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Antiviral Prescriptions to U.S. Ambulatory Care Visitswith a Diagnosis of Influenza before and after High Levelof Adamantane Resistance 2005–06 Season Yu-Hsiang Hsieh1*, Kuan-Fu Chen1,3, Charlotte A. Gaydos2, Richard E. Rothman1,2, Gabor D. Kelen1 1 Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 3 Department of Emergency Medicine, Chang Gung Memorial Hospital, Taipei, Background: Rapid emergence of influenza A viruses resistance to anti-influenza drugs has been observed in the past fiveyears. Our objective was to compare antiviral prescription patterns of ambulatory care providers to patients with a diagnosisof influenza before and after the 2005–2006 influenza season, which was temporally concordant with the emergence ofadamantane resistance. We also determined providers’ adherence to Centers for Disease Control and Prevention (CDC) 2006interim treatment guidelines for influenza after the dissemination of guidelines.
Methodology/Principal Findings: We conducted a multi-year cross-sectional analysis using 2002–2006 data from thenational representative ambulatory care surveys, National Ambulatory Medical Care Survey and National HospitalAmbulatory Medical Care Survey. Our main outcome measure was prescription of any anti-influenza pharmaceuticalmedication, including amantadine, rimantadine, oseltamivir, and zanamivir. Analyses were performed using procedurestaking into account the multi-stage survey design and weighted sampling probabilities of the data source. Overall, therewere 941 visits to U.S. ambulatory care providers for which the diagnosis of influenza was made, representing 12,140,727visits nationally. Antiviral drugs were prescribed in 21.7% of visits. Even though prescription rates were not significantlydifferent by influenza season (2001–02: 26.4%; 2002–03: 11.2%; 2003–04: 16.5%; 2004–05: 18.0%; 2005–06: 35.8%; 2006–07:46.5%, p = 0.061), significantly higher prescription rates were observed in the high adamantane resistance period (18.7%versus 37.0%, p = 0.023), and after the announcement of the 2006 guidelines (18.5% versus 38.8%, p = 0.032). Use ofadamantanes decreased over time, in that they were commonly used during influenza seasons 2001–03 (60.1%), but usedmuch less frequently during seasons 2003–05 (31.9%), and used rarely after high adamantane resistance emerged (2.2%)(p,0.001). Adherence to 2006 guidelines was 97.7%. After March 2006, no prescriptions for adamantanes were given topatients with a diagnosis of influenza.
Conclusions/Significance: In this nationally representative study of U.S. ambulatory care visits, we found a completeabsence of the use of adamantanes in all ambulatory care settings after March 2006, closely corresponding to release of the2006 CDC interim guidelines. Adherence to such practice is an essential element for control and prevention of influenza,especially during the era of emergence of resistance to anti-viral drugs.
Citation: Hsieh Y-H, Chen K-F, Gaydos CA, Rothman RE, Kelen GD (2010) Antiviral Prescriptions to U.S. Ambulatory Care Visits with a Diagnosis of Influenza beforeand after High Level of Adamantane Resistance 2005–06 Season. PLoS ONE 5(1): e8945. doi:10.1371/journal.pone.0008945 Editor: Joseph S. Ross, Mount Sinai School of Medicine, United States of America Received November 1, 2009; Accepted January 12, 2010; Published January 28, 2010 Copyright: ß 2010 Hsieh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Dr. Hsieh, Dr. Gaydos, Dr. Rothman and Dr. Kelen are supported in part by a grant from the United States Department of Homeland Security (GrantNumber N00014-D6-1-0991). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
influenza drugs, the adamantanes (amantadine and rimantadine)emerged in the United States, with resistance rates increasing from Each year, Americans make more than 20 million clinic visits 14.5% during the 2004–2005 influenza season, to 92.3% during per year for influenza. Of these, only 19% of visits receive antiviral the 2005–2006 season [3]. In response, the US Centers for Disease prescription from their medical providers [1]. This low rate of Control and Prevention (CDC) recommended that adamantanes antiviral treatment observed in practice may hamper public health should not be used for treatment or prophylaxis of influenza on efforts to minimize mortality, shorten the course of disease, and January 14, 2006 in the interim treatment guidelines [4]. Since decrease transmission in the communities for the current novel that time, after only 3 influenza seasons, rates of oseltamivir- influenza A (H1N1) [2] or future pandemics.
resistant to seasonal influenza A virus (H1N1) stains have risen Rapid emergence of influenza A viruses resistance to anti- from 12% to nearly 99% [5]. Accordingly, the CDC now influenza drugs has been observed in the past five years. First, recommends that when influenza A (H1N1) virus infection or resistance of seasonal influenza A viruses to once first-line anti- exposure is suspected, zanamivir or a combination of oseltamivir January 2010 | Volume 5 | Issue 1 | e8945 and rimantadine are more appropriate options than oseltamivir codes of 487, 487.0, 487.1 or 487.8. All visits with a diagnosis of alone [6]. Only a few months later in the early summer of 2009, influenza during the study period were included for analysis. Six the first influenza pandemic in more than 40 years has arrived [2].
(in 2002) or eight (2003–2006) medications that were ordered or The CDC recommends use of oseltamivir or zanamivir for the first provided were collected and coded in the data set. Our main line treatment and/or prevention of infections since the circulating outcome measure was prescription of any anti-influenza pharma- strain is resistant to the adamantanes [7]. Few cases of oseltamivir- ceutical medication, including amantadine, rimantadine, oselta- resistance strains of novel influenza A (H1N1) have been mivir, and zanamivir. A visit with a prescription of anti-influenza drug by providers was defined as medications matching for Timely and effective dissemination of these interim treatment NAMCS and NHAMCS drug entry codes for amantadine guidelines for influenza from CDC to medical providers is crucial (Symmetrel), rimantadine (Flumadine), oseltamivir (Tamiflu), and to prescribe appropriate antivirals for patients with confirmed or suspected influenza. In the past decade, CDC has disseminated NAMCS and NHAMCS data from the years 2002–2006 were treatment information (which could be a CDC Health Advisory, merged for data analysis. A sample weight that considers selection Health Alert, or Health Update) via CDC Health Alert Network probability, nonresponse adjustment, and ratio adjustment for (HAN) to state and local health officers, public information different total sample size each year is assigned for each patient officers, epidemiologists, state laboratory directors, weapons of visit to generate unbiased national estimates of ambulatory mass destruction coordinators, HAN coordinators, as well as medical care visits. Although the sampling fraction is relatively public health associations and clinician organizations [9]. Few, if small, the weighted numbers calculated by the method suggested any studies, have examined U.S. medical providers’ antiviral drug by the CDC represent unbiased national estimates of the US prescription usage patterns and trends for patients with a diagnosis ambulatory medical care population. Study period was catego- of influenza, before and after the emergence of drug resistance.
rized into 6 influenza seasons beginning October 1 to the end of Notably, studies have been conducted evaluating provider September of the following year. In addition, study periods were adherence with CDC treatment guidelines for other infectious further categorized into (1) pre-high adamantane resistance period diseases, with rates varying significantly across syndromes, i.e. 30% versus high adamantane resistance period, based on the time when for pelvic inflammatory disease [10] and upper respiratory adamantane resistance rates reached over 90% [3], i.e. October infections [11], 50%–85% for acute epididymitis [12], and over 2005, or (2) before versus after the announcement of the 2006 interim treatment guidelines, based on the time of release of the Utilizing the national representative ambulatory medical care 2006 CDC interim treatment guidelines [4], i.e. January 14, 2006.
surveys National Ambulatory Medical Care Survey (NAMCS) and Adherence to the 2006 CDC interim treatment guidelines was defined as no adamantane prescribed to patients with a diagnosis (NHAMCS) [14] by National Center for Health Statistics, CDC, of influenza, following the announcement of the treatment we compared antiviral prescription patterns of ambulatory medical care providers for patient visits with a diagnosis of Descriptive demographic analyses of patient visits with a influenza before and after the 2005–2006 influenza season, which diagnosis of influenza, and patient visits with antiviral medications was temporally concordant with the emergence of adamantane for influenza, were performed. Comparison of proportions, e.g.
resistance. We also determined medical provider’s adherence to prescription rate in pre-high adamantane resistance period versus CDC 2006 interim treatment guidelines for influenza after the that in high adamantane resistance period, was assessed by chi- dissemination of the CDC guidelines.
square test. All p values were 2-sided, with p,0.05 consideredsignificant. Multivariate analyses and estimation of 95% CI were not conducted if the sample size of interest was less than 30, as theestimate is considered unreliable under NAMCS and NHAMCS We conducted a multi-year cross-sectional analysis using 2002– analysis recommendations [17]. Analyses were performed using 2006 data from three national representative ambulatory medical SAS 9.1 SURVEYFREQ procedure which takes into account the care surveys. The data from these three surveys include weighted multi-stage survey design and weighted sampling probabilities of samples of U.S. patient visits to non-federally employed office- the data source (SAS version 9.1, SAS Institute Inc., Cary, North based physicians from the NAMCS, U.S. emergency department Carolina). Results were reported as weighted frequencies, (ED) visits from the ED component of the NHAMCS, and U.S.
percentages, and 95% confidence intervals (CI).
hospital outpatient visits, from the outpatient component ofNHAMCS. NAMCS and NHAMCS data were collected by a standard survey form collected by physicians, office workers, orhospital staff. The multi-stage probability sampling scheme, the Overall, during 2002–2006, there were 941 visits to U.S.
visit, and the reliability of coding and data entry for NAMCS and ambulatory care providers for which the diagnosis of influenza was NHAMCS have been detailed elsewhere [15]. The NAMCS and NHAMCS data are publicly accessible and deidentified. Accord- 10,116,136–14,165,318) patient visits nationally, or 0.22% (95% ingly, the Johns Hopkins University Medicine institutional review CI: 0.18–0.25) of all visits over this time. Demographics, type of board (IRB) deemed our study as nonhuman-subjects research, ambulatory care, and influenza season in which patient visits resulted in a diagnosis of influenza were summarized in Table 1.
In this study, we employed the data collected by the NAMCS Office-based physician visits represented the highest volume and NHAMCS, including demographic characteristics, diagnoses, (9,459,918 visits, 77.9%), followed by ED visits (1,872,200 visits, and medications of the patient visits. Up to three diagnoses were 15.4%) and outpatient visits (808,609 visits, 6.7%). Among visits recorded as free text and coded centrally by Constella Group, Inc.
with a diagnosis of influenza, those which occurred during periods and subject to quality control procedures [16]. A visit with a of high adamantane resistance, and after the announcement of diagnosis of influenza was defined as International Classification of 2006 CDC interim treatment guidelines accounted for 18.7% and Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) January 2010 | Volume 5 | Issue 1 | e8945 Table 1. National estimates of ambulatory medical care visits with a diagnosis of influenza and the antiviral prescription bydemographics in the United States, 2002–2006.
*Ethnicity missing for 4.7% of sample.
{MSA: Metropolitan Statistical Area.
{NA: Not applicable due to the sample size of interest in the surveys was less than 30, as the estimate is considered unreliable under NAMCS and NHAMCS analysis Antiviral drugs against influenza were prescribed in 21.7% differences in prescription rates by demographic variables of visits (weighted 2,629,129 visits; 95% CI: 1,886,292–3, except by the U.S. region. Even though, prescription rates 371,966). Prescription rates by each demographic character- were not significantly different by influenza season, signifi- istic and type of ambulatory care were summarized in Table 1.
cantly higher antiviral drug prescription rates were observed in Although EDs had the highest prescription rate, (29.0%), there the high adamantane resistance period, and after the was no statistical difference observed by type of ambulatory announcement of the 2006 CDC interim treatment guidelines care setting (p.0.05). In addition, there were no statistical January 2010 | Volume 5 | Issue 1 | e8945 Table 2. National estimates of ambulatory medical care visits with a diagnosis of influenza and the antiviral prescription byinfluenza season, high adamantane resistance period, and announcement of 2006 CDC guidelines in the United States, 2002–2006.
*NA: Not applicable due to the sample size of interest in the surveys was less than 30, as the estimate is considered unreliable under NAMCS and NHAMCS analysis Numbers of antiviral prescriptions for influenza in U.S.
increased over time, becoming the predominant anti-influenza ambulatory care visits resulting in a diagnosis of influenza were prescription in all three ambulatory care settings during the high summarized in Table 3. Use of adamantanes decreased over time, adamantane resistance period, i.e. after October 2005 (97.8%; in that they were commonly used during influenza seasons 2001– 95% CI: 93.9–100%). There were no statistical differences in anti- 02 and 2002–03 (60.1%), but were used much less frequently influenza prescriptions by type of ambulatory care or by other during seasons 2003–04 and 2004–05 (31.9%), and were used demographic variables, before or during high adamantane rarely after high adamantane resistance emerged (2.2%) (p,0.001) resistance period (data not shown). Therefore, a multivariate (Figure 1). In contrast, oseltamivir accounted for only 36% of total analysis was not performed on use of adamantanes or oseltamivir antiviral prescription during the influenza season 2001–02, but Table 3. Numbers of antiviral prescription for influenza in U.S. ambulatory care visits with a diagnosis of influenza during 2002–2006.
*Zanamivir was prescribed, therefore, percentages of prescription in these horizontal rows were not added up to 100%.
{P-value cannot be computed for all influenza seasons because at least one table cell has 0 frequency (season 2006–07). P-value was calculated based on the comparison of influenza season 2001–02 to season 2005–06.
January 2010 | Volume 5 | Issue 1 | e8945 Figure 1. Prescription of anti-influenza agents for patient visits with a diagnosis of influenza in US ambulatory care includingemergency department visits, outpatient visits and physician office visits, by antiviral drug, influenza season 2001–2007. a The timeCDC declared interim guidelines for use of anti-influenza drugs. b The start of high adamantane resistance period. c Adamantanes include amantadineand rimantadine.
doi:10.1371/journal.pone.0008945.g001 Overall, adherence with the 2006 CDC interim treatment intensity of media reporting, and the ease of implementation.
guidelines was 97.7% (95% CI: 93.0%–100%). After March 2006, Together these factors could contribute to the significant no prescriptions for adamantanes were given to ambulatory-care differences between the nearly perfect provider adherence patients with a diagnosis of influenza (last prescription in the observed for CDC treatment guidelines for influenza, versus that dataset: office-based physician visit: February 2005; ED visit: seen for PID, upper respiratory infections, and acute epididymitis February 2006; outpatient visit: March 2006).
[10,11,12]. One infectious disease in which clinician adherencewith CDC guidelines is also high is genital chlamydial infection, where, effective dissemination of updates, implementation ofelectronic order-entry systems, and national continuing medical In this nationally representative study, we found that the use of education efforts have been reported to increase rates of adamantanes markedly decreased after the influenza 2002–2003 compliance in at least 2 large managed care organizations [13].
season, and were rapidly replaced by oseltamivir as the Since patients with suspected influenza visit a variety of predominantly prescribed anti-influenza drug therapy in U.S.
ambulatory care settings in the U.S., timely and concentrated non-federally employed office-based physician, ED, and outpatient electronic communication messages and interaction between the visits. The major shift occurred during the early influenza 2005– CDC and each medical society and institution, as well as effective 2006 season, paralleling the rapid emergence of adamantane dissemination from the society or institution to its own members is resistance of influenza A viruses seen in both Asia [18] and the likely critical for ensuring adherence with the most up to date U.S. [3]. We also identified a complete absence of adamantane treatment guidelines during a pandemic. Individual institutional prescriptions in all ambulatory medical care settings after March utilization of modern information technology, e.g. electronic 2006, which closely corresponded to release of the CDC interim medical record system, is also certainly important in promotion guidelines for use of antiviral agents for 2005–06 influenza season.
of new treatment guidelines and will aid in minimizing Both findings suggest that the antiviral prescribing practice for inappropriate use of treatment regimen in the case that guidelines influenza treatment or prophylaxis among U.S. ambulatory are modified [19,20]. To what extent these interventions medical care providers was closely in line with the most up-to- contributed to the high rates of compliance seen here is not date global epidemiological resistance patterns, as well as the CDC recommendations, which provides encouraging news regarding The NAMCS and NHMACS databases do not have a specific medical provider’s capacity to adhere with evolving changes in focus on adamantanes prescriptions and potential emergence of antiviral treatment recommendations, particularly relevavant to resistance, as this is not the primary purpose of these survey tools.
the current circulating novel H1N1 influenza virus, as well as other Accordingly, associated factors not collected in NAMCS and potential emerging influenza pandemics.
NHAMCS, such as virus subtype coverage (i.e., influenza A versus Prescription patterns and compliance with existing CDC B), medication side effects, prior antiviral prescriptions, and treatment guidelines vary by diseases. The reasons for the clinician’s knowledge of emerging resistance, may have contrib- variation are beyond the scope of our study. However, potential uted to the observed trends. In addition, other factors, e.g. ease of contributors include severity of disease, individual provider antiviral medication administration, need to adjust dosage perception regarding the individual patient and public health according to age and renal function, and prior antiviral impact of effective treatment/post-exposure prophylaxis, the prescriptions may have contributed to the observed temporal January 2010 | Volume 5 | Issue 1 | e8945 decline from 2002–2005 in prescription of adamantanes in U.S.
element for control and prevention of influenza, especially during ambulatory care settings. Finally, ICD-9-CM coding, which is not the era of emergence of resistance to anti-viral drugs.
a gold standard for influenza case reporting, was used to definecases of influenza rather than other potentially more valid standards – e.g. laboratory confirmed tests.
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