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Antibiotic resistance: Careful antibiotic use can help control the growing problem

Antibiotic resistance is a serious and growing health problem, gaining national attention as resistance increases at an alarming rate in both hospital and physician practice settings.1,8 To help curb resistance, there is an urgency to both improve physician prescribing practices and for more accurate diagnosing of those conditions for which an antibiotic is indicated. This is reflected through increased efforts on behalf of national organizations, including the Centers for Disease Control (CDC), National Institutes of Health (NIH) and the World Health Organization (WHO), to address this problem.1,8 For example, the CDC recently implemented multidisciplinary partnerships to reduce antibiotic use.1 Additionally, the Alliance for the Prudent Use of Antibiotics (APUA) was established in 1981, to focus solely on the issue of curbing antibiotic resistance. This organization, established by leading worldwide thoughtleaders in infectious disease, public health and human and veterinary medicine, has a network of members in 100 countries and works in collaboration with public health groups including CDC, NIH and WHO. Despite numerous published guidelines from respected governmental and professional groups, antibiotic restriction policies in many hospitals, and entreaties by colleagues, some physicians continue to prescribe antibiotics excessively and inappropriately and some patients continue to demand antibiotics against their doctors' advice.2

Antibiotic resistance30,31,32
Antibiotic resistance has become an increasingly pressing problem in the US.3,4 Bacteria that consistently have been susceptible to antimicrobial agents for decades now have developed resistance not only to classic therapies but to newer agents as well. Other bacteria have developed resistance to recent antibiotics almost as soon as the drugs have been marketed.5 In some cases, strains of bacteria, both hospital- and community-acquired, that have developed resistance to numerous antibiotics have become so prominent that keeping patients with serious infections alive has become a difficult task, just as in the pre-antibiotic era.6,7

Bacterial resistance to drug therapy was first discovered in the 1940s, following the introduction of penicillin.1,8 However, more types of bacteria have demonstrated resistance, and at an increasingly swift rate, to newer and more powerful antibiotics.1,8 In fact, some common strains of disease-causing bacteria show antibiotic resistance in as many as 50 to 90 percent of strains. Medical care costs associated with treating infections in humans due to antibiotic-resistant microorganisms are estimated to be over $4 billion annually in the US.8

Bacteria that fight back
Bacteria are microorganisms with simple cell structures that invade the body, multiply quickly and can cause infection. Antibiotics combat infection by interfering with vital functions and/or reproduction of bacteria. However, bacteria have a natural ability to become resistant to drugs through mutation. When bacteria mutate, they change their structure to prevent drug contact, or produce chemicals, which interfere with drug effects, ultimately resulting in antibiotic resistance.9

For example, when a person takes an antibiotic to treat an illness, the drug kills susceptible bacteria, while sparing others that can resist it. These surviving bacteria-those that have the ability to resist the antibiotic - then multiply, increasing their numbers exponentially, becoming a predominant microorganism.

Why the growth of antibiotic resistance?
Three factors influence the evolution of resistant microorganisms:9

• mutations in common bacterial genes;
• exchange of genetic material (e.g., DNA) between bacteria, a process called transformation, has moved some resistance genes from their original hosts into new organisms, causing them to become resistant to additional antimicrobial agents; and
• selective pressure caused by the use of large quantities of antibiotics not just within the hospital environment, but in community, farm and aquaculture settings.

The laws of natural selection dictate that bacteria will eventually develop resistance to practically any antibiotic. Selective pressure exerted by widespread antimicrobial use is a driving force in the development of antibiotic resistance.7 This is why improving the use of antibiotics is the one known thing we, as humans, can do to control antibiotic resistance.

Societal factors contribute to resistance
According to a recent article in The Journal of the American Medical Association, physicians often over-prescribe antibiotics because of patient expectations, insufficient time to discuss with patients why an antibiotic is not needed, and concern that they may misdiagnose bacterial infections when an antibiotic is indicated.10 According to the CDC, it is estimated that 50 percent of all antibiotic prescriptions written by doctors are unnecessary.11 Much of the increase in antibiotic resistance is a result of the use of antibiotics for viral infections, such as the common cold. Additionally, unlike years ago, physicians have less time to spend with patients in order to make an accurate diagnosis.12 Together, these factors may contribute to the misdiagnosis of diseases and the misuse of antibiotics.
In today's society, patients assume a more active role in their health care, diagnosis and treatment. Patients are much more educated about illnesses and available treatment options.12 Many times patients often expect, sometimes even demand, to be prescribed antibiotics for their illnesses, even when it may not be appropriate.12 Patients also request specific antibiotics which may be stronger than necessary to treat their bacterial infection. Other times patients request antibiotics even after a physician explains that an illness is viral and that prescribing antibiotics will not be effective.12 These patient-related factors can contribute to the development of resistant bacteria.13

Illustrative examples: careful treatment of simple infections may help prevent resistance in more serious infections

Urinary tract infections
In the US, UTIs account for approximately 5.2 million office visits each year and add $1 billion to the cost of ambulatory care. In addition, the financial burden for hospitalized patients is considerable because the urinary tract is the most common site for hospital-acquired infections.14 It is estimated that one in two women develop a UTI at some point in their lives, and even worse, approximately 80 percent of these women will have a recurring UTI within 12 to 18 months.15
Acute cystitis (a common form of UTI) in young women is caused predominantly by Escherichia coli (E. coli) and Staphylococcus saprophyticus (S. saprophyticus). These two bacteria are responsible for up to 95 percent of all cases of acute cystitis while the remainder is caused primarily by Klebsiella species and Proteus mirabilis.16 Due to the fact that a limited number of bacteria are responsible for the majority of acute cystitis cases in young women, narrow spectrum antibiotics targeted specifically to those bacteria may be employed.

Otitis media28, 29
Otitis media, or inflammation of the middle ear, is the most frequent diagnosis recorded for children under the age of 15 who visit physicians for illness. Approximately one-third of all children in the US have more than three ear infections during the first three years of life, resulting in 30 million doctor visits per year. Additionally, otitis media is the most common cause of hearing loss in children however, if treated promptly and effectively, it is not serious and hearing can almost always be restored to normal. Eighty to 85 percent of cases of otitis media are caused by bacteria, mainly Streptoccoccus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis.
The CDC considers otitis media the most common condition resulting in unnecessary use of antibiotics. Seventy percent of children with otitis media will get better without antibiotics. Although otitis media is most common in young children, it affects adults occasionally, and occurs most commonly in the winter and early spring months. As with UTIs, since a limited number of bacteria are responsible for most otitis media infections, narrow spectrum antibiotics targeted specifically to those bacteria should be employed as the first line agents.

Treatment for UTIs and otitis media
Physicians often treat acute cystitis and otitis media with broad spectrum antibiotics such as cephalosporins and fluoroquinolones.17 However, simple infections like acute cystitis and acute otitis media can be treated with narrow spectrum antibiotics, in order to preserve the broad spectrum antibiotics for more serious infections.18 Many experts agree that treatment should start with narrow spectrum antibiotics and antibiotics that achieve low tissue concentrations. It is expected that drugs with these characteristics will target specific bacteria in specific areas of the body, resulting in a decreased risk of drug resistance in more serious infections.2,18

Bacterial resistance in the community: controlling the problem
Before 1987, antibiotic-resistant Streptococcus pneumoniae (bacteria responsible for community-acquired pneumonia, meningitis, middle ear infections in children and other illnesses) were uncommon in the US However, recent reports document an increase in pneumonoccal infections resistant to commonly used antibiotics.7 In fact, penicillin-resistant strains to S. pneumoniae in the US are now approaching 45 percent.3,4
According to the CDC, most antibiotic use in humans is for treatment of outpatient infections. For example, in 1992, an estimated 110 million courses of antibiotic therapy were prescribed by office-based physicians in the US, a 28 percent increase from 1980.7 Without changes in treatment practices, resistant strains such as these will become commonplace, as is already the case in other parts of the world.3,4
Most alarming, is the recent appearance in the community of a lethal strain of a resistant S. aureus germ, which resulted in the death of four children and sickness of over 200 people in Minnesota and North Dakota over a two-year period. This development surprised infectious disease experts who are now concerned that this superbug has ventured out from the intensive care units, and can now wreak havoc in community settings such as schools and day care centers.

Reducing antibiotic resistance
Both health care practitioners and patients can play an active role in helping to curb the growing problem of antibiotic resistance. In the past, antibiotic resistance was considered a global health concern that had limited relevance for individual physicians. However, now as primary care physicians are witnessing resistance in their own communities and practices, they are beginning to recognize that they must alter their prescribing patterns and educate their patients about ways to prevent this problem from escalating.

Several factors can help minimize the development of antibiotic resistance. From a physician standpoint these include:23

• making an accurate diagnosis
• using appropriate antibiotic combinations
• considering use of a narrow spectrum antibiotic in simple infections in order to preserve broad spectrum antibiotics for more serious infections
• avoiding unnecessary antibiotic use for viral infections, such as the common cold, and overuse for serious infections
• if treating empirically, revising treatment based on patient progress and/or test results

Additionally, patients can help to reduce antibiotic resistance by following several simple guidelines including:24,27

• taking antibiotics exactly as directed since certain medications are required to be taken with or without food;
• avoiding demand for antibiotics against your physician's advice;
• taking all medication prescribed even if symptoms disappear because if treatment stops too soon, some bacteria may survive and re-infect; and
• avoiding request of specific antibiotics from your physician because the medication chosen needs to be tailored to the specific type of infection.

Conclusion
For many decades, the first line of defense against bacterial resistance has been the development of new antimicrobials. However, new classes of antibiotics that can be used against organisms that have been resistant to previous antibiotic treatments are not likely to be available for several years, and any new antibiotic that comes out is doomed to a short life without adhering to prudent use guidelines.7,25 Overuse and misuse of newer, broad spectrum antimicrobial agents has accelerated the problem.8,9 Improving antimicrobial use is a cornerstone of dealing with multiresistant hospital and community organisms.23
If the problem of antibiotic resistance is to be reduced, clinicians need to concentrate their efforts not only on antibiotic use (misuse/overuse) but also on additional factors that contribute to resistance, such as handwashing and other infection control measures.26 However, the problem will not be solved until the entire health-care delivery system becomes involved in the campaign.25 The medical establishment, regulatory committees, infectious disease specialists and community physicians need to come together to provide leadership for promoting proper use of antibiotics. Without aggressive collaboration, we may be faced with a public health crisis and return to the pre-antibiotic era.9

References

1. Low DE and Scheld WM. Strategies for stemming the tide of antimicrobial resistance. JAMA 1988; 279(5):394-395.
2. Goldman DA, Weinstein RA, Wenzel RP, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals: A challenge to hospital leadership. JAMA 1996; 275(3):234-240.
3. Doern GV. Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract. Am J Med 1995; 99(Suppl 6B):3S-7S.
4. Doern GV, Brueggamann A, Holley HP, et al. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the united States during the winter months of 1994 - 1995: Results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996; 40:1208-1213.
5. Coronodo BG, Edwards JR, Culver DH, et al. Ciprofloxacin resistance among nosocomial Psuedomonas aeruginosa and Staphylococcus aureus in the United States. Infect Control Hosp Epidemiol 1995; 16:71-75.
6. Cohen ML. Epidemiology of drug resistance: Implications for a post-antimicrobial era. Science 1991; 257:1050-1055.
7. Greenwood D. Preserving the miracle of antibiotics. Lancet 1995; 345:1371.
8. Report of the ASM Task Force on Antibiotic Resistance. American Society of Microbiology. Supplement to Antimicrob Agents Chemother. 1995.
9. Tenover FC and McGowan JE. Reasons for the emergence of antibiotic resistance. Am J Med Sci 1996; 311(1):9-16.
10. Schwart BH, Bell DM, Hughes JM. Preventing the emergence of antimicrobial resistance: A call for action by clinicians, public health officials, and patients. JAMA 1997; 278(11):944-945.
11. Cohen M. Antimicrobial Resistance: Issues and Options (Harrison PR & Lederberg J, Eds) pp. 38 - 41. Institute of Medicine, National Academy Press, Washington, DC, 1998.
12. Cohen M. Antimicrobial Resistance: Issues and Options (Harrison PR & Lederberg J, Eds) pp. 44 - 49. Institute of Medicine, National Academy Press, Washington, DC, 1998.
13. US Congress, Office of Technology Assessment. Impacts of Antibiotic-Resistant Bacteria. OTA-H-629. Washington, DC, September 1995. Presented by Mitchell L. Cohen, Centers for Disease Control and Prevention, 1997.
14. Powers RD. New direction in the diagnosis of urinary tract infections. Am J Obst Gynecol 1991; 164:1387-1389.
15. National Institute of Diabetes & Digestive & Kidney Disease, NIH Publication No. 88-2097, April 1988.
16. Stamm WE. Management of acute uncomplicated cystitis in women. Hospital Medicine 1996; June Supplement:3-8.
17. Hatton J, Hughes M, Raymond CH. Management of bacterial urinary tract infections in adults. Ann Pharmacother 1994; 28:1264-1272.
18. Culp LA and Culley CC. Antibiotic resistance in the genitorurinary system. Contemporary Urology 1998; 10(7):58-75.
19. Reid G and Seidenfeld A. Drug resistance amongst uropathogens isolated from women in a suburban population: Laboratory findings over 7 years. Can J Urol 1997; 4(4):432-437.
20. Cunney RJ, McNally RM, McNamara, et al. Susceptibility of urinary pathogens in a Dublin teaching hospital. Ir J Med Sci 1992; 161:623-625.
21. Thomson KS, Sanders WE, Sanders CC. USA resistance patterns among UTI pathogens. J Antimicrob Chemother 1994; 33(Suppl A):9-15.
22. Cuhna BA. Factors in the development and maintenance of a rationale antibiotic formulary. Formulary 1998; 33:558-572.
23. Stratton, CW. Avoiding fluoroquinolone resistance: Strategies for primary care practice. Postgraduate Medicine 1997; 101(3):247-250, 255.
24. PDR Family Guide Encyclopedia of Medical Care.
25. Gaynes R. Antibiotic resistance in ICUs: A multifaceted problem requiring a multifaceted solution. Infect Control Hosp Epidemiol 1995; 16:328-330.
26. Patterson JE, Sanchez RO, Hernandez J, et al. Special organism isolation: Attempting to bridge the gap. Infect Control Hosp Epidemiol 1994; 15:335-338.
27. Alliance for the Prudent Use of Antibiotics patient pamphlet. Sponsored by Procter & Gamble and approved by the American Academy of Family Physicians.
28. American Academy of Otolaryngology - Head and Neck Surgery public service brochure.
29. American Medical Association web site.
30. Levy SB. 1993. Confronting multidrug resistance: a role for each of us. JAMA 269(14): 1840-1842.
31. Levy SB. 1998. Multi-drug resistance - As sign of the times. New England Journal of Medicine 338(19): 1376-1378.
32. Levy SB. 1998. The challenge of antibiotic resistance. Scientific American 278(3): 32-39.

Published 11/99