Editorials

Controlling Antibiotic Resistance: Will We Someday See Limited Prescribing Autonomy?

ARCH G. MAINOUS III, PH.D.
WILLIAM J. HUESTON, M.D.
Medical University of South Carolina
Charleston, South Carolina

See article in this issue.

In their article in this issue of American Family Physician, Hooten and Levy¹ point out that drug-resistant microorganisms are a growing global problem. Use of antimicrobial agents creates an environment open to the development of resistance, placing both general populations and individual patients at risk. Antibiotic resistance has been shown to be proportional to the volume of antibiotic consumption; reduction in resistance requires a proportional reduction in consumption.² Consequently, judicious use of antibiotics must be part of the solution to the problem of drug resistance. Otherwise, the current concern about a "post-antimicrobial era," in which antimicrobial agents will no longer be effective, may become a reality.

Recently, the U.S. Food and Drug Administration proposed that all antibiotics dispensed in the United States contain warning labels encouraging physicians to prescribe antibiotics only when clinically necessary and to talk with patients about taking the medication exactly as directed.³ As an example, although evidence documents the lack of benefit and possible harm of antibiotic therapy for the treatment of many respiratory tract infections, antibiotics continue to be prescribed for these primarily viral conditions.^4,5

The overall goal of reducing antibiotic prescriptions should be to minimize antibiotic resistance while appropriately delivering quality health care. Effective strategies to accomplish this goal must be identified, and all health care groups must promote and participate in efforts to reduce antibiotic resistance. Education is integral to Hooton and Levy's¹ plan to reduce antibiotic resistance.

Overuse of antibiotics may relate to misinformation or misunderstanding about which infections benefit from the use of an antibiotic. For example, most patients understand that antibiotics are not needed for colds. But when they find they have discolored, rather than clear, nasal discharge with symptoms of a cold, the vast majority of them think an antibiotic is necessary treatment.⁶ Where did they learn this? This misinformation may have come from physicians and pharmacists who, when presented with the same description of signs and symptoms, also thought antibiotic therapy was necessary.^7,8 Knowing not to use antibiotics to treat viral infections is not the only thing that matters--knowing what is a viral infection is also important.

Currently, in the United States, access to antibiotics is more restricted than it is in many other countries. In many countries, antibiotics are legally available without a prescription or existing regulations are not uniformly enforced. Studies indicate that in countries with little regulation of antibiotics, substantial misuse occurs. People in these countries frequently self-diagnose their ailments and buy antibiotics in quantities too small to kill all bacteria but large enough to promote resistance.^9-14 In a town on the U.S. side of the U.S.­Mexico border, 75 percent of those questioned had purchased antibiotics in Mexico without a prescription.¹⁰

It is likely that the use of antibiotics without a prescription mirrors cultural systems of self-diagnosis and self-management. In a study¹⁵ of Bronx residents, 26 percent reported using nonprescribed antibiotics for upper respiratory tract infections in the past year. Thirty-one percent of the persons in this study believed that antibiotics should be available on an over-the-counter basis. Depending on their birthplace or the birthplace of their mother, persons were divided into three groups that reflected control of antibiotic access in the different countries. Those from countries where antibiotics are available without a prescription were more likely than those from countries with some regulations or the U.S. group to report using antibiotics that were not prescribed by a physician to treat a cough or a cold (40 percent versus 30 percent versus 20 percent, respectively; P < 0.05).

It is clear that education is warranted, but many of the general passive educational interventions employed up to this point have yielded disappointing results. An exception was shown in the results of a study¹⁶ conducted in a closed setting in which education was provided by physicians' immediate supervisors. Widespread dissemination of practice guidelines is not an effective means of changing practice.¹⁷ Even government-sponsored or third-party feedback on prescribing patterns has not been shown to have an impact on the antibiotic prescribing habits of generalist physicians.^18,19

In contrast, the use of administrative or financial controls has been successful in limiting antibiotic use and decreasing resistance. Antibiotic control policies are usually institutional interventions that create barriers to inappropriate practices and limit prescriber autonomy. Administrative interventions may also come from governmental agencies, which enforce specific practices through laws, regulations or recommendations.

Inpatient antibiotic control programs have been successful and contain mechanisms such as automatic therapy stop dates. Other programs require clinical justification for the specific antibiotic order before it can be dispensed by the pharmacy. In a 1996 survey,²⁰ 81 percent of university-affiliated teaching institutions were shown to have used antibiotic restriction policies and 56 percent to have used official recommendations to guide antibiotic use.

Restricting the use of specific antibiotics and antibiotic classes has been effective in altering patterns of resistance in individual institutions. In a hospital with significant rates of cephalosporin-resistant Klebsiella pneumoniae, an antibiotic control policy was developed that, in general, excluded the use of cephalosporins without prior approval from an infectious disease expert.²¹ In one year, ceftazidime-resistant Klebsiella was reduced by 36 percent in nosocomial infections.

In Finland, a national initiative²² restricted the use of erythromycin and other macrolide antibiotics in the treatment of respiratory and skin infections in outpatients in an effort to combat erythromycin resistance among group A streptococci. This initiative led to a decline in the use of macrolide antibiotics from 2.4 defined daily doses per 1,000 in 1991 to 1.38 defined daily doses per 1,000 in 1992. In return, a decrease in the frequency of erythromycin resistance was noted, from 16.5 percent in 1992 to 8.6 percent in 1996.

Currently, the biggest risk factor for the development of drug resistance in the United States is that patients continue to consult a physician for help with a viral infection. Because of the limited success of most guidelines and educational interventions coupled with the increasing levels of antibiotic resistance, extraordinary strategies may be required to prevent antibiotic resistance. We must find a way to educate patients about when it is necessary to see a physician for upper respiratory symptoms, keep ourselves from prescribing antibiotics or change the way these medications are used. The choice from the physicians' perspective is clear. If we fail to reduce injudicious antibiotic use ourselves, someone else will find a way to do it for us.

Arch G. Mainous III, Ph.D. is an associate professor and director of research in the Department of Family Medicine at the Medical University of South Carolina in Charleston, S.C.

William J. Hueston, M.D., is a professor and chair of the Department of Family Medicine at the Medical University of South Carolina.

Address correspondence to Arch G. Mainous III, Ph.D., Department of Family Medicine, Medical University of South Carolina, P.O. Box 250192, 295 Calhoun St., Charleston, SC 29425.

REFERENCES

1. Hooten TM, Levy SB. Antimicrobial resistance: a plan of action. Am Fam Phys 2001;63:1087-96, 1097-8.
2. Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci USA 1999;96: 1152-6.
3. Warnings sought for antibiotic prescriptions. The Nation's Health Nov 2000:1,12.
4. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901-4.
5. Mainous AG 3d, Hueston WJ, Clark JR. Antibiotics and upper respiratory infections: do some folks think there is a cure for the common cold? J Fam Pract 1996;42:357-61.
6. Mainous AG 3d, Zoorob RJ, Oler MJ, Haynes DM. Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization. J Fam Pract 1997;45:75-83.
7. Mainous AG 3d, Hueston WJ, Eberlein C. Colour of respiratory discharge and antibiotic use [Letter]. Lancet 1997;350:1077.
8. Mainous AG 3d, MacFarlane LL, Connor MK, Green LA, Fowler K, Hueston WJ. Survey of clinical pharmacists' knowledge of appropriateness of antimicrobial therapy for upper respiratory infections and acute bronchitis. Pharmacotherapy 1999;19:388-92.
9. Multicenter study on self-medication and self-prescription in six Latin American countries. Drug Utilization Research Group, Latin America. Clin Pharmacol Ther 1997;61:488-93.
10. Casner PR, Guerra LG. Purchasing prescription medication in Mexico without a prescription. The experience at the border. West J Med 1992;156:512-6.
11. Van Duong D, Binns CW, Van Le T. Availability of antibiotics as over-the-counter drugs in pharmacies: a threat to public health in Vietnam. Trop Med Int Health 1997;2:1133-9.
12. Schorling JB, De Souza MA, Guerrant RL. Patterns of antibiotic use among children in an urban Brazilian slum. Int J Epidemiol 1991;20:293-9.
13. Calva J, Bojalil R. Antibiotic use in a periurban community in Mexico: a household and drugstore survey. Soc Sci Med 1996;42:1121-8 [Published erratum appears in Soc Sci Med 1996;43(1):I].
14. Hossain MM, Glass RI, Khan MR. Antibiotic use in a rural community in Bangladesh. Int J Epidemiol 1982;11:402-5.
15. McKee MD, Mills L, Mainous AG 3d. Antibiotic use for the treatment of upper respiratory infections in a diverse community. J Fam Pract 1999;48:993-6.
16. Gonzales R, Steiner JF, Lum A, Barrett PH. Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults. JAMA 1999;281:1512-9.
17. Bero LA, Grilli R, Grimshaw JM, Harvey E, Oxman AD, Thomson MA. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. The Cochrane Effective Practice and Organization of Care Review Group. BMJ 1998;317:465-8.
18. O'Connell DL, Henry D, Tomlins R. Randomised controlled trial of effect of feedback on general practitioners' prescribing in Australia. BMJ 1999; 318:507-11.
19. Mainous AG 3d, Hueston WJ, Love MM, Evans ME, Finger R. An evaluation of statewide strategies to reduce antibiotic overuse. Fam Med 2000;32(1): 22-9.
20. Lesar TS, Briceland LL. Survey of antibiotic control policies in university-affiliated teaching institutions. Ann Pharmacother 1996;30(1):31-4.
21. Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J, et al. Class restrictions of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 1998; 280:1233-7.
22. Seppala H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med 1997;337:441-6.

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Cancer Screening in Perspective

THOMAS J. GATES, M.D.
Lancaster General Hospital
Lancaster, Pennsylvania

See article in this issue.

One of the most common reasons for visits to family physicians is the detection of asymptomatic disease, or screening--especially screening for cancer. In this issue of American Family Physician, Zoorob and colleagues¹ provide a useful summary of current guidelines for cancer screening in adults. Two facts stand out from their review. First, compelling evidence and relatively unanimous agreement exist for only three cancer screening recommendations: Papanicolaou (Pap) smears; mammography in women older than 50 years; and fecal occult blood testing (FOBT), flexible sigmoidoscopy or colonoscopy to screen for colon cancer. Second, a plethora of medical organizations, government task forces, specialty societies and advocacy groups are making recommendations that are sometimes contradictory. I believe that in order to make sense of current as well as future screening controversies, three tasks are essential for the family physician.

1. We must understand the nature of evidence that is required to justify screening tests. The value of screening and early detection seems intuitively obvious to us but, in fact, our intuition is often misleading. Specifically, certain types of bias frequently lead to an overestimation of the benefits of screening.^2,3

"Lead-time" bias occurs because diagnosis by screening during the asymptomatic period will lead to improvement in such surrogate measures as five-year survival rates and median survival rates, even in the absence of therapy. However, the apparent increase in survival time does not necessarily mean that patients are living longer but, rather, that they find out about their disease earlier. Final mortality may remain unchanged despite improvements in five-year survival rates, as it did in lung cancer screening trials.⁴

"Length-time" bias occurs because slow-growing, less aggressive tumors by definition have a longer asymptomatic period and are therefore more likely to be detected by screening. Consequently, screening programs preferentially identify a cohort of patients with less aggressive tumors; even in the absence of therapy, these patients will have a better prognosis than patients who present with symptomatic disease.

Finally, "screening" bias refers to the observation that patients who volunteer for screening (or in randomized trials, those who comply with screening recommendations) tend to be healthier than those who do not volunteer or do not comply. Thus, an observed benefit may be the result of self-selection of a cohort of healthier volunteers rather than an observed benefit from screening.

Because of the complex and unpredictable nature of these various biases, the only reliable way to prove the effectiveness of a screening intervention is to demonstrate a lower mortality rate in a randomly assigned screened population, compared with unscreened control patients, using intention-to-treat analysis.^2,3 Such studies are long and expensive, but screening interventions that have not met this standard should be considered unproven and experimental.

2. We must recognize the unique ethical context of the screening encounter. In ordinary medical practice, the patient initiates the encounter because of a troubling symptom and is often willing to accept reasonable but unproven therapy in hopes of finding relief. In contrast, the screening encounter is usually initiated by the physician (although sometimes indirectly, through professional or advocacy groups) and involves an asymptomatic and presumably healthy patient. In this situation, there is an "implied promise," not just that the screening procedure might be worthwhile, but that it is, in fact, of proven benefit, and likely to result in more good than harm being done.²

Even if a screening test has proven benefits, those benefits accrue to only a few individuals. In contrast, everyone who participates in a screening program is at risk of harm.⁵ Over and above the cost and discomfort of the actual test, screening can harm patients by having false-positive results (e.g., the 50 percent 10-year cumulative false-positive rate for mammography),⁶ false-negative results (e.g., false reassurance in a smoker with a negative result on chest radiography), and even by a true-positive result if the therapy is unproven and potentially dangerous (e.g., radical prostatectomy for low-grade localized prostate cancer).

Exposing healthy asymptomatic patients to known harm when benefits are unproven creates an undeniable ethical burden, which is too often neglected by physicians during the screening encounter.^5,7,8

3. Finally, for proven screening interventions, we must understand the magnitude of the potential benefit and be able to convey this to our patients in a meaningful way. The efficacy of screening interventions is most often reported in terms of the relative risk reduction (RRR); for example, "mammography reduces breast cancer mortality by 23 percent" rather than the absolute risk reduction (ARR); for example, "annual mammography has a 0.2 percent chance of preventing an individual woman's death from breast cancer over 10 years."

However, the number needed to screen (analogous to the number needed to treat in therapeutic trials, calculated as the reciprocal of the ARR)⁹ provides a better method of expressing the effectiveness of a screening intervention.¹⁰ Numbers needed to screen (i.e., the number of patients that would have to be enrolled in an ongoing screening program, here normalized over 10 years, to prevent one death from the disease in question) vary from about 540 (for mammography in women older than 50 years) to about 1,100 (for Pap smears), with numbers for FOBT screening falling between those two.

Physicians may become discouraged by the apparent inefficiency of screening for cancer as measured by the relatively high numbers needed to screen. We must keep in mind, however, that by scrupulous adherence to cancer screening guidelines and proven screening interventions, the average family physician can expect to prevent several premature deaths from cancer over the course of a professional career. High numbers needed to screen also remind us that true prevention (e.g., preventing lung cancer by encouraging smoking cessation) will usually be more efficient than early detection through screening. Likewise, these numbers remind us that, for most patients, careful attention to cardiovascular risk factors (smoking, hypertension, hyperlipidemia and physical inactivity) will yield higher dividends than cancer screening.¹⁰

One of our most challenging tasks as family physicians is to better convey this kind of prioritizing information to our patients--especially those sedentary, noncompliant, hypertensive patients who smoke, and who come in each year for their prostate-specific antigen screening.

Thomas J. Gates, M.D., is associate director of the family practice residency program at Lancaster General Hospital, Lancaster, Pa.

Address correspondence to Thomas J. Gates, M.D., Department of Family Medicine, Lancaster General Hospital, 555 N. Duke St., Lancaster, PA 17604.

REFERENCES

1. Zoorob R, Anderson R, Cefalu C, Sidani M. Cancer screening guidelines. Am Fam Physician 2001;63: 1101-12
2. Sackett DL. Clinical epidemiology: a basic science for clinical medicine. 2d ed. Boston: Little, Brown, 1991:153-70.
3. Barratt A, Irwig L, Glasziou P, Cumming RG, Raffle A, Hicks N, et al. Users' guides to the medical literature: XVII. How to use guidelines and recommendations about screening. JAMA 1999;281:2029-34.
4. Collins MM, Barry MJ. Controversies in prostate cancer screening. Analogies to the early lung cancer screening debate. JAMA 1996;276:1976-9.
5. Marshall KG. Prevention. How much harm? How much benefit? 4. The ethics of informed consent for preventive screening programs. Can Med Assoc J 1996;155:377-83.
6. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998;338:1089-96.
7. Malm HM. Medical screening and the value of early detection. When unwarranted faith leads to unethical recommendations. Hastings Cent Rep 1999;29:26-37.
8. Doukas DJ, Fetters M, Ruffin MT 4th, McCullough LB. Ethical considerations in the provision of controversial screening tests. Arch Fam Med 1997;6: 486-90.
9. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310:452-4.
10. Rembold CM. Number needed to screen: development of a statistic for disease screening. BMJ 1998;317:307-12.

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