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| Home > News & Publications > Publications Download > Lahey Clinic Medical Ethics Journal |
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A Medical Ethics Forum from Harvard Medical School: The misuse of antibioticsA recent report published in the Journal of the American Medical Association indicated that from 1994 to 2000 the effectiveness of ciprofloxacin, a fluoroquinalone antibiotic, in intensive care settings decreased significantly, with an additional 10 percent of gram-negative bacteria becoming resistant to ciprofloxacin. 1 Bacteria previously destroyed by ciprofloxacin now survive exposure to this agent. While fluoroquinolones comprise only one segment of the physician's antimicrobial armamentarium, drug resistance poses an increasingly general threat to the treatment of infectious disease. The causes of antibiotic resistance are manifold. Antibiotics are over-prescribed, being given for conditions that they do not treat, and broad spectrum antibiotics are used when those with a narrower spectrum that are less likely to cause resistance would be just as effective. Physicians contribute to the problem of antibiotic resistance by prescribing in cases of diagnostic uncertainty, or by succumbing to patient requests. The pharmaceutical industry also shares responsibility in light of their aggressive marketing campaigns.
There are many facets to the drug resistance problem, with the most contributing factors being the antibiotic, which selects, and the resistance genes, which are being selected. Bacteria, in many instances, are just the innocent bystanders of antibiotic onslaught who have to (and will) survive. If you were a bacterium, you would have a very hard time finding a place to hide in the face of antibiotics, antibiotic soaps and disinfectants, all of which are trying to destroy you. There are approximately 115 available antimicrobial agents, falling into roughly 15 large classes. Yet, antibiotic use, whether it is in salmon fisheries, animal husbandry, spraying fruit trees, hospital care or in homes, brings broad ecological consequences. As a result, we face multi-drug resistance among many types of bacteria in our hospitals and our communities. Some of these strains have become untreatable. In the United States, an estimated 35 million pounds of antibiotics are produced and used, with roughly half consumed by humans and the other half by animals. Another 300,000 pounds are sprayed onto fruit trees as a prophylaxis against bacterial disease. These widespread applications, often applied in subtherapeutic doses, produce innumerable Darwinian"survivors," microbes that linger and propagate through both genetic and non-genetic mechanisms. Regarding the overuse of antibiotics, it is a recognized fact that patients can insist on them, if not outright demand them. FOX-Television, upon reading the first edition of my book, The Antibiotic Paradox, 2 sent a 26-year-old associate director into four Denver doctors' offices. Four out of four times, in less than 10 minutes, she had a prescription for a different antibiotic. Of course, there is the widely known example at an area hospital where a woman came into the emergency room and wanted to be seen for a case of acne. The astute, well trained physician said, "Change your diet. There is no need for an antibiotic." She got irate and demanded, "Look here, I want tetracycline." He stood his ground, replying, "I am not going to give it for this." To which, she said as she was escorted out, "All right, I will call my lawyer and I will see you in court." The APUA has been working to correct these patient expectations and physician prescribing practices since 1981. 3 There have been, however, a few prominent challenges to our efforts. Number one is the miracle feature of antibiotics. Over the past 50 years, a large portion of the population has embraced the excitement over penicillin and tetracycline, and what these drugs accomplished in the fight against infectious disease. Admittedly, many factors contributed to the reduction in mortality, but much of the public attributed it all to antibiotics. There exists this myth that antibiotics are something utterly fantastic, and no consumer should be denied. In the early days you could get antibiotics over the counter, even in face creams. Finally, the FDA designated antibiotics as prescription drugs. Even so, they were not thinking about resistance at the time, but rather the side effects, the allergic reaction to penicillin and such. The FDA's actions did little to diminish that mystique of the antibiotic. The second challenge is something that Alexander Fleming, the discoverer of penicillin, foreshadowed. When penicillin becomes an oral antibiotic, Fleming warned, one could expect resistance to emerge. Today, many antibiotics can be acquired easily and kept in the home. The "miracle-ness" of penicillin suggested that it should not do any harm. Antibiotics are made not to be toxic. (I always wonder if they had a little toxicity whether people would take them so readily.) People keep them in their medicine chest and they take them a little bit at a time for whatever ailment. When I speak to kids at area schools, they tell me their parents sometimes say, "When I was your age, my mom gave me an antibiotic and that is what you are going to get." This is an assumption that we need to correct, and it is this education gap that is being partially met by APUA's outreach programs. The third challenge derives from the fact that no other drug therapy resembles antibiotics. Antibiotics are social drugs. You can improperly take a neuroleptic or a cardiac medication, and it is basically your problem. When you misuse an antibiotic, however, you present a problem to the rest of society. For example, there were studies done in England that examined homes where patients were chronically taking antibiotics for acne. When they surveyed the skin flora of family members, they found astounding differences from the flora present in homes without antibiotic use. There were thousand-fold differences in the antibiotic resistance of the staphylococci on the skin. While resistant microbes on the skin might not pose, at first glance, a societal problem, we know that bacteria have the ability to amplify that resistance and transfer it to other bacteria. Such simple abuses jeopardize treatments in more urgent areas.
What I would like to do in the next few minutes is to provide an introduction to some of the commercial interests involving antibiotics. Among U.S. residents in the year 2000, there were approximately 83 million bacterial infections, with the vast majority (97 percent) acquired and treated outside hospitals. For a marketer, that is important data because it tells him that the prescriptions for these antibiotics are written by community-based physicians. In fact, primary care physicians wrote more than 60 percent of all of the antibiotic prescriptions in the United States. Additionally, the market itself is highly fragmented, with no single antibiotic holding even 25 percent share. The largest single antibiotic, amoxicillin, has 17 percent of the market with over 200 million prescriptions annually. However, amoxicillin itself represents many brands, as it is available generically. In contrast, Zithromax (azithromycin) is the largest patented brand, with 13 percent of the pie. Of the many other antibiotics, none represents more than 1 percent of the marketplace. While the market is highly fragmented, it is still worth a heck of a lot, nearly $6 billion a year, excluding animal use. These market percentages do not tell the entire story. For example, amoxicillin comprises 17 percent of the total prescriptions written, but only 2 percent of the actual sales dollars. That is because it is a generic drug. In contrast, Zithromax's 13 percent of the market accounts for 60 percent of the total dollars. The remaining groups of antibiotics, in comparison, represent only 38 percent of the sales income. The market, as a result, is both very fragmented and very competitive. The pharmaceutical industry invests a lot of money in selling antibiotics, conducting almost six million sales calls on physicians and delivering more than 55 different types of sample packages last year. Now, why are they doing that? Well, coupled with this $6 billion market and heavy competition, is the fact that pharmaceutical firms have a relatively short period to optimize their sales before their patents expire. Within the pharmaceutical sector there is a rule of thumb indicating that when a drug loses its patent, you can expect sales to decrease by 60 percent to 70 percent within 12 to 18 months. The rule suggests an urgency to make money while one can. Why is all of this important? The simple answer is that lots of antibiotics are soon to lose their patents, including some very large ones (e.g., Augmentin, Cipro, Zithromax); this is a change that will alter the marketplace dramatically. Given the large sums of money at stake, the limited window of opportunity, and the number of manufacturers competing for the same market share, we might correctly wonder if the "appropriate use of antibiotics" is in the best interest of the pharmaceutical industry? I believe the answer is actually "yes," precisely because of these market conditions. Appropriate use protects the research investments of pharmaceutical firms. If they develop a compound that then is rendered ineffective because of resistance, that investment goes down the drain. Appropriate use aligns the industry with the interests of their customers, both physicians and patients. Promoting appropriate use can avoid legal restrictions by federal and state governments. We may already be moving in that direction. If the industry learns how to police itself, it would certainly foster good will. Yet, there is plenty of evidence suggesting that the industry has not promoted appropriate use. For example, a wire release from January, 2003 announced that: "Pfizer, Inc. has agreed to resolve a multi-state investigation into allegations that it employed deceptive advertising to market its blockbuster drug, Zithromax, and has promised to pay for an education campaign aimed at clearing up misconceptions. Under terms of the agreement, Pfizer said it will add certain disclosure statements to future advertisements for Zithromax and will reimburse the states a total of $4 million for legal costs, as well as fund a $2 million public education campaign on the appropriate use of antibiotics. The company did not admit to any legal wrongdoing." We might remember that $6 million accounts for less than one-half of 1 percent of Zithromax's sales, so it is not terribly painful punishment.
Dr. Levy and Mr. Star have outlined several aspects to the problem of antibiotic resistance, and before I offer my remarks, I would like to repeat four of them. First, the problem of antibiotic resistance is growing and will likely pose a significant threat to public health in the coming decades. Second, physicians overprescribe newer broad-spectrum antibiotics, both in general instances where antibiotics are not likely to have therapeutic value and in cases where older narrow-spectrum antibiotics would work as well. Third, patients demand antibiotics from their physicians for ailments better suited to non-antibiotic treatments, often requesting the antibiotic by trade name. Fourth, the antibiotic market is highly fragmented, competitive and lucrative, presenting pharmaceutical firms with strong incentives to aggressively promote new broad-spectrum antibiotics before their profits are undercut by patent expiration and generic competition. At this point in our consideration, we might want to reflect on the relationship between this final factor and the prior three. In particular, we might wonder how much blame should be placed on the pharmaceutical giants for the problem of antibiotic resistance. Unfortunately, I will not be able to offer a quantitative reply to this question. Instead, I hope to broadly depict the nature of this connection by closely examining one particular firm, Pfizer, and one antibiotic, Zithromax. My remarks could apply equally well to other firms and other drugs, but I believe that my choice of examples is particularly illustrative. By all measures, Pfizer represents one of the giants among the big pharmaceutical firms, steadily increasing its market share year after year. Beyond its well-publicized mergers and acquisitions, Pfizer relies heavily on advertising to sustain its revenues and profits. In 1997, for example, Pfizer allocated $370 million to promoting its sundry products, $13.8 million of which it devoted to Zithromax. Pfizer netted $12.5 billion from its prescription drugs that year. By 1998, Pfizer stood as the 44th largest domestic purchaser of media advertising, promoting such blockbusters as Lipitor, Viagra, Zoloft and Zyrtec. 4 Pharmaceutical industry analysts have repeatedly praised Pfizer for its relentless marketing. Business Week, for example, named Karen Katen, President of Pfizer's U.S. Pharmaceuticals division, as one of its top 25 executives of 1998, in part because she beefed-up the domestic sales force by adding 750 additional drug reps, raising Pfizer's U.S. sales force to above 10,000 persons. In gushing terms, Fortune depicted Pfizer as a promotional juggernaut and a "marketing machine," noting that its reps logged an average of 459 doctor visits over a single six-month period (representing some 4,606 minutes of persuasion per rep). 5 Pfizer introduced the antibiotic Zithromax to the U.S. market in 1992, but did not bring the full force of its promotional might until some years later. In 1997, the company recruited the Minneapolis firm Campbell Mithun Esty to launch Zithromax's print campaign, the first ever direct-to-consumer effort for an antibiotic in the United States. Pfizer's initial "advertorials" appeared in such magazines as McCall's, Ladies Home Journal, and Newsweek, and offered a photograph of a baby gawking at 10 spoonfuls of medicine. The tagline highlighted Zithromax's lower dosage of five spoonfuls, reminding anxious parents that "Five days and you're done." In the fall of 1999, Pfizer transferred its estimated $15 million Zithromax direct-to-consumer account to the New York firm of Cline, Davis & Mann. Similar to the print ads of Campbell, Cline's campaigns targeted parents, and stressed Zithromax's shorter treatment regimen. Nevertheless, it was Pfizer's other promotional efforts, particularly those featuring Max the Zebra mascot, that drew attention. Almost immediately, Pfizer sales representatives began delivering plastic replicas of Max by the thousands, encouraging pediatricians to hang them from their stethoscopes and clip them to their hospital coats. For those pediatricians facing anxious youngsters, Pfizer reps supplied stuffed zebras as fuzzy comfort. At Children's Hospital in Boston, Max became so ubiquitous that several families assumed that the zebra was the hospital's mascot. The American Academy of Pediatric News, among other journals, were soon mailed with wrap-around advertisements featuring zebra stripes. Pfizer even donated a living zebra named Max to the San Francisco Zoo. Like R.J. Reynold's Joe Camel, Max the Zebra sauntered across many media formats. 6 The PBS's show Sesame Street announced, in 1999 and 2000, that its daily show was made possible by Pfizer, which "brings parents the letter Z, as in Zithromax." The spot featured a zebra and several children at play and a colorful tumbling wooden block with a Z on its sides. According to a global bench-marking study conducted by Innovara between 2001 and 2003, Pfizer's marketing of Zithromax set an enviable standard. Pfizer established "one of the most aggressive direct-to-consumer media campaigns that reinforced the brand through the use of the Zebra" image. Moreover, it "created pills with a large print brand name on them that require very little effort to pop out of their blister packs." Less than a year after the launch of the campaign, "not only were customers aware of the product and requesting it but doctors were prescribing it by simply writing 'Z Pak.' The report also cited the clever strategy of copyrighting the package, creating a nonsubstitutable product to help sustain brand loyalty after the patent expired. 7 Max certainly helped sales. Measured by the number of written prescriptions in 2003, Zithromax outpaced every other Pfizer product, with the exception of Lipitor. Yes, Pfizer sold more Zithromax than it did Norvasc, Zoloft, Viagra and Zyrtec. Zithromax represented the fifth most prescribed medicine in the country, netting Pfizer almost $1.5 billion in revenue. Moreover, by 2003, doctors wrote more prescriptions for Zithromax (39 million) than amoxicillin (37.7 million). And, its share of the market continues to rise. One year prior, Zithromax represented the 14th most commonly prescribed drug, while amoxicillin held the 12th spot. 8 As a recent synopsis in Advertising Age quipped, "No doubt that if you've been sick enough to head to the doctor, you've heard your physician talk about Pfizer's Z-Pack." We can return to my guiding question: does brand identification lead to antibiotic misuse? As many of you are aware, the subtleties and effectiveness of the large pharmaceutical firms' marketing efforts are well-documented. Physicians and American Medical Association officials have increasingly acknowledged the level of influence exercised by the glut of free pens, food, samples, flashlights, educational seminars, travel junkets and canvas bags. 9,10 Combined with direct-to-consumer-fueled patient expectations, this brand awareness might partially explain why nearly one-fifth of all prescriptions for broad-spectrum antibiotics were written for viral conditions (e.g., the common cold) where there is little clinical rationale for their use. With respect to Zithromax, the inappropriate use can actually be measured against Pfizer's promotional efforts. The print copy for many of its 1999 direct to consumer ads read: "Your son has another bacterial ear infection. He may need an antibiotic, and remember, he has to take all of it." As with its earlier promotions, the copy stressed the five day, once-a-day, dose. Yet, this campaign directly contradicted the recommendations of the Centers for Disease Control and Prevention (CDC). Pfizer marketed Zithromax for pediatric otitis media, despite its having no established therapeutic superiority over the generic amoxicillin. In fact, the CDC, backed by a panel of national pediatric experts, chose not to list Zithromax as the second-, or even the third-line, antibiotic. Furthermore, the guidelines warned that its use for otitis might encourage the development of resistant strains, as azithromycin often failed to kill the bacteria contributing to ear infections. Of course, Zithromax is highly effective against many types of adult pneumonia, as well as against other respiratory-tract infections, but from a marketing perspective, pediatric otitis proffered pay dirt. Ear infections constitute the most common reason that parents bring their child to a physician, prompting some 25 million office visits per year. Pfizer's pecuniary motives came under public scrutiny in the summer of 1999, when Dr. Sidney M. Wolfe, Director of the Public Citizen's Health Research Group, obtained an internal Pfizer company document. The memo specified that the new campaign's focus was "to counter the CDC guidelines," and convince doctors, via paid teleconferencing, to forego the inexpensive amoxicillin ($19 per full course) in favor of the more costly Zithromax ($35). In response, Wolfe and Joshua Sharfstein, then a Fellow in General Pediatrics at Boston Medical Center, sent an open letter to Donna Shalala, Secretary of Health and Human Services, decrying Pfizer's efforts.11 Within months, Oregon and 18 other states initiated investigations and legal action, alleging that the advertisements misrepresented the efficacy of Zithromax in comparison to other antibiotics in treating pediatric otitis. Specifically, the state attorneys general argued that Pfizer's direct-to-consumer ads failed to mention that physicians need to consider other factors besides dosing convenience, including antibiotic resistance, when prescribing antibiotics to treat ear infections. As Mr. Star mentioned, Pfizer reached a $6 million settlement with the 19 states. As part of that settlement, Pfizer agreed to fund "a $2 million public service announcement campaign during the next three years about the appropriate use of the medicine." These announcements will appear during the cold season, and will stress to parents that all antibiotics are ineffective against viral infection and that "only your doctor can decide what type of infection your child has and the best way to treat it." Still, Pfizer admitted no wrongdoing, and offered no apologies for its promotion of Zithromax for cases of childhood ear infections. Given this mild retreat, we might wonder what effect this $667,000 per cold-season public service campaign will have in the face of the $13.8 million that Pfizer spends promoting the drug. And, if we conclude that big pharmaceutical firms have an overriding incentive to promote new broad-spectrum antibiotics despite the long-term consequences, I wonder who might take the needed action to curb the counterproductive abuse of these vital drug therapies. Stuart B. Levy: I quite honestly believe that the responsibility lies with the prescriber and with the consumer. We are failing in our medical schools in that we do not teach our physicians to evaluate the data and deal with marketing. What disturbs me about the industry is their direct advertising to the consumer, which leads not only to patient demands, but also to consumer stockpiling of antibiotics. If I gave a more expanded lecture, I would have certainly mentioned pharmaceutical marketing. But if I am to highlight just two important features of antibiotic resistance, industry advertising is not going to be one of them. Larry Star: I think that there is common ground between the needs of the pharmaceutical industry and the needs of the medical profession. I also believe that pharmaceutical dollars could be spent on public education, without the pharmaceutical companies directing the content of these educational campaigns. We might think of the advertising campaigns developed to increase awareness of blood cholesterol. These ads informed Americans on the importance of knowing one's cholesterol level, and suggested means to reduce one's cholesterol. Those same marketing and communications techniques could be brought to bear on this issue as well. I am interested in pushing this issue of industry advertising just a bit further. Advertising, as we know, approaches the physician not just in a rational way, but also targets his or her motivations, psychological states and emotional frames. In essence, ads can target the nonrational aspects of prescribing. I am wondering if Larry Star might say a little on how the industry looks at physician motivation, and how the ad copy and images target those nonrational components. Larry Star: Physicians are consumers like all consumers. In the interviews with many, many thousands of physicians that I have conducted over my career in market research, I have found that if you ask them rational questions, they will give you rational answers. If you ask them different kinds of questions, however, you will get emotional responses. Pharmaceutical marketers, like all product marketers, look to manipulate those emotional connections in order to get physicians to prefer and choose certain products and particular brands. It is a common practice. We might look at some of the issues that came up today, such as the threat of legal liability. That is a huge concern hanging over the heads of many physicians. An ad for effective antibiotics might refer to an emergency room at 12 midnight, with a doctor examining a patient who might not get the right follow-up. The copy and image might begin with the thought: "If you can't be 100 percent sure, you can get some more peace of mind by just writing for an antibiotic." In market research, we try to understand those emotional triggers that would lead a physician to make the decision to prescribe a brand. Audience Member: When I hear Mr. Star and Dr. Levy refusing to assign any responsibility to the pharmaceutical industry on the grounds that, after all, the doctor is the prescriber, I think of the ethics of the bribe. Who is more culpable, the briber or the bribee? Doctors are in effect bribed to prescribe and pharmaceutical companies clearly bribe them to prescribe. My answer is that the responsibility rests with both sides; I don't excuse the medical profession, and I don't excuse the pharmaceutical industry either. Stuart Levy: I will still say that the professional groups bear the responsibility and we as physicians, should stand up and decide when the industry behaves in an unethical manner. Certainly the industry will not make these changes on its own. Footnotes1 Neuhauser M, et al. Antibiotic resistance among gram-negative bacilli in US intensive care units: Implications for flouroquinolone use. JAMA 2003;289:885-88. 2 Levy S. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys their Curative Powers. Cambridge: Perseus Publishing, 2002. 3 Alliance for the Prudent Use of Antibiotics. 4 10 drugs by prescription source: NDC Health through November 2003 Advertising Age (22 Dec. 2003);74:28-30. 5 Clifford L. Tyrannosaurus Rx. Fortune 2003;142(10):140. 6 Petersen M. What's black and white and sells medicine? The New York Times August 27, 2000:p.C1 [http://www.nytimes.com/library/ financial/sunday/082700biz-pfizer.html]. 7 Blauvelt B. Benchmarks for blockbuster launches. Pharmaceutical Executive 2003;(2):56. 8 Vaczek D. Top 200 drugs of 2000. Pharmacy Times 2003;69(4):20-4. 9 Wazana A. Physicians and the pharmaceutical industry: is a gift ever just a gift? JAMA 2000; 283:373-80. 10 Sharfstein J. Pfizer night at Boston Billiards. N Eng J Med 1997;337(2):134. 11 Sharfstein J, Wolfe SM. Letter to the department of health and human services concerning Pfizer's campaign to counter the Centers for Disease Control recommendations for treatment of ear infections. August 3, 1999.
The opinions expressed in the journal, Lahey Clinic Medical Ethics, |
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