pharmacoepidemiology and drug safety 2003; 12: 177–182Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.828

ORIGINAL REPORT

Increased US prescription trends associated with the CDCBacillus anthracis antimicrobial postexposure prophylaxiscampaigny,z

Douglas Shaffer MD, MHS, George Armstrong RPh, MPH, Karen Higgins ScD,Peter Honig MD, MPH, Philip Coyne MD, MSPH, Debra Boxwell PharmD,Julie Beitz MD*, Brad Leissa MD and Dianne Murphy MD

Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD, USA

SUMMARY

Purpose We evaluated national outpatient antimicrobial prescription trends in relation to the first United States case ofinhalational anthrax due to the intentional delivery of Bacillus anthracis (B. anthracis) spores.Methods We queried IMS HEALTH’s National Prescription Audit Plus7TM database for two 6-month periods (July–December) in 2001 and 2000 to describe outpatient prescription trends of antimicrobials recommended during the Centersfor Disease Control and Prevention’s (CDC) postexposure prophylaxis campaign.Results Overall, antimicrobial utilization for the referent 6-month time frame was greater in 2000 compared to 2001. Incontrast, ciprofloxacin utilization was greater in 2001 during October, the month following the index case, increasing bymore than 40% over utilization in October 2000. Similarly, doxycycline utilization increased by 30% during October/November. This corresponded to relative increases in US utilization for ciprofloxacin of approximately 160 000 prescrip-tions for the month of October and for doxycycline of approximately 96 000 prescriptions during October and 120 000 pre-scriptions for November.Conclusions We conclude more widespread prescribing of ciprofloxacin and doxycycline occurred in response to the firstUS bioterrorist-associated anthrax attacks than was warranted based upon confirmed or suspected B. anthracis exposurealone. Published in 2003 by John Wiley & Sons, Ltd.

key words— anthrax; ciprofloxacin; doxycycline; amoxicillin; postexposure; prophylaxis; drug utilization

INTRODUCTION

On 4 October 2001, the first United States case ofinhalational anthrax due to the intentional deliveryof Bacillus anthracis (B. anthracis) spores was

reported in Florida.1,2 The Centers for Disease Con-trol and Prevention (CDC) and state and local publichealth departments subsequently launched an aggres-sive campaign directed against the nation’s first bio-terorrism-related public health threat that eventuallyincluded four states and the District of Columbia.Sixty-day antimicrobial postexposure prophylaxis(PEP) was ultimately recommended for approxi-mately 10 000 persons potentially exposed to anthraxin Connecticut, Florida, New Jersey, New York Cityand Washington, DC.3–7 The PEP recommendationswere confined to individuals with documented con-firmed or suspected B. anthracis exposure.8–10 Inresponse to the resulting demand for PEP, NationalPharmaceutical Stockpile antimicrobial drugs were

Received 2 July 2002Revised 22 November 2002

Published in 2003 by John Wiley & Sons, Ltd. Accepted 11 December 2002

* Correspondence to: Dr J. Beitz, Office of Drug Safety (HFD 400),Center for Drug Evaluation and Research, US Food and DrugAdministration, Rm. 15B-08, 5600 Fishers Lane, Rockville, MD20857, USA. E-mail: BeitzJ@cder.fda.govyThis article is a US Government work and is in the public domainin the USA.zNo direct or indirect support was received for this manuscript. TheFDA by contractual agreement has access to IMS HEALTH dataand conducted independent analyses.

deployed to support state and local health departmentneeds.7,11 The CDC National Pharmaceutical Stock-pile (NPS) Program’s mission is to ensure the avail-ability and rapid deployment of life-saving medicalsupplies to any US location in the event of a terroristattack directed against a civilian population.12

While the B. anthracis PEP campaign was direc-ted by the CDC, reports and speculation appearedregarding more widespread prescription writing forprophylactic antimicrobials beyond the CDC recom-mendations.13,14 Formal analysis and description ofsuch widespread antimicrobial utilization remainsunavailable. IMS HEALTH tracks US drug utilizationand offers an opportunity to examine antimicrobialutilization in association with the B. anthracis bio-terrorism attacks. We aim to describe US prescriptiontrends for antimicrobials recommended by theCDC based upon the temporal relationship to theB. anthracis PEP campaign.

METHODS

We queried IMS HEALTH’s National PrescriptionAudit (NPA) Plus7TM database to obtain weekly esti-mates of outpatient prescriptions dispensed by chain,independent, food store and mail order pharmacies. Inbrief, IMS HEALTH is a commercial entity that pro-vides drug utilization data to pharmaceutical compa-nies and other interested third parties.15 NPA Plus7TM

tracks drug movement out of pharmacies and into thehands of consumers via formal prescriptions. Nationalweekly estimates of new prescriptions dispensed arecompiled based upon statistical projections. The uni-verse of stores consists of approximately 55 000 in theUS. Each week, the number of sample stores reportingconsists of approximately 20 000 with 98% commonfrom week to week. The data are projected to thenational level, using proprietary methodology.16

Our evaluation focused on antimicrobials recom-mended by the CDC in their B. anthracis PEP cam-paign: oral ciprofloxacin and doxycycline (primary),and amoxicillin (alternative).1,3 We collected infor-mation on the weekly number of antimicrobial pre-scriptions dispensed from July to December for2000 and 2001 for these antimicrobials as well as oralazithromycin and cefuroxime, drugs often used foroutpatient respiratory tract infections but not recom-mended for B. anthracis. This allowed for compari-sons of antimicrobial utilization changes from 2000to 2001 in antimicrobials recommended by the CDCas well as the selected comparators for the time periodbefore and after the index inhalational anthrax case.

Graphs of the number of weekly prescriptions overtime and percentage change in the number of prescrip-tions for 2001 versus the corresponding weeks in 2000over time are presented to correlate changes in utiliza-tion with the CDC’s B. anthracis campaign. The meanweekly numbers of antimicrobial prescriptions dis-pensed (henceforward used interchangably with‘utilization’) for the following three time frames werecompared between 2001 and 2000: 6 months (27weeks), July–December, in order to obtain a referenttime frame before and after the index case (4 October2001); 3 months, October–December, following theindex and subsequent cases; and 1 month, October,immediately after the index case and during the peakof the anthrax scare. Data are presented as the weeklynumber of prescriptions dispensed (mean, standarddeviation and median). The Wilcoxon Signed RankTest was used for comparison of the median numberof prescriptions for paired time periods between2001 and 2000, the null hypothesis being that theoverall difference between the 2 years is zero and thatany deviation from that is strictly random. Non-para-metric testing was used since the number of weeksevaluated was low, and the weekly utilization esti-mates were not normally distributed.

RESULTS

Examination of prescriptions dispensed during 2001and 2000 demonstrates nearly identical utilizationcurves except for ciprofloxacin and doxycycline(Figure 1). Both ciprofloxacin and doxycycline utili-zation plots are nearly identical from July throughSeptember for both 2001 and 2000. However, a nota-ble spike in ciprofloxacin prescriptions occurred inOctober 2001 during the CDC’s B. anthracis PEPcampaign. A less pronounced increase occurred indoxycycline prescriptions beginning in October andpeaking in November 2001. No such spike was seenin amoxicillin utilization, an alternative PEP antimi-crobial. There was a slight, brief increase in the amox-icillin utilization during October and November 2001.A slightly larger change was also seen with azithro-mycin, an antimicrobial not recommended for PEP.

The percentage change for prescriptions dispensedin year 2001 versus 2000 offers an appreciation of therelative increases during the B. anthracis PEP cam-paign. Figure 2 also shows the overall lower use ofantimicrobials in 2001 versus 2000 with most utiliza-tion curves demonstrating 0–10% percent changes.Only ciprofloxacin and doxycycline utilizationshowed a percent change in 2001 greater than 10%.

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Figure 1. Anthrax and Comparator Antimicrobial 6-Month Utilization* (2001 & 2000). Six-month, July through December, utilizationplots of weekly number of prescriptions dispensed for anthrax postexposure prophylaxis antimicrobials (ciprofloxacin, doxycycline andamoxicillin) and two comparators (azithromycin, cefuroxime) for 2001 (solid lines with triangles) and 2000 (dashed lines with squares)demonstrate nearly overlapping antimicrobial patterns for all antimicrobials except ciprofloxacin and doxycycline. Y axes are adjusted toaccommodate data and are not equal

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There was a spike in early October, representing a42% increase in ciprofloxacin utilization. Similarly,there was a smaller but prominent spike in doxycy-cline utilization in mid-October/early November,representing a 30% increase in utilization. Lessimpressive increases in amoxicillin (2%) as well asazithromycin (8%) utilization occurred during thesame time frame. Cefuroxime utilization was lessthroughout 2001 compared to 2000.

Antimicrobial utilization overall for the referent 6-month time frame was greater in 2000 compared to2001 for all antimicrobials except doxycycline, signif-icantly so for ciprofloxacin, amoxicillin and cefurox-ime (Table 1). In contrast, ciprofloxacin, doxycycline,amoxicillin and azithromycin utilization was greaterin 2001 during October, the month immediately afterthe index case, by approximately 160 000, 96 000,12 000 and 152 000 prescriptions, respectively. Doxy-cycline utilization was even greater during November(approximately 120 000 prescriptions) and was signif-icantly greater from October through December 2001.While median azithromycin utilization was greater in2001 compared to 2000 for October, the overall utili-zation was also approximately 2–4 times greater thanciprofloxacin and doxycycline for both years. Bothmean cefuroxime and azithromycin utilization, how-ever, were lower for October through December

2001, although this was not the case for median azi-thromycin utilization.

DISCUSSION

Our results suggest that considerably more wide-spread prescribing of antimicrobials recommendedfor B. anthracis PEP occurred than can be ascribedto the CDC’s recommendations. During October2001, US ciprofloxacin and doxycycline utilizationincreased by approximately 160 000 and 96 000 pre-scriptions relative to 2000, respectively. Theseincreases, far exceeding the approximate 10 000recommended for 60-day prophylaxis by the CDC,support the suggestion that widespread antimicrobialutilization occurred. This is enforced by the fact thatthe National Pharmaceutical Stockpile was used tosupply antimicrobials for the PEP campaign andwould not be represented in these utilization figures.7

Concurrent treatment of US infectious diseases andseasonal variations may confound our estimates ofrelative ciprofloxacin and doxycycline utilizationincreases. This may be reflected by the isolatedincrease in azithromycin use (potentially for anyinfectious etiology including presumed anthrax expo-sure) noted in October 2001. However, it is unlikely

Figure 2. Anthrax and Comparator Antimicrobial Utilization Changes* (2001 vs 2000). The percentage change for weekly number ofantimicrobial prescriptions dispensed in year 2001 versus 2000 demonstrates a positive spike reflecting a relative increase in ciprofloxacinutilization following the first reports of inhalational (A) anthrax. A smaller but prominent spike in doxycycline utilization follows in midOctober/early November

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that these estimates are biased by annual antimicrobialutilization increases since we have demonstrated thatoverall utilization was greater in 2000 and similarincreases to those observed with ciprofloxacin anddoxycycline were not observed with other antimicro-bials during this period. While the prescription indica-tion was unavailable, the temporal relationship of theutilization increases to the index case strongly sup-ports an association to the anthrax bioterrorist attacks.Furthermore, the prescription peaks (ciprofloxacinfollowed by doxycycline) are consistent with theCDC’s initial, focused use of ciprofloxacin followedby more widespread utilization of doxycycline towardthe end of the PEP campaign once susceptibility pat-terns for the isolated B. anthracis strains wereknown.1,3,7

It is possible that a proportion of the US prescrip-tion increases represents stockpiling of antimicrobialsby concerned Americans and thus the increasesobserved may not reflect consumption by the prescrip-tion holders. In fact, 10% of surveyed participants inthe CDC PEP campaign indicated that they took noantimicrobial prophylaxis but collected an initial sup-ply.7 The ramifications of such potential widespreadantimicrobial prescribing beyond the CDC’s recom-mendations are noteworthy and may include the pro-pagation of antimicrobial resistance, unwarranted riskfor adverse effects and sub-optimal care for indivi-duals warranting more extensive clinical evalua-tion.17,18 The CDC is conducting an extensiveevaluation of individuals recommended to receive60-day PEP in an effort to understand compliance,adverse events and outcomes.19,20 No such epidemio-logical evaluation, surveillance or follow-up may be

assured for individuals prescribed antimicrobialsbeyond the scope of the CDC’s campaign.

An advantage of our analysis is the use of IMSHEALTH data representing antimicrobial utilizationacross the continental US. IMS HEALTH is report-edly the world’s leading provider of pharmaceuticalinformation.15 However, caution is necessary regard-ing generalizations that can be drawn from theseresults. IMS HEALTH is a public company providingmarket research and sales management information tonumerous recipients including pharmaceutical com-panies. Data is not prospectively collected for the soleintent of pharmacoepidemiological analyses andmethods used (e.g. sampling, projection, lack of con-trol) may limit such analyses. For this reason, wechose to use primarily descriptive statistics andfeel these potential limitations are outweighedby the ability to describe US prescription trend inresponse to the first US bioterrorist attack. This isthe first description to provide such data to our knowl-edge.

We chose to use the Wilcoxon signed rank testbased upon the distribution of the data and numberof weekly comparisons considered. This methodinvokes limitations in that the Wilcoxon signed ranktest treats the weeks as independent observations, doesnot take into account the variability of the weekly esti-mates based upon IMS HEALTH projections and doesnot consider the magnitude of the observations. Thedata could also be analyzed as incidence rates usingmore sophisticated statistical tests. However, wechose not to use more sophisticated analyses due tothe nature of outliers in the data, confounding (e.g.infectious seasonal variation, prescription indication)

Table 1. Weekly antimicrobial utilization* in association with the CDC B. anthracis postexposure prophylaxis campaign

Ciprofloxacin Doxycycliney Amoxicillin Azithromycin Cefuroxime

2001 2000 2001 2000 2001 2000 2001 2000 2001 2000

July– 227 780 234 636 158 850 148 857 931 759 987 386 540 655 551 550 73 147 79 283December (30 708) (14 110) (26 910) (16 667) (200 151) (220 553) (169 298) (193 896) (15 772) (18 876)

[225 235]§ [239 049] [150 346]§ [148 298] [945 571]§ [1 009 857] [564 148] [558 046] [76 246]§ [79 806]October– 227 972 229 774 181 408 160 741 1 112 000 1 175 840 694 826 719 253 87 061 95 063December (44 126) (16 412) (19 655) (13 457) (97 193) (138 568) (74 943) (125 288) (8038) (13 405)

[216 584] [235 765] [188 434]§ [159 594] [1 091 805]{ [1 160 440] [683 731] [674 460] [85 444]{ [88 999]October 278 584 238 442 180 211 155 997 1 049 228 1 046 507 631 671 594 121 80 717 83 250

(45 143) (3633) (11 495) (1765) (37 441) (16 037) (18 332) (13 122) (486) (794)[278 395] [237 649] [182 184] [156 631] [1 056 863] [1 049 148] [638 517] [595 898] [80 770] [83 375]

yDoxycycline utilization for November only: 2001—185 926 (24 950), [192 948]; 2000—156 455, (14 906), [161 802].

*IMS HEALTH, National Prescription Audit Plus7TM.Weekly number of prescriptions dispensed (mean, standard deviation in parentheses and median in brackets) are presented forantimicrobials recommended for B. anthracis postexposure prophylaxis (ciprofloxacin, doxycycline and amoxicillin). Azithromycin andcefuroxime are included for comparators. Significant differences for two-sided tests are reported at the p� 0.005§ and p� 0.05{ levels.

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and our premise that descriptive statistics are appro-priate for the nature of the data and manuscript aim.

In conclusion, more widespread prescribing ofciprofloxacin and doxycycline occurred in responseto the first US bioterrorist-associated anthrax attacksthan was warranted based upon documented con-firmed or suspected B. anthracis exposure alone.While both the public and physicians’ concern is war-ranted during such a period of uncertainty, judiciousprescribing of antimicrobials must be consideredbased upon not only potential benefits offered butrisks accrued as well.

DISCLAIMER

The views expressed in this manuscript are those ofthe authors solely and not necessarily of the Foodand Drug Administration.

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