 91-102
CrossRef42
Anne Moscona. (2008) Medical Management of Influenza Infection. Annual Review of Medicine 59:1, 397-413
CrossRef43
Olivier Ferraris, Bruno Lina. (2008) Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. Journal of Clinical Virology 41:1, 13-19
CrossRef44
PD Griffiths. (2008) Whatever happened to bird flu?. Reviews in Medical Virology 18:1, 1-3
CrossRef45
Jessica A. Belser, Xiuhua Lu, Kristy J. Szretter, Xiaoping Jin, Laura M. Aschenbrenner, Alice Lee, Stephen Hawley, Do Hyong Kim, Michael P. Malakhov, Mang Yu, Fang Fang, Jacqueline M. Katz. (2007) DAS181, A Novel Sialidase Fusion Protein, Protects Mice from Lethal Avian Influenza H5N1 Virus Infection. The Journal of Infectious Diseases 196:10, 1493-1499
CrossRef46
Robert C. Moellering, John R. Graybill, John E. McGowan, Lawrence Corey. (2007) Antimicrobial resistance prevention initiative—an update: Proceedings of an expert panel on resistance. American Journal of Infection Control 35:9, S1-S23
CrossRef47
F. Debarre, S. Bonhoeffer, R. R Regoes. (2007) The effect of population structure on the emergence of drug resistance during influenza pandemics. Journal of The Royal Society Interface 4:16, 893-906
CrossRef48
Xiao Y Chen, Taixiang Wu, Guan J Liu, Qin Wang, Jie Zheng, Jiafu Wei, Juan Ni, Likun Zhou, Xin Duan, Jieqi Qiao, Xiao Y Chen. 2007. Chinese medicinal herbs for influenza. .
CrossRef49
Richard J Whitley. (2007) The role of oseltamivir in the treatment and prevention of influenza in children. Expert Opinion on Drug Metabolism & Toxicology 3:5, 755-767
CrossRef50
Phillip Andrew Reece. (2007) Neuraminidase inhibitor resistance in influenza viruses. Journal of Medical Virology 79:10, 1577-1586
CrossRef51
Yaji Xu, Linda J.S. Allen, Alan S. Perelson. (2007) Stochastic model of an influenza epidemic with drug resistance. Journal of Theoretical Biology 248:1, 179-193
CrossRef52
Craig LaForce, Choy Y. Man, Frederick W. Henderson, Janet E. McElhaney, Frank C. Hampel, Robert Bettis, Laila Kudule, Julia Harris, Philip Yates, Margaret Tisdale, Alison Webster. (2007) Efficacy and Safety of Inhaled Zanamivir in the Prevention of Influenza in Community-Dwelling, High-Risk Adult and Adolescent Subjects: A 28-day, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Clinical Therapeutics 29:8, 1579-1590
CrossRef53
M. E Alexander, C. S Bowman, Z. Feng, M. Gardam, S. M Moghadas, G. Rost, J. Wu, P. Yan. (2007) Emergence of drug resistance: implications for antiviral control of pandemic influenza. Proceedings of the Royal Society B: Biological Sciences 274:1619, 1675-1684
CrossRef54
Robert C. Moellering, John R. Graybill, John E. McGowan, Lawrence Corey. (2007) Antimicrobial Resistance Prevention Initiative—An Update: Proceedings of an Expert Panel on Resistance. The American Journal of Medicine 120:7, S4-S25
CrossRef55
Paul J. Drinka, Tom Haupt. (2007) Emergence of Rimantadine-Resistant Virus Within 6 Days of Starting Rimantadine Prophylaxis with Oseltamivir Treatment of Symptomatic Cases. Journal of the American Geriatrics Society 55:6, 923-926
CrossRef56
Yaseen Arabi, Charles D. Gomersall, Qanta A. Ahmed, Bruce R. Boynton, Ziad A. Memish. (2007) The critically ill avian influenza A (H5N1) patient*. Critical Care Medicine 35:5, 1397-1403
CrossRef57
R. F. Chemaly, H. A. Torres, E. A. Aguilera, G. Mattiuzzi, M. Cabanillas, H. Kantarjian, V. Gonzalez, A. Safdar, I. I. Raad. (2007) Neuraminidase Inhibitors Improve Outcome of Patients with Leukemia and Influenza: An Observational Study. Clinical Infectious Diseases 44:7, 964-967
CrossRef58
Salin Chutinimitkul, Kamol Suwannakarn, Thaweesak Chieochansin, Le Quynh Mai, Sudarat Damrongwatanapokin, Arunee Chaisingh, Alongkorn Amonsin, Olfert Landt, Thaweesak Songserm, Apiradee Theamboonlers, Yong Poovorawan. (2007) H5N1 Oseltamivir-resistance detection by real-time PCR using two high sensitivity labeled TaqMan probes. Journal of Virological Methods 139:1, 44-49
CrossRef59
Jeanine P. Wiener-Kronish. (2007) Infection Control for the Anesthesiologist. ASA Refresher Courses in Anesthesiology 35:1, 219-225
CrossRef60
John R. Wingard. (2007) Facing the Next Pandemic: Ready or Not. Biology of Blood and Marrow Transplantation 13, 107-109
CrossRef61
Karen M. Bromfield, Henrik Gradén, Daniel P. Hagberg, Thomas Olsson, Nina Kann. (2007) An iron carbonyl approach to the influenza neuraminidase inhibitor oseltamivir. Chemical Communications:30, 3183
CrossRef62
Mark R. Looney. (2006) Newly Recognized Causes of Acute Lung Injury: Transfusion of Blood Products, Severe Acute Respiratory Syndrome, and Avian Influenza. Clinics in Chest Medicine 27:4, 591-600
CrossRef63
Adnan Mushtaq, Mohamed El-Azizi, Nancy Khardori. (2006) Category C Potential Bioterrorism Agents and Emerging Pathogens. Infectious Disease Clinics of North America 20:2, 423-441
CrossRef64
P. L. L. Bruijnzeel. (2006) Oseltamivir-resistentie gedurende behandeling van influenza (H5N1) infectie. MFM 44:4, 114-115
CrossRef65
(2006) Oseltamivir Resistance in Influenza A (H5N1) Infection. New England Journal of Medicine 354:13, 1423-1424
Full Text66
Stephen M Ford, John D Grabenstein. (2006) Pandemics, Avian Influenza A (H5N1), and a Strategy for Pharmacists. Pharmacotherapy 26:3, 312-322
CrossRef
