Societal Costs Versus Savings from Wild-Card Patent Extension ...

Infection

Clinical and Epidemiological Study

Societal Costs Versus Savings from Wild-Card Patent Extension Legislation to Spur Critically Needed Antibiotic Development B. Spellberg, L. G. Miller, M. N. Kuo, J. Bradley, W. M. Scheld, J. E. Edwards Jr

Abstract Background: Over the last two decades, an alarming rise in infections caused by antibiotic-resistant microbes has been paralleled by an equally alarming decline in the development of new antibiotics to deal with the threat. In response to this brewing “perfect storm” of infectious diseases, the Infectious Diseases Society of America (IDSA) has released a white paper that proposes incentives to stimulate critically needed antibiotic development by pharmaceutical companies. A cornerstone of the recommendations is establishment of a “wild-card patent extension” program. This program would allow a company receiving United States (US) Food and Drug Administration (FDA) approval for a new anti-infective agent targeting a drug-resistant pathogen to extend the patent on a drug within their active portfolio. However, wild-card patent extension legislation is highly controversial due to concerns regarding its societal cost. Methods: We performed a systematic literature review to estimate the societal cost of wild-card patent extension compared to the savings resulting from the availability of one new antibiotic to treat multi-drug-resistant Pseudomonas aeruginosa. Results: We conservatively estimate that wild-card patent extension applied to one new antibiotic would cost $7.7 billion over the first 2 years, and $3.9 billion over the next 18 years. Thus, even if the new antibiotic abrogated only 50% of the annual societal cost of multidrug-resistant P. aeruginosa (estimated $2.7 billion), wild-card patent extension would be cost neutral by 10 years after approval of the new antibiotic, and would save society approximately $4.6 billion by 20 years after approval. Conclusions: Wild-card patent extension appears to be a cost-effective strategy to spur anti-infective development. Although our analysis is limited by the precision of published data, our model employed conservative assumptions.

Infection 2007; 35: 167–174 DOI 10.1007/s15010-007-6269-7

Infection 35 · 2007 · No. 3 © URBAN & VOGEL

Background The emergence of multi-drug-resistant microbes is considered a substantial threat to United States (US) public health and national security by the National Academy of Science’s Institute of Medicine [1] and the Infectious Diseases Society of America (IDSA) [2]. Unfortunately, even though increasing antimicrobial resistance is creating an urgent need for new antibiotics with novel mechanisms of action, pharmaceutical companies are abandoning the development of anti-infectives [3–5]. The financial disincentives driving pharmaceutical companies away from anti-infective development have been extensively summarized [6, 7], and largely relate to the low return on investment intrinsic to anti-infective drug development. Due in part to increasingly complicated regulatory requirements, drug development in general is facing increasing challenges given the high costs required, currently estimated at $400–$800 million per approved agent [8]. Unfortunately, antibiotics have a lower relative rate of return on investment compared to other drugs [6], which provides particular disincentive to develop antibiotics as compared to other drug classes. In response to this growing crisis, the IDSA has prepared a white paper entitled Bad Bugs, No Drugs:

B. Spellberg (corresponding author), L. G. Miller, J. E. Edwards Jr Division of Infectious Diseases, Harbor-University of California at Los Angeles Medical Center, and the Los Angeles Biomedical Research Institute, 1124 W. Carson St., Torrance CA 90502, USA; Phone: (+1/310) 222 3813, Fax: 782 2016, e-mail: [email protected] B. Spellberg, L. G. Miller, J. E. Edwards Jr The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA M. N. Kuo St. Mary Medical Center, Long Beach, CA, USA J. Bradley Children’s Hospital San Diego, San Diego, CA, USA J. Bradley University of California at San Diego, San Diego, CA, USA W. M. Scheld Division of Infectious Diseases, University of Virginia Health System, Charlottesville, VA, USA Received: September 22, 2006 • Revision accepted: January 22, 2007

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Societal Costs Versus Savings from Wild-Card Patent

As Antibiotic Discovery Stagnates, A Public Health Crisis Brews, which proposes potential solutions to the problem of decreasing antibiotic development [2]. A key element of the report’s recommendations is the establishment of legislation promoting “wild-card patent extension”. In brief, Congress would establish “an independent Commission to Prioritize Antimicrobial Discovery (CPAD)…to identify target pathogens that are…a significant threat to public health due to drug resistance” [2]. Any company receiving US Food and Drug Administration (FDA) approval for a new antibiotic that treats a pathogen targeted by the CPAD could be granted a patent extension of 6 months to 2 years on one other drug that company sells. The wild-card patent extension program has been extremely controversial due to the perception that it would incur a significant financial cost to society. However, development of novel antibacterial agents has the potential to dramatically decrease the cost to society of drug-resistant infections, which may offset the cost of implementation of wild-card patent extension. We therefore performed a systematic literature review to investigate the societal cost of the wild-card patent extension program if it were applied to the development of a theoretical drug to treat a multidrug-resistant pathogen, Pseudomonas aeruginosa.

Methods The Model To estimate the cost of the wild-card patent extension program, we developed a model to calculate both the cost of a one-time wild-card patent extension and the savings engendered by the availability of one new antibiotic to treat infections caused by an archetypal multidrug-resistant bacterium, P. aeruginosa. Our model used a societal perspective [9] when considering costs, and contained several key assumptions intended to refine multiple complex issues surrounding antibiotic development (Table 1). The first assumption was that the primary costs would be derived from two factors: (1) the annual sales of a non-antibiotic, blockbuster drug for up to 2 years beyond its normal patent lifespan; and (2) the annual sales of the newly approved antibiotic which allowed the company to be eligible for the wild-card patent extension program. The annual sales of the newly approved antibiotic were assumed to decline by 75% after the antibiotic went off-patent [10]. Patent expiration was assumed to occur after year 12 following approval, based on the average time to patent expiration reported by multiple sources [10–13]. Actual sales data were utilized to determine costs, and all costs were adjusted to 2005 dollars utilizing the Consumer Price Index inflation calculator established by the US Department of Labor, Bureau of Labor Statistics [14]. The model assumed that these costs would be mitigated by cost reductions due to the availability of a new antibiotic targeting a multi-drug-resistant pathogen. In the base-case estimate, availability of the new antibiotic was assumed to abrogate only 50% of the excess costs of each multi-drug-resistant infection. To generate a conservative estimate of cost savings, indirect costs (i.e. lost productivity due to multi-drug-resistant infections) were assumed to be zero in the basecase model, but were built into sensitivity analyses (subsection following the next). In calculating the net cost of the program, all costs were discounted at a rate of 3% per year [9]. Finally, in the base-case

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model we assumed a 2% annual increase in resistance to the newly approved antibiotic [15], resulting in a 2% annualized decrease in cost savings from the new antibiotic and a 2% annualized decrease in sales of the new antibiotic.

Epidemiology and Cost of P. aeruginosa Infections We focused on multi-drug-resistant P. aeruginosa infections for several reasons. First, it is difficult to quantify the incidence of all drug-resistant infections caused by all microbes. In contrast, considerable epidemiological data is available to quantify the incidence of P. aeruginosa infections. Second, P. aeruginosa infections are a common cause of drug-resistant infections [16]. Third, a peer-reviewed estimate of the cost increase caused by multi-drug resistance in P. aeruginosa is available [17]. Finally, several new antibiotics with novel mechanisms of action have recently or will soon become available for treating resistant gram-positive infections [3, 4]. Conversely, there continues to be a dearth of antibiotics in development that have new mechanisms of action against P. aeruginosa [3, 4]. The PubMed database was searched for title word “Pseudomonas” and title/abstract word “incidence” OR “cost” OR “multidrug”, from 1990 to 2006 (search completed 1/30/06). This search identified 408 abstracts. Two investigators (B.S., M.N.K.) selected manuscripts providing numerical estimates of pseudomonal incidence, costs of infection, or frequency of multi-drug resistance as a percentage of all P. aeruginosa isolates. If there were discrepancies in opinion, a third investigator (L.G.M.) reviewed the abstract and a group discussion was conducted until a consensus was achieved. Costs reported in the literature were adjusted to 2005-adjusted dollars using the Consumer Price Index inflation calculator as above. In published literature, P. aeruginosa multi-drug resistance has typically been defined as resistance to ≥ 3 or ≥ 4 drugs from amongst penicillins, cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides [18–22]. Two potential sources of bias in estimates of the frequency of multi-drug resistance in P. aeruginosa isolates are lack of susceptibility testing against all of these classes of antibiotics (which artificially lowers the frequency of multi-drug resistance because resistance cannot be reported against a drug which has not been tested), and reporting of data from single, outlier institutions, such as small, community hospitals or tertiary care academic centers (which might be expected to have lower or higher rates of resistance, respectively). We therefore defined the frequency of multidrug resistance based on studies that reported resistance to ≥ 3 antibiotics and tested susceptibility against all five classes of these commonly used, anti-pseudomonal antibiotics, and that included data from multi-centered investigations.

Sensitivity Analyses Sensitivity analyses were performed to model the impact of variations in key assumptions. Published epidemiological data were utilized to model variations in the incidence of P. aeruginosa infections and the incidence of a multi-drug-resistant phenotype. To evaluate the potential impact of indirect costs, the sensitivity analysis assumed up to 17 days of extra hospitalization due to infection caused by a multi-drug-resistant versus a non-multi-drug-resistant, P. aeruginosa [17, 23]. Furthermore, each workday lost was assumed to result in $211 of indirect costs (in 2005 dollars) [24, 25]. For cost of the patent-extended blockbuster drug, sensitivity analyses were modeled based on US sales of the top-ten selling drugs.


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Table 1 Base-case estimate variables and assumptions.

Factor

Base-case estimate derivation

Societal costs of patent extension: Prolonged sales of blockbuster drug

·Base-case estimate for 2 years of sales based on mean annual sales of top ten selling drugs in the US

Annual sales of newly approved antibiotic

·Base-case estimate based on mean 2003 sales of on-patent antibiotics with anti-pseudomonal activity ·Base-case estimate assumes sales decline by 75% after year 12 following approval [10–13], as the antibiotic goes off-patent

Societal savings from newly approved antibiotic: Diminished cost of multidrug-resistant P. aeruginosa infection

·Cost = incidence of P. aeruginosa infections * incidence of multi-drug resistance * cost per multidrug-resistant infection ·Base-case model assumed 50% recovery of multi-drug-resistant costs due to availability of newly approved antibiotic

Reduced indirect costs (i.e. lost productivity)

·Indirect costs assumed to be 0 in base-case model

Adjustments: Cost discount

·3% annual adjustment [9]

Inflation

·All costs adjusted to 2005 dollars

Resistance to the newly approved antibiotic

·Base-case model assumed 2% annual increase in resistance ·Result of resistance is decreased cost-savings from the newly approved antibiotic but also decreased sales of the newly approved antibiotic

For cost of the newly approved antibiotic, the sensitivity analyses were based on the US sales of on-patent antibiotics with pseudomonal activity. Other variables in the model with limited published data were varied by 50%–200% [26] in sensitivity analyses.

Results Annual Incidence of P. aeruginosa Infections in the United States According to the Centers for Disease Control, as of 2002 there were two million nosocomial infections per year in the US [27], of which 10% were caused by P. aeruginosa [16]. An alternate estimate of the number of nosocomial infections caused by P. aeruginosa derives from a more recent, population-based estimate from Europe, which reported the incidence of P. aeruginosa infections to be 126 cases per 100,000 population [28]. Extrapolating this dataset to the US, with a population of 300,000,000 [29], generates an estimate of 378,000 nosocomial infections caused by P. aeruginosa annually. Hence a crude estimate of the incidence of P. aeruginosa infection in hospitalized patients in the US is 200,000–378,000 cases per year. The mean (289,000 cases per year) was used as the base-case estimate in our model (Table 2).

Frequency of Multi-drug-resistant P. aeruginosa Infections Only one study, an investigation of more than 50,000 P. aeruginosa isolates sent to a national reference laboratory for susceptibility testing, fit our criteria of being


multi-institutional and defining multi-drug resistance as ≥ 3 drugs from amongst penicillins, cephalosporins, carabapenems, fluoroquinolones, and aminoglycosides [18]. This investigation revealed that, between 1999 and 2002, 25% of P. aeruginosa isolates were resistant to ≥ 3 antibiotics. Other surveys of P. aeruginosa resistance tested isolates against only a limited set of antimicrobials or were single center studies [19, 22, 30, 31]. Nevertheless, their estimates of the percentage of P. aeruginosa that were multidrug resistant were used to determine the upper and lower boundaries for sensitivity analyses.

What is the Cost of Multi-drug-resistant P. aeruginosa Infections? Harris et al. [17] reviewed infections caused by multidrug-resistant P. aeruginosa from 1994 to 1997 at Beth Israel Deaconness Medical Center. Multi-drug-resistant P. aeruginosa was defined as being resistant to piperacillin, imipenem, ceftazidime, and ciprofloxacin. The investigators reported that the mean cost per patient was $54,081 for those infected by multi-drug-resistant P. aeruginosa versus $22,116 for those infected by non-multi-drug-resistant P. aeruginosa. Therefore, the cost of multi-drug resistance in P. aeruginosa infections was $31,965 per infection in 1999, or $37,399 in 2005-adjusted dollars. Given the available estimates of the cost increase caused by multi-drug resistance in P. aeruginosa and the frequency of multi-drug-resistant P. aeruginosa infections in the US, the base-case estimate for the

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P. aeruginosa, was $0.5 billion in 2005 dollars (Table 3). Because the IDSA has proposed Factor Base-case Range Reference that the wild-card patent extension last estimate for 6 months to 2 years, we estimated Direct cost savings: the aggregate cost of the program Incidence of P. aeruginosa 289,000 200,000–378,000 [16, 27–29] over the upper limit of 2 years to be infections in cases/year ($6.8 billion in sales of the blockbuster % of P. aeruginosa isolates that 25% 9.9%–32% [18, 19, 22, drug) + ($1 billion in sales of the new are multi-drug resistanta 30, 31] antibiotic) – ($0.1 billion to account b for 3% discounting in year 2) = $7.7 [17] Cost per infection incurred by $37,399 multi-drug resistance billion per newly developed antibiotic (in 2005 dollars). In subsequent years, b Fraction of costs prevented by 50% n/a the only cost incurred would be the newly approved antibiotic sales of the newly approved antibiotic, c Indirect cost savings : which would slowly decrease as resisExcess hospital days due to 0 17 (upper limit) [17, 23] tance to the antibiotic increased, and multi-drug-resistant which would decrease precipitously P. aeruginosa infection prevented after the drug went off-patent. by newly approved antibiotic Balanced against these costs [24, 25] Cost per lost day of work $211 n/ab would be the savings realized by havCosts of wild-card patent extension: ing a new agent with which to treat infections caused by multi-drug-resistant Sales of blockbuster drug with $6.8 billion $4.4–$13.6 bil[32, 33] P. aeruginosa. If the development of a 2-year patent extension (based lion on top ten selling drugs in the new antibiotic mitigated 50% of the US) costs of multi-drug resistance, the total savings would be $1.35 billion per year. Time to off-patent status for the 12 years 6–18 years [10–13] newly approved antibiotic Therefore, the net cost of wild-card patent extension in the first 2 years Decline in sales due to off75% 37.5–90% [10] would be approximately $5 billion (depatent status for the newly approved antibiotic rived by subtracting $2.7 billion saved from $7.7 billion spent over 2 years). Annual sales of newly approved $0.5 billion $0.02–$1.6 bilSee Table 3 However, it must be emphasized antibiotic with activity against lion P. aeruginosa that the major cost of the program a (patent extension) would only be inMulti-drug resistance defined as resistant to ³ 3 drugs; b published data are not availcurred in the first 2 years. Thereafter, able to allow estimate of range, so base-case estimate varied 50%–200% in sensitivity the blockbuster drug’s patent would analyses; c indirect costs assumed to be 0 in the base-case model, but the recovery of such costs is modeled in sensitivity analysis (Table 4) expire, while the cost savings from successful treatment of multi-drug-reannual cost of multi-drug resistance in P. aeruginosa in the sistant P. aeruginosa would continue. With these continued US is as follows: 289,000 cases of P. aeruginosa × 25% savings, it would take approximately 10 years from the apmulti-drug-resistant phenotype × $37,399 per case = $2.7 proval of the new antibiotic for the program to achieve billion. cost-neutrality. Due to continued mitigation of the costs of multi-drug resistance in P. aeruginosa, the program would What is the Cost of Implementation of Wild-Card save to society a cumulative total of $4.6 billion by 20 years Patent Extension? after approval of the new antibiotic. An upper limit of the cost of patent extension can be Sensitivity Analyses estimated by evaluating the annual sales of the most profSensitivity analyses were performed to model the impact itable drugs currently on the market. The top-ten selling of changes in the variables from the base-case model. drugs in the US generated an average of $3.4 billion (range The outcomes modeled in the sensitivity analyses in$2.2–$6.8) per drug in sales in 2003 (in 2005-adjusted cluded time to cost-neutrality, as well as the minimum dollars) [32–34]. Sales of the newly developed antibior maximum value of each variable required to achieve otic can be estimated based on sales of comparable cost-neutrality at 20 years following approval of the products currently on the market. The average 2003 US new antibiotic. Many analyses resulted in estimates of sales of on-patent anti-infectives with broad gramcost-neutrality less than 20 years following approval of negative activity, including reliable activity against Table 2 Base-case estimates and ranges.

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Table 3 2003 Sales of on-patent drugs with activity against P. aeruginosa.

Drug

2003 Sales (billions)a

Source

Levofloxacin

$1.6

[33]

Ciprofloxacin

$1

[33]

Piperacillin-tazobactam

$0.4

[33]

Meropenem

$0.3

[42]a

Ceftazidime

$0.3

[43]b

Cefepime

$0.2

[44]

Imipenem

$0.15

[45]

Aztreonam

$0.02

[42]

Average

$0.5

a

Adjusted to 2005 dollars; b projected 2003 sales

the new antibiotic, and several modifications led to costneutrality estimates of only 3–7 years post-approval of the new antibiotic (Table 4).

Discussion Despite the critical need for new antibiotics due to increases in drug resistance, large pharmaceutical companies are substantially moving away from anti-infective research and development due to significant financial disincentives [1, 3–7, 35]. In response to this growing crisis, the IDSA has made recommendations to address the complex issues


underlying this conundrum [2]. A critical component of IDSA’s proposed solutions is the institution of wild-card patent extension to spur antibiotic development. However, this recommendation has been controversial due to its perceived potential to increase societal health care costs by prolonging the sales of on-patent, blockbuster drugs. The ongoing controversy has led to considerable doubt about the feasibility of passing congressional legislation that includes a wild-card patent extension provision [36, 37]. What has gone largely unrecognized in this debate is the potential for the program to actually decrease societal heath care expenditures by mitigating the cost of infections caused by drug-resistant organisms. Therefore, we undertook this study to estimate the net financial impact to society of the wild-card patent extension program. There are limitations to our analysis. First, only a single, retrospective dataset is available to estimate the cost of multi-drug-resistant P. aeruginosa infections. Although it would be preferable to base-cost estimates on more than one study, we have been unable to locate any other data that addresses the cost of multi-drug resistance in P. aeruginosa. However, a recent analysis reported an excess cost of ~$33,000 per infection caused by imipenem-resistant versus imipenem-susceptible P. aeruginosa infections [38]. Although the study did not meet our criteria for defining multi-drug resistance, the findings for imipenem-resistant P. aeruginosa are entirely consistent with, and validate, our analysis. Nor are robust data available regarding the cost of multi-drug resistance in other organisms. Nevertheless, there is a critical need to make policy decisions now so that antibiotic development can be re-invigorated on an

Table 4 Sensitivity analyses.

Variable

Range

Years to costneutrality

Value to achieve costneutrality at 20 years

Incidence of P. aeruginosa

200,000–378,000

17–7

206,592

% of P. aeruginosa isolates that are multi-drug resistant

9.9%–32%

>20–7

17.9%

Direct cost per case of multi-drug-resistant P. aeruginosa

$18,700–$74,798

>20–4

$26,735

Fraction of direct costs recovered by availability of newly approved antibiotic

25%–100%

>20–4

35.4%

Indirect costs recovered per case of multi-drug-resistant P. aeruginosa

$3,485

9

n/aa

Annual rate of increased resistance to newly approved antibiotic

1%–4%

10–12

5.8%

Annual sales of blockbuster drug with extended patent

$2.2–$6.8 billionb

5 to >20

$5.7 billion

Annual sales of newly approved antibiotic

$0.02–$1.6 billion

6 to >20

$1.01 billion

Time to off-patent status for the newly approved antibiotic

6–18 years

9–10

n/a

Decline in sales due to off-patent status for the newly approved antibiotic

37.5%–90%

10c

n/a

a

Increasing recovery of indirect costs shortens the duration to cost-neutrality; b based on #1 and #10 selling drug in US [32, 33]; c variations do not impact base-case estimate


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urgent basis. While additional research in this area is clearly needed, we believe that, given the time-critical nature of the policy decision regarding wild-card patent extension, the data utilized are sufficient to serve as a foundation for the current analysis. We are unaware of any other formal analysis of the feasibility of wild-card patent extension. An unknown portion of the cost increase from multidrug-resistant P. aeruginosa infections may be due to uncontrolled variables that differed between patients with and without multi-drug-resistant infections [17]. Therefore, it is unclear how much of the cost difference would be recoverable with the availability of an effective antibiotic. To mitigate this limitation, in the base-case model we assumed that only 50% of the increased cost due to drug resistance would be recoverable by the availability of a novel antibiotic. Sensitivity analyses were then used to model higher and lower estimates. Because the proportion of P. aeruginosa isolates that are multi-drug resistant continues to increase over time [39], our model is conservative and likely underestimates the true frequency of multi-drug-resistant P. aeruginosa in 2006 and in the future. Therefore, the cost-effectiveness of the wild-card patent extension program will increase over time, as the frequency and cost of infections caused by multi-drug-resistant bacteria continue to increase. To underscore the conservative assumptions of our model, we evaluated the potential impact of a new antibiotic on only one multi-drug-resistant pathogen. It is highly likely that a newly developed antibiotic capable of treating drug-resistant P. aeruginosa would also possess activity against other related drug-resistant organisms. Infections caused by multi-drug-resistant Acinetobacter and extended spectrum beta lactamase (ESBL)-producing Klebsiella and Enterobacter likely markedly increase the cost of hospitalization [40, 41]. Hence, reduction in the cost due to these other organisms would dramatically improve the overall cost savings from implementation of the wildcard patent extension. Again to underscore our model’s conservative estimates, we utilized high estimates for the cost of patent extension by estimating the cost of 2 years of patent extension (the upper limit of the time period proposed by the IDSA), and by using as our benchmark the sales of the top ten most profitable drugs in the US. Because total cost of the top 200 selling drugs in the US is heavily skewed towards these top 10 drugs [33, 34], use of average sales figures for only these top 10 drugs is conservative. Furthermore, our estimate of the cost of sales of the newly developed antibiotic is heavily skewed by the inclusion of fluoroquinolones. Despite the resulting non-normal distribution of the sales data (Table 3), for our base-case model we intentionally averaged the sales of the drugs rather than utilizing the median value ($0.3 billion), which would have led to a significantly lower estimate of the costs of the program (cost-neutral by year 7 post-approval). Finally,

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we did not attempt to place a monetary value on suffering of the patient and family, long-term disability from injury, or lost wages and family support from death, which would have increased the savings resulting from having a new antibiotic to treat multi-drug-resistant infections. Given the conservative estimates in our base-case model, the time to cost-neutrality of a single application of wild-card patent extension might occur years earlier than our estimates, as demonstrated in the sensitivity analyses. Society is in urgent need of new strategies to deal with the perpetually increasing prevalence of drug-resistant microbes [3]. Development of novel immunoprophylactic (e.g. vaccines) or immunotherapeutic (e.g. antibodies) strategies, and increasing focus on infection control methods (e.g. handwashing) to limit spread of infection, are laudable goals to diminish the impact of drug-resistant infections. Nevertheless, new antibiotics are needed to treat those infections that occur. Given the increasing antimicrobial resistance in common pathogens, and the potentially catastrophic consequences of a bioterrorist attack with multi-drug-resistant pathogens, we need aggressive and robust solutions to remove current barriers to new antimicrobial drug development. Our analysis indicates that the wild-card patent extension, as proposed by the IDSA, is an economically viable solution that would result in significant cost savings to society over time if appropriately applied. Finally, in light of the paucity of published data on the impact of antibiotic resistance on increased hospital costs, and the lack of data on the impact of new antibiotics on these costs, more study of these areas is needed.

Acknowledgments The authors would like to thank Dr. Tracy Lieu for helpful discussions — Financial Support: National Institutes of Allergy and Infectious Diseases Public Health Service grants KO8 AI06064101 (BS) and R01 AI19990, R01 AI063382, and R41 AI071554 to J.E.E. — Financial Disclosures: B. Spellberg has received speaking honoraria from Fujisawa and Astellas, and is on the speaker’s bureau of Merck, Pfizer, and Astellas. L.G. Miller has received speaking honoraria from Bristol-Myers Squibb, Pfizer, and Abbott Laboratories. J. Bradley’s employer has received research grants from AstraZeneca, Elan, Glaxo SmithKline, Johnson and Johnson, and Novartis, and reimbursement for Dr. Bradley’s role in consulting for Johnson and Johnson, RX3, Cerexa, and Wyeth. W.M. Scheld serves on advisory boards of Pfizer, Cubist, and GlaxoSmithKline and serves on speakers’ bureaus of these same companies, plus those of Schering-Plough and Bristol-Myers Squibb. J. E. Edwards is also supported by an unrestricted Infectious Diseases Research Award from Bristol-Myers Squibb, and has received grants from Pfizer, Merck, Gilead Sciences, and Elan Pharmaceuticals for research on the pathogenesis and treatment of fungal infections. These funding sources played no role in the preparation of this manuscript.


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