The judicious use of antibiotics - An investment towards optimized health care
http://www.100md.com
《美国医学杂志》
1 Department of Infectious Diseases, St. Jude Children's Research Hospital, and Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
2 Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Abstract
During the past century the excitement of discovering antibiotics as a treatment of infectious diseases has given way to a sense of complacency and acceptance that when faced with antimicrobial resistance there will always be new and better antimicrobial agents to use. Now, with clear indications of a decline in pharmaceutical company interest in anti-infective research, at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of the available agents to fight these micro-organisms. Injudicious use of antibiotics is a global problem with some countries more affected than others. There is no dearth of interest in this subject with scores of scholarly articles written about it. While over the counter access to antibiotics is mentioned as an important contributor towards injudicious antibiotic use in developing nations, as shown in a number of studies, there are many provider, practice and patient characteristics which drive antibiotic overuse in developed nations such as the United States. Recognizing that a thorough review of this subject goes far and beyond the page limitations of a review article we provide a summary of some of the salient aspects of this global problem with a focus towards readers practicing in developing nations.
Keywords: Antibiotics; Anti-microbial agents; Multi-drug resistant micro-organisms
Antibiotic resistance is a natural phenomenon - resistant strains of micro-organisms have been noted close on the heels of antimicrobial discovery.[1] It is undeniable that antibiotic use (and overuse) contributes to development of resistance. The development of newer antibiotics, in part responding to the emergence of resistant microorganisms, has resulted in a sense of complacency on the part of the general public and medical care providers. Now, with clear indications of a decline in pharmaceutical company interest in anti-infective research, at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of the available agents to fight these micro-organisms.[2]
The dictionary meaning of judicious is "having or showing reason and good judgment in making decisions". With reference to antibiotics, judicious use implies using an antibiotic only when indicated , choosing a cost-effective agent which provides appropriate antimicrobial coverage for the diagnosis that is suspected and prescribing the optimal dose and duration of the antimicrobial. The WHO Global Strategy for Containment of Antimicrobial Resistance defines the appropriate use of antimicrobials as the cost-effective use which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance (http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf).
Injudicious use of antibiotics for both humans and animals[3] has long been recognized as a global problem. While over the counter access to antibiotics is mentioned as an important contributor towards injudicious antibiotic use in developing nations, as shown in a number of studies there are many provider, practice and patient characteristics which drive antibiotic overuse in developed nations such as the United States. Numerous approaches have been proposed as a solution to this complex, multi-factorial problem. While some countries have shown a striking improvement in antibiotic use, in some cases associated with a drop in the problem of antimicrobial resistance,[4] there is abundant opportunity for improvement in most of the world.
Implications of injudicious antibiotic use
There is no dearth of original research articles and reviews on this subject; there has been ongoing research in this area for many decades and yet the problem is far from being solved. An understanding that the roots of this problem are entrenched in societal and cultural beliefs and expectations is the first step in attaining a solution. There are complex reasons that drive continuation of a habit and it is important not only to review the laundry list of "possible dire consequences" of the habit but also to be cognizant that amongst the list there will be some reasons which may motivate the individual and some with more societal implications that may only motivate policy makers.
Injudicious use of antibiotics effects the individual and society in a number of ways. At the outset we should clarify that there is some debate about how much antibiotic use and overuse contributes to the development of resistance,[5],[6] and what expectations are realistic in terms of gains that can be made in reversing resistance with more prudent use of these agents,[7];[8] While one group of researchers reported finding relatively high levels of antimicrobial resistance in commensal enterobacteria isolated from wild rodents in the British countryside,[5] (suggesting that the development of resistance might be common in the absence of antibiotic exposure), other groups have failed to detect antibiotic resistance in E. coli isolated from wild animals in more remote locations (e.g., northern Finland),[6] where prior exposure to antimicrobials is extremely unlikely. Some studies suggest that antibiotic resistance, once acquired, is lost very slowly. Examples include the persistence of streptomycin[9] or sulfonamide resistance in E. coli[7] despite decrease in antibiotic use and the persistence of vancomycin-resistant enterococci in Norway after the avoparcin ban.[10] Such debates should not distract us from the undeniable fact that there is no rationale for using antibiotics inappropriately i.e. an unindicated use or incorrect choice of antibiotic, its dose or treatment duration. First, there is clear evidence that antibiotic resistance develops under antibiotic pressure. While this may not be the only factor contributing to the development of antibiotic resistance and reduction in antibiotic use may not always be followed by a decrease in resistance, a decrease in antibiotic overuse will remain the number one intervention in our attempts towards slowing down the development of antimicrobial resistance. Second, injudicious use of antibiotics comes with a cost. Not only is there a cost of paying for a medication that was not needed, there is the cost of adverse drug reactions[11] and ultimately, the inevitable cost of managing resistant microorganisms.[12] In the US in 1998, an estimated 76 million primary care office visits for acute respiratory tract infections resulted in 41 million antibiotic prescriptions. Antibiotic prescriptions in excess of the number expected to treat bacterial infections amounted to 55% (22.6 million) of all antibiotics prescribed for acute respiratory tract infections at a cost of approximately $726 million.[13] Third, injudicious use of antibiotics clearly influences the ecosystem. Antibiotic use in humans and animals has been shown to change the microbial flora of the gut and the ecosystem. Finally, ongoing antibiotic misuse perpetuates a culture of injudicious use where every contributor to this undesirable practice makes it more difficult to change the habit. Of all the reasons cited above, the possibility of avoidable side effects and unnecessary cost would most likely appeal to individuals while reducing antibiotic resistance, minimizing the detrimental impact on the ecosystem and reversing the evolving culture of antibiotic misuse should motivate the physician community, governments and policy makers.
Understanding the pathogenesis of injudicious use of antibiotics
There are numerous factors varying by geographical region, social circumstances and existing health care systems that influence antibiotic use and misuse in various parts of the world. In this productivity driven society, patients may seek a fast fix to every illness and find waiting for the "natural evolution of a viral illness unacceptable". Doctors may experience real or perceived pressure from their patients to prescribe an antibiotic - pressure that is compounded by fear of losing a patient to another provider or fear of the possibility of medico legal implications if they failed to catch something "treatable" early. Economic pressures that influence patients and physicians to antibiotic overuse are often talked about but less well studied. The pharmaceutical industry may feel the pressure to sell their product to realize the costs of the investments made and in doing so may "reach" out to its clients including both patients and physicians in questionable ways. Under such circumstances it is a wasted effort to identify the sinner because no one is innocent, but it is appropriate to accept that regardless of the reasons that drive injudicious use of antibiotics every person who contributes to the problem by being a participant perpetuates this deep rooted practice.
Various patient and provider characteristics that are associated with antibiotic use and misuse are summarized below. The nontherapeutic use of antibiotics in animal agriculture has recently been reviewed elsewhere.[14]
Provider characteristics
Provider experience. Numerous studies have shown widespread unnecessary use of antimicrobials in patients with viral upper respiratory tract infections.[15],[16] Interestingly, we recently found that antibiotic prescribing in the context of an outpatient visit for a diagnosis suggestive of a viral respiratory tract illness occurs more commonly among staff physicians than trainees, and among staff physicians, more commonly in non-teaching compared to teaching institutions.[15] This study used data collected from ambulatory clinics associated with hospitals in the United States as part of the National Hospital Ambulatory Care Survey from 1995 to 2000. Among other things we speculate that trainees may feel protected in an academic environment and perceive less medico-legal risk when withholding antibiotics in specific clinical situations compared to practicing clinicians in hospital based outpatient departments. Additionally our findings may represent a "cohort effect;" trainees may be more familiar with recently administered guidelines and may be more comfortable with antibiotic restraint than providers who trained and practiced prior to the dissemination of these guidelines. Mainous et al using information from the Kentucky Medicaid database, reported that the "high prescribers" of antibiotics for children with upper respiratory tract infections were significantly more years from medical school graduation (27 vs 19 years) than "low prescribers".[17] In a study reported by Steinke et al, non-training practices in Tayside, UK were in general found to prescribe significantly more antibiotics as well as a higher proportion of broad spectrum penicillins, a higher proportion of newer antibiotics and a greater number of different antibiotics per doctor compared to training practices.[18] We and others have shown that non-pediatricians prescribe antibiotics more often to children with colds, bronchitis and upper respiratory tract infections (URI) than pediatricians.[15],[16]
Time spent with the patient. Physician time constraint is a factor that is frequently mentioned as a hypothesis for antibiotic overuse.[19] However, few studies have examined this hypothesis. Surrogate measures for shorter visit times as measured by number of patients seen in a week or type of remuneration (fee-for-service) have been associated with higher antibiotic prescription rates. The presumption is that the necessity of shorter patient-visit times leads physicians to prescribe antibiotics rather than take the time to explain why an antibiotic is not indicated. However, our findings in a study examining the relationship between physician visit time and antibiotic prescribing in the context of other factors that may play a role in antibiotic prescribing for viral respiratory tract infections, do not support the contention that it takes longer 'not to prescribe' antibiotics in ambulatory care settings.[20]
Inadequate information among various antibiotic "providers". Lack of knowledge contributes to inappropriate antimicrobial use. In many countries, including India, antibiotics are dispensed not only by physicians but a host of other providers with variable training backgrounds including those with no medical training. A study from China provides a good example of the magnitude of the problem and the challenge of providing adequate information.[21] Through multistage stratified sampling, 100 of the 1508 Heath Care Workers (HCWs)s working in a county in China were selected for observation of their management of acute respiratory tract infections (ARI). Assessment of diagnostic standards, antibiotic abuse and appropriateness of antibiotic use was based on the WHO definition. There were three categories of HCWs in the county: (1) "doctors" who after a Bachelor's degree and a competitive entrance examination, have undergone 4 to 6 years of training at an University; (2) HCWs who after middle or high school have undergone 3 years of training in a secondary medical or nursing school (this category includes practitioners of traditional Chinese medicine); (3) village workers who have only 6 to 24 months of training on the local level. Not sampled but present in the county were traditional healers who also provided antibiotics. Antibiotics available in the county included penicillins (principally penicillin G and ampicillin); sulfonamides (mainly trimethoprim-sulfamethoxazole); macrolides (mostly erythromycin, medemycin, spiramycin); and lincomycin. Before the parents sought medical care, 47% of children in the county hospitals, 25% of those in the townships and 18% of those in the villages had already received antibiotics available without prescription. Among the HCWs, antibiotic abuse (antibiotics for presumably viral disease) was detected in the treatment of 97% of cases, and severe abuse (such as prescription of two incompatible antibiotics) was detected in 37%. Most (197 of 200) patients with bacterial disease received antibiotics, but inappropriate antibiotic treatment (dose or type) was observed in 63% of these cases. HCWs with University training and those with higher test scores on knowledge and attitude prescribed antibiotics more judiciously than those lacking those attributes. This situation is not unique to this county in China and symbolizes the problems with the health care infrastructure of many countries. Contributing to this lack of knowledge of appropriate choice of antimicrobials may be factors such as limited access to updated, unbiased information especially regarding local antibiotic resistance patterns, and the availability of treatment guidelines that provide a cost-effective approach to common clinical syndromes using available antibiotics. It is not uncommon for drug company sales representatives and the commercially oriented publications they provide to be the main sources of information for many prescribers.[22]
Real time monitoring of antimicrobial resistance and ongoing feedback to the prescribers in a community is very important. Medical care costs and lack of affordable culture and sensitivity tests often limits the availability of patient specific information. Under such circumstances empiric therapy of real or perceived "treatable" infections with broad spectrum agents is common. Additionally, prescribing just to be safe increases when there is diagnostic uncertainty, lack of prescriber knowledge regarding optimal diagnostic approaches, lack of opportunity for patient follow-up, and/or fear of possible litigation.[19],[23] Diagnostic uncertainty can be viewed as having two components - an uncertainty of whether a patient has a bacterial infection or not and/or if a bacterial infection, the uncertainty of what antibiotic to use. It is important to acknowledge that even in the hands of the best clinician there will be patient case scenarios associated with a "diagnostic uncertainty" and in situations where the potential consequences of misdiagnosis are great such as a patient with suspected meningitis, empiric antibiotic use is unavoidable and understandable. In sharp contrast is the "diagnostic uncertainty" of an "otitis media" where the consequences of a delayed diagnosis are minimal.
Cultural and Economic factors. In some cultural settings, antimicrobials given by injection are considered more efficacious than oral formulations. This tends to be associated with the over prescribing of broad-spectrum injectable agents when a narrow spectrum oral agent would be more appropriate. Gumodoka et al reported that one in four patients in their medical districts received antimicrobials by injection and that approximately 70% of these injections were unnecessary.[24] Prescribers may fear the potential loss of future patients and revenue if they do not respond to perceived demands for antimicrobials.[25] In focus group studies, prescribers expressed concern that, if they did not prescribe antimicrobials, patients would seek other sources of care where they could obtain antimicrobials. Furthermore, in some countries, prescribers profit from both prescribing and dispensing antimicrobials, so that it is in their financial interest to prescribe antimicrobials even when they are not clinically indicated. Additional profit is sometimes gained by recommending newer and more expensive antimicrobials in preference to older and cheaper agents. In countries where physicians are poorly paid, pharmaceutical companies have been known to pay commissions to prescribers who use their products.[26]
Patient characteristics
When a parent or child has received an antibiotic prescription for an illness in the past, that experience engenders expectations that the same therapy is required should such symptoms recur.[27] Parental expectation is often cited as a reason for antibiotic prescriptions.[28] However, at least one study shows that physicians' perceptions of parents' expectations are not always correct.[29] In this study while physicians were significantly more likely to inappropriately prescribe if they believed a parent desired antimicrobials, there was poor agreement between actual pre-visit expectations reported by parents and physician-perceived expectations. Actual parental expectations did not have an effect on the decision to prescribe after controlling for covariates. Of interest, this study found that when physicians thought a parent wanted an antimicrobial, otitis media and sinusitis were both significantly more likely to be diagnosed. Additionally, studies have also shown that misconceptions regarding antibiotic use are widespread among patients and parents.[30],[32],[32]
In a study by Macfarlane et al the authors assessed patients' views and expectations when they consult their general practitioners in the UK with acute lower respiratory symptoms and the influence these have on management.[33] They found that most patients think their symptoms are caused by infection, think an antibiotic will help, and want antibiotics. Three quarters of previously well adults in this study consulting with the symptoms of an acute lower respiratory tract illness received antibiotics even though their general practitioners assessed that antibiotics were definitely indicated in only a fifth of such cases. Patients' expectations and views and doctors' concern that the patient may otherwise reconsult had a powerful effect on doctors' decision to prescribe. Patients who did not receive an antibiotic that they wanted were more likely to be dissatisfied and reconsulted twice as frequently. In a survey of 3610 patients conducted by Branthwaite and Pechθre,[34] over 50% of interviewees believed that antimicrobials should be prescribed for all respiratory tract infections with the exception of the common cold. It was noted that 81% of patients expected to see a definite improvement in their respiratory symptoms after three days and that 87% believed that feeling better was a good reason for cessation of antimicrobial therapy. Most of these patients also believed that any remaining antimicrobials could be saved for use at a later time.
These and other patient misconceptions combined with access to antimicrobials without a prescription in many countries creates the perfect environment for injudicious use of antibiotics. In a Brazilian study, it was determined that the three most common types of medication used by villagers were antimicrobials, analgesics and vitamins. The majority of antimicrobials were prescribed by a pharmacy attendant or were purchased by the patient without prescription[35] despite having prescription-only legal status. In addition to obvious uncertainty as to whether the patient has an illness that will benefit from antimicrobial treatment, self-medicated antimicrobials are often inadequately dosed[36] or may not contain adequate amounts of active drug, especially if they are counterfeit drugs.[37] Patients may shop by brand name of antibiotics not realizing that different brand name products may contain the same antibiotic. Specific patient demand caused one pharmacy in South India to stock more than 25 of the 100 or so brands of co-trimoxazole.[38] In countries with such free access to antibiotics there is often unregulated growth of companies that manufacture these products. This raises concern about the quality of many antibiotic products and ultimately the impact this would have on the problem of antimicrobial resistance.
Direct-to-consumer advertising allows pharmaceutical manufacturers to market medicines directly to the public via television, radio, print media and the Internet. Where permitted, this practice has "the potential to stimulate demand by playing on the consumer's relative lack of sophistication about the evidence supporting the use of one treatment over another".[39]
Poor adherence to medication doses and duration of therapy is a well recognized cause of resistance. This is especially so with illness requiring long term therapy such as tuberculosis and HIV. Adding to the complexity of the problem is the fact that in many countries most of the patients pay out of pocket for medical treatment. It is not unusual for patients to buy "aliquots" of medications based on what they can afford and to skip doses or take inadequate doses when feeling well or when short on money.
Interventions to promote judicious use of antibiotics
A number of interventions have been tried to promote judicious use of antibiotics around the world. The applicability of these interventions differs not only based on the clinical setting of antibiotic use i.e. management of acute infections in an outpatient setting vs. inpatient setting vs. treatment of chronic infections, but also on a number of other factors such as site characteristics (private practice vs. academic setting), available resources (such as electronic data management and electronic prescriptions) and patient characteristics (literacy, cultural beliefs, socio-economic status). No single intervention is likely to have a significant impact by itself and a combined approach using multiple interventions is necessary. Additionally, while the enormity of the problem and the degree to which it has become pervasive in society, especially in some countries may be daunting, every effort that is made to promote judicious antibiotic use will have some benefit. A list of ideas and interventions is provided below realizing that not all of them may be practical or applicable to every country or clinic setting. This list includes some recommendations made as part of the WHO Global strategy for containment of antimicrobial resistance (http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf), a review of interventions reported successful in various studies and authors opinion. The WHO Global strategy for containment of antimicrobial resistance is a comprehensive source of information regarding judicious antibiotic use and other measures to address the problem of antimicrobial resistance. Readers are encouraged to browse the cited WHO Global Strategy link to get complete details on this topic. Based on existing resources, feasible options should be considered.
Interventions directed to patients and the non-medical community:
1. Education: Physicians have cited patient/parent pressure as one of the factors that influences their antibiotic prescribing practice. For this and other reasons educating patients and the general public is critical to the efforts to promote judicious antibiotic use. Educational messages should be directed on the following themes:
a. Education regarding common diseases and the role of antibiotics (where they work and where they do not)
b. Efforts to increase awareness of antibiotic resistance and its impact on individuals and the society.
c. Education to discourage self-initiation of treatment and encourage appropriate and informed health care seeking behavior. Education on suitable alternatives to antimicrobials for relief of symptoms should be provided where applicable.
d. Education to promote adherence to the prescribed treatment.
As with any other public health related intervention creative use of locally available and applicable resources that take into account patient literacy should be done to effectively impart education related to the above mentioned themes. These messages can be delivered by the media, in clinic waiting rooms,[40] during prescriber-patient interaction and during dispenser-patient interaction. Based on patient literacy, information leaflets can be provided.[41] A number of websites provide patient education material and evidence based recommendations on antibiotic use. Examples of such resources from US based organizations are the Center for Disease Control and Prevention (www.cdc.org) and Alliance for the Prudent Use of Antibiotics (http://www.tufts.edu/med/apua/). Among other things the CDC website provides the template for a "prescription pad" that can be used in patients with a viral illness. Such information can be used to create patient information material in regional languages with the message modified where necessary to fit the local culture and beliefs. Some drug resistant bacteria i.e. "super bugs" have caught the media attention and this limelight should be used to present information regarding judicious antibiotic use to the community. In addition to the media, information can be provided at community health events and through local community leaders as part of other public health messages that increase overall health awareness in the community.
2. Incentives and reassurance: Patients seek reassurance, symptomatic relief (often a quick fix) and especially when paying 'out of pocket' for the medical services they expect something concrete out of the visit to justify the money or time they have spent to access care. Keeping this in mind, some interventions that can be considered, include:
a. The use of delayed prescribing techniques.[19] A strategy of providing the patient with a prescription for an antibiotic but asking that the prescription not be filled unless symptoms do not get better within a few days has been successfully used in one study.[41]
b. Some physicians say that they promise a free return visit if the patient feels that a re-consultation is necessary because they did not receive antimicrobials.[19] Another approach (if the resources are available) is to arrange for the office staff such as a nurse to make a follow-up phone call to the patient. This can potentially decrease the insecurity felt by a patient/parent when leaving the clinic without an antibiotic prescription.
c. Suitable alternatives to antimicrobials for relief of symptoms should be provided where applicable.
d. From acute care to comprehensive care: For patients with poor access to health care, visits for acute illnesses are the window of opportunity for the physician to provide health-related education, immunizations, and treatment of common illnesses such as anemia and helminthiasis.
Interventions directed to the prescribers and dispensers of antibiotics:
1. Education: While the need for ongoing education of all clinical care providers regarding judicious use of antibiotics is widely accepted the question of "who should do it" and "how should it be done in preferably an evidence based manner" needs to be answered based on local health care and political infrastructure. While it is important to provide this information as part of all clinical provider training programs (medical schools, pharmacy schools etc), based on information we presented earlier the value of continuing medical education for practicing physicians cannot be over emphasized. As with patient education, multiple avenues to disseminate information have to be identified. These include printed materials (journals, periodicals, newsletters), continuing medical education (CME) activities (meetings, conferences, online access), and point of care services (pop up prompts triggered by electronic prescribing).[42] Previous studies have shown that didactic sessions alone do not help.[43],[44],[45] Educational outreach or "academic detailing", which consists of brief, targeted, face-to-face educational visits to clinicians by specially trained staff,[44];[46] is successful but may not be practical or cost-effective in many countries. Engaging local opinion leaders in the process of disseminating targeted educational messages to their peer group has been shown to be another successful strategy.[40],[47]
2. Affordable, reliable microbiology laboratory services: Reliable culture and antimicrobial susceptibility studies are critical to optimizing antimicrobial use in the hospitals and the community. Access to such services is often unaffordable or under utilized in developing countries. Diagnostic uncertainty as described before (does the patient have a bacterial infection and if so what empiric antibiotic to use) is often cited as a reason for over prescribing and broad-spectrum antibiotic use. Availability of low cost microbiology facilities for individual patient care is desirable but in many countries is not always feasible. Especially in such settings, systematic collection of reliable and comparable antimicrobial resistance data by regional government and private laboratories and dissemination of this information on a regular basis to prescribers in the community is very important.
3. Clinical care guidelines: Clinical care guidelines can address both forms of diagnostic uncertainty. Access to updated regionally appropriate treatment guidelines for common infections facilitates evidence based standard of care.[48] These guidelines should be based on existing antibiotic resistance patterns. In 1998 the CDC and the American Academy of Pediatrics published evidence based principles to define judicious antimicrobial use for pediatric upper respiratory tract infections that account for majority of outpatient antimicrobial use in the United States.[49] Dissemination of such guidelines using multiple methods including CME activities, academic detailing, local opinion leaders and others will optimize the impact of these guidelines.
4. Education for "other" clinical care providers: In many countries including India the presence of non-physician providers with no formal training who continue to provide health care services to a large section of society is well recognized. These providers persist because of cultural, financial or lack of affordable alternative reasons. Recognizing the logistical difficulties of removing such "non-traditional" providers and dispensers, taking steps to provide them with drug and disease related education, including judicious antibiotic use may reduce antibiotic misuse.
5.Hospital therapeutic committees and antibiotic audits: While the major contributor to the overall volume of antimicrobial overuse may be outpatient prescribing, measures to address judicious antibiotic use in the hospitals are also important. Besides the overall benefits of promoting judicious antibiotic use, hospital based interventions may affect the prescribing habits of not only trainees but community physicians with admitting privileges. The beneficial role of hospital therapeutic committees in the promotion of rational prescribing habits, monitoring of drug usage and cost containment is well established in developed countries.[50] There is paucity of literature about the feasibility and effectiveness of such committees in developing nations. Such committees are responsible for development of written policies and guidelines for appropriate antimicrobial usage in the hospital, based on local resistance surveillance data. They assist in selection and provision of appropriate antimicrobials in the pharmacy after consideration of local clinical needs. Additionally they define an antimicrobial utilization review program, with audit and feedback on a regular basis to providers, and promotion of active surveillance of the nature and amount of antimicrobial use in the hospital. Despite the logistical challenges of creating and empowering such committees in hospitals where a culture of complete physician autonomy exists the potential benefits of having such a self regulating committee should be explored.
Interventions directed to Governments and other policy makers: It is beyond the scope of this article to go into the nuances of some of the suggested interventions and how they would be applied based on the unique political healthcare infrastructure and societal circumstances of each country. For example, a crackdown on antibiotic dispensing to make these available only with a prescription without looking into the feasibility of patients to access a "prescription provider" or the ability to authenticate the credentials of the person who writes the prescription is unlikely to be effective and may have other undesirable ripple effects including breeding corruption. In many countries overall or region specific (for e.g. in rural areas) lack of trained health care providers combined with poverty, low literacy rate and out of pocket expenses for medical care have allowed untrained prescribers of antibiotics to flourish. It is also not unheard of for the drug dispensers and pharmacies to offer "free medical advice" including suggestions about antimicrobials. Understanding these problems and suggesting a remedy to them is not easy and requires government initiative and policy changes.
The importance of taking the essence of each of the recommendations and distilling them into practical, regionally appropriate actions cannot be overemphasized.
1. Governments and physician organizations should provide funding and resources to educate patients, prescribers and dispensers as delineated in the previous paragraphs.
2. Governments should develop and enforce regulations limiting over-the-counter purchase of antimicrobials.
3. Governments should develop and enforce regulations to ensure the quality of antibiotics that are available in the market.
4. Governments and physician organizations should link professional registration requirements for prescribers and dispensers to requirements for training and continuing education.
5. Government schemes should subsidize the creation of affordable microbiology laboratory services.
6. Governments and physician organizations should provide funding and collaboration to optimize antimicrobial resistance surveillance.
7. Government schemes should subsidize the cost of certain preferred antimicrobials and/or provide free access to them through specific centers. This is especially important for medications used for chronic illnesses such as tuberculosis and HIV.
8. Governments should control and monitor pharmaceutical company promotional activities and direct-to-consumer advertising and limit these to only those that have educational benefit.
Conclusion
Many parts of the world have witnessed a change in society's views about smoking, diet and obesity - a similar level of awareness and motivation is needed in regards to antibiotic use. Measures to improve the use of antibiotics are not limited to addressing this problem alone but are far overreaching. In a way the interventions discussed earlier go towards creating a society of informed consumers who receive rationale health care. While the goal is far from being reached, a reader who makes it to the end of this review article is encouraged to pause for a moment, reflect on his practice and decide what he as an individual can do to address this problem.
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31. Belongia EA, Sullivan BJ, Chyou PH, Madagame E, Reed KD, Schwartz B. A community intervention trial to promote judicious antibiotic use and reduce penicillin-resistant Streptococcus pneumoniae carriage in children. Pediatrics 2001; 575-583.
32. Kuzujanakis M, Kleinman K, Rifas-Shiman S, Finkelstein JA. Correlates of parental antibiotic knowledge, demand, and reported use. Ambul Pediatr 2003; 203-210.
33. Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patients' expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. BMJ 1997; 1211-1214.
34. Branthwaite A, Pechere JC. Pan-European survey of patients' attitudes to antibiotics and antibiotic use. J Int Med Res 1996; 229-238.
35. Haak H. Pharmaceuticals in two Brazilian villages: lay practices and perceptions. Soc Sci Med 1988; 1415-1427.
36. Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, Vauzelle-Kervroedan F, Bouvenot G, Eschwege E. Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 365-370.
37. Kunin CM, Lipton HL, Tupasi T, Sacks T, Scheckler WE, Jivani A, Goic A, Martin RR, Guerrant RL, Thamlikitkul V. Social, behavioral, and practical factors affecting antibiotic use worldwide: report of Task Force 4. Rev Infect Dis 1987;S270-S285.
38. Nichter M, Vuckovic N. Agenda for an anthropology of pharmaceutical practice. Soc Sci Med 1994; 1509-1525.
39. Shapiro MF. Regulating pharmaceutical advertising: what will work CMAJ 1997; 359-361.
40. Finkelstein JA, Davis RL, Dowell SF, Metlay JP, Soumerai SB, Rifas-Shiman SL, Higham M, Miller Z, Miroshnik I, Pedan A, Platt R. Reducing antibiotic use in children: a randomized trial in 12 practices. Pediatrics 2001; 1-7.
41. Macfarlane J, Holmes W, Gard P, Thornhill D, Macfarlane R, Hubbard R. Reducing antibiotic use for acute bronchitis in primary care: blinded, randomised controlled trial of patient information leaflet. BMJ 2002; 91-4.
42. Christakis DA, Zimmerman FJ, Wright JA, Garrison MM, Rivara FP, Davis RL. A randomized controlled trial of point-of-care evidence to improve the antibiotic prescribing practices for otitis media in children. Pediatrics 2001; E15.
43. Thomson O'Brien MA, Freemantle N, Oxman AD, Wolf F, Davis DA, Herrin J. Continuing education meetings and workshops: effects on professional practice and health care outcomes. Cochrane. Database Syst Rev 2001; CD003030.
44. Thomson O'Brien MA, Oxman AD, Davis DA, Haynes RB, Freemantle N, Harvey EL. Educational outreach visits: effects on professional practice and health care outcomes. Cochrane. Database. Syst Rev 2000; CD000409.
45. Davis DA, Thomson MA, Oxman AD, Haynes RB. Changing physician performance. A systematic review of the effect of continuing medical education strategies. JAMA 1995; 700-705.
46. Avorn J, Soumerai SB. Improving drug-therapy decisions through educational outreach. A randomized controlled trial of academically based "detailing". N Engl J Med 1983; 1457-1463.
47. Thomson O'Brien MA, Oxman AD, Haynes RB, Davis DA, Freemantle N, Harvey EL. Local opinion leaders: effects on professional practice and health care outcomes. Cochrane. Database Syst Rev 2000; CD000125.
48. Mandell LA, Bartlett JG, Dowell SF, File TM, Jr., Musher DM, Whitney C. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003; 1405-1433.
49. Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Principles of judicious use of antimicrobial agents for pediatric upper respiratory tract infections. Pediatrics 1998; 163-165.
50. Weekes LM, Brooks C. Drug and Therapeutics Committees in Australia: expected and actual performance. Br J Clin Pharmacol 1996; 551-557.(Gaur Aditya H, English B )
2 Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Abstract
During the past century the excitement of discovering antibiotics as a treatment of infectious diseases has given way to a sense of complacency and acceptance that when faced with antimicrobial resistance there will always be new and better antimicrobial agents to use. Now, with clear indications of a decline in pharmaceutical company interest in anti-infective research, at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of the available agents to fight these micro-organisms. Injudicious use of antibiotics is a global problem with some countries more affected than others. There is no dearth of interest in this subject with scores of scholarly articles written about it. While over the counter access to antibiotics is mentioned as an important contributor towards injudicious antibiotic use in developing nations, as shown in a number of studies, there are many provider, practice and patient characteristics which drive antibiotic overuse in developed nations such as the United States. Recognizing that a thorough review of this subject goes far and beyond the page limitations of a review article we provide a summary of some of the salient aspects of this global problem with a focus towards readers practicing in developing nations.
Keywords: Antibiotics; Anti-microbial agents; Multi-drug resistant micro-organisms
Antibiotic resistance is a natural phenomenon - resistant strains of micro-organisms have been noted close on the heels of antimicrobial discovery.[1] It is undeniable that antibiotic use (and overuse) contributes to development of resistance. The development of newer antibiotics, in part responding to the emergence of resistant microorganisms, has resulted in a sense of complacency on the part of the general public and medical care providers. Now, with clear indications of a decline in pharmaceutical company interest in anti-infective research, at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of the available agents to fight these micro-organisms.[2]
The dictionary meaning of judicious is "having or showing reason and good judgment in making decisions". With reference to antibiotics, judicious use implies using an antibiotic only when indicated , choosing a cost-effective agent which provides appropriate antimicrobial coverage for the diagnosis that is suspected and prescribing the optimal dose and duration of the antimicrobial. The WHO Global Strategy for Containment of Antimicrobial Resistance defines the appropriate use of antimicrobials as the cost-effective use which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance (http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf).
Injudicious use of antibiotics for both humans and animals[3] has long been recognized as a global problem. While over the counter access to antibiotics is mentioned as an important contributor towards injudicious antibiotic use in developing nations, as shown in a number of studies there are many provider, practice and patient characteristics which drive antibiotic overuse in developed nations such as the United States. Numerous approaches have been proposed as a solution to this complex, multi-factorial problem. While some countries have shown a striking improvement in antibiotic use, in some cases associated with a drop in the problem of antimicrobial resistance,[4] there is abundant opportunity for improvement in most of the world.
Implications of injudicious antibiotic use
There is no dearth of original research articles and reviews on this subject; there has been ongoing research in this area for many decades and yet the problem is far from being solved. An understanding that the roots of this problem are entrenched in societal and cultural beliefs and expectations is the first step in attaining a solution. There are complex reasons that drive continuation of a habit and it is important not only to review the laundry list of "possible dire consequences" of the habit but also to be cognizant that amongst the list there will be some reasons which may motivate the individual and some with more societal implications that may only motivate policy makers.
Injudicious use of antibiotics effects the individual and society in a number of ways. At the outset we should clarify that there is some debate about how much antibiotic use and overuse contributes to the development of resistance,[5],[6] and what expectations are realistic in terms of gains that can be made in reversing resistance with more prudent use of these agents,[7];[8] While one group of researchers reported finding relatively high levels of antimicrobial resistance in commensal enterobacteria isolated from wild rodents in the British countryside,[5] (suggesting that the development of resistance might be common in the absence of antibiotic exposure), other groups have failed to detect antibiotic resistance in E. coli isolated from wild animals in more remote locations (e.g., northern Finland),[6] where prior exposure to antimicrobials is extremely unlikely. Some studies suggest that antibiotic resistance, once acquired, is lost very slowly. Examples include the persistence of streptomycin[9] or sulfonamide resistance in E. coli[7] despite decrease in antibiotic use and the persistence of vancomycin-resistant enterococci in Norway after the avoparcin ban.[10] Such debates should not distract us from the undeniable fact that there is no rationale for using antibiotics inappropriately i.e. an unindicated use or incorrect choice of antibiotic, its dose or treatment duration. First, there is clear evidence that antibiotic resistance develops under antibiotic pressure. While this may not be the only factor contributing to the development of antibiotic resistance and reduction in antibiotic use may not always be followed by a decrease in resistance, a decrease in antibiotic overuse will remain the number one intervention in our attempts towards slowing down the development of antimicrobial resistance. Second, injudicious use of antibiotics comes with a cost. Not only is there a cost of paying for a medication that was not needed, there is the cost of adverse drug reactions[11] and ultimately, the inevitable cost of managing resistant microorganisms.[12] In the US in 1998, an estimated 76 million primary care office visits for acute respiratory tract infections resulted in 41 million antibiotic prescriptions. Antibiotic prescriptions in excess of the number expected to treat bacterial infections amounted to 55% (22.6 million) of all antibiotics prescribed for acute respiratory tract infections at a cost of approximately $726 million.[13] Third, injudicious use of antibiotics clearly influences the ecosystem. Antibiotic use in humans and animals has been shown to change the microbial flora of the gut and the ecosystem. Finally, ongoing antibiotic misuse perpetuates a culture of injudicious use where every contributor to this undesirable practice makes it more difficult to change the habit. Of all the reasons cited above, the possibility of avoidable side effects and unnecessary cost would most likely appeal to individuals while reducing antibiotic resistance, minimizing the detrimental impact on the ecosystem and reversing the evolving culture of antibiotic misuse should motivate the physician community, governments and policy makers.
Understanding the pathogenesis of injudicious use of antibiotics
There are numerous factors varying by geographical region, social circumstances and existing health care systems that influence antibiotic use and misuse in various parts of the world. In this productivity driven society, patients may seek a fast fix to every illness and find waiting for the "natural evolution of a viral illness unacceptable". Doctors may experience real or perceived pressure from their patients to prescribe an antibiotic - pressure that is compounded by fear of losing a patient to another provider or fear of the possibility of medico legal implications if they failed to catch something "treatable" early. Economic pressures that influence patients and physicians to antibiotic overuse are often talked about but less well studied. The pharmaceutical industry may feel the pressure to sell their product to realize the costs of the investments made and in doing so may "reach" out to its clients including both patients and physicians in questionable ways. Under such circumstances it is a wasted effort to identify the sinner because no one is innocent, but it is appropriate to accept that regardless of the reasons that drive injudicious use of antibiotics every person who contributes to the problem by being a participant perpetuates this deep rooted practice.
Various patient and provider characteristics that are associated with antibiotic use and misuse are summarized below. The nontherapeutic use of antibiotics in animal agriculture has recently been reviewed elsewhere.[14]
Provider characteristics
Provider experience. Numerous studies have shown widespread unnecessary use of antimicrobials in patients with viral upper respiratory tract infections.[15],[16] Interestingly, we recently found that antibiotic prescribing in the context of an outpatient visit for a diagnosis suggestive of a viral respiratory tract illness occurs more commonly among staff physicians than trainees, and among staff physicians, more commonly in non-teaching compared to teaching institutions.[15] This study used data collected from ambulatory clinics associated with hospitals in the United States as part of the National Hospital Ambulatory Care Survey from 1995 to 2000. Among other things we speculate that trainees may feel protected in an academic environment and perceive less medico-legal risk when withholding antibiotics in specific clinical situations compared to practicing clinicians in hospital based outpatient departments. Additionally our findings may represent a "cohort effect;" trainees may be more familiar with recently administered guidelines and may be more comfortable with antibiotic restraint than providers who trained and practiced prior to the dissemination of these guidelines. Mainous et al using information from the Kentucky Medicaid database, reported that the "high prescribers" of antibiotics for children with upper respiratory tract infections were significantly more years from medical school graduation (27 vs 19 years) than "low prescribers".[17] In a study reported by Steinke et al, non-training practices in Tayside, UK were in general found to prescribe significantly more antibiotics as well as a higher proportion of broad spectrum penicillins, a higher proportion of newer antibiotics and a greater number of different antibiotics per doctor compared to training practices.[18] We and others have shown that non-pediatricians prescribe antibiotics more often to children with colds, bronchitis and upper respiratory tract infections (URI) than pediatricians.[15],[16]
Time spent with the patient. Physician time constraint is a factor that is frequently mentioned as a hypothesis for antibiotic overuse.[19] However, few studies have examined this hypothesis. Surrogate measures for shorter visit times as measured by number of patients seen in a week or type of remuneration (fee-for-service) have been associated with higher antibiotic prescription rates. The presumption is that the necessity of shorter patient-visit times leads physicians to prescribe antibiotics rather than take the time to explain why an antibiotic is not indicated. However, our findings in a study examining the relationship between physician visit time and antibiotic prescribing in the context of other factors that may play a role in antibiotic prescribing for viral respiratory tract infections, do not support the contention that it takes longer 'not to prescribe' antibiotics in ambulatory care settings.[20]
Inadequate information among various antibiotic "providers". Lack of knowledge contributes to inappropriate antimicrobial use. In many countries, including India, antibiotics are dispensed not only by physicians but a host of other providers with variable training backgrounds including those with no medical training. A study from China provides a good example of the magnitude of the problem and the challenge of providing adequate information.[21] Through multistage stratified sampling, 100 of the 1508 Heath Care Workers (HCWs)s working in a county in China were selected for observation of their management of acute respiratory tract infections (ARI). Assessment of diagnostic standards, antibiotic abuse and appropriateness of antibiotic use was based on the WHO definition. There were three categories of HCWs in the county: (1) "doctors" who after a Bachelor's degree and a competitive entrance examination, have undergone 4 to 6 years of training at an University; (2) HCWs who after middle or high school have undergone 3 years of training in a secondary medical or nursing school (this category includes practitioners of traditional Chinese medicine); (3) village workers who have only 6 to 24 months of training on the local level. Not sampled but present in the county were traditional healers who also provided antibiotics. Antibiotics available in the county included penicillins (principally penicillin G and ampicillin); sulfonamides (mainly trimethoprim-sulfamethoxazole); macrolides (mostly erythromycin, medemycin, spiramycin); and lincomycin. Before the parents sought medical care, 47% of children in the county hospitals, 25% of those in the townships and 18% of those in the villages had already received antibiotics available without prescription. Among the HCWs, antibiotic abuse (antibiotics for presumably viral disease) was detected in the treatment of 97% of cases, and severe abuse (such as prescription of two incompatible antibiotics) was detected in 37%. Most (197 of 200) patients with bacterial disease received antibiotics, but inappropriate antibiotic treatment (dose or type) was observed in 63% of these cases. HCWs with University training and those with higher test scores on knowledge and attitude prescribed antibiotics more judiciously than those lacking those attributes. This situation is not unique to this county in China and symbolizes the problems with the health care infrastructure of many countries. Contributing to this lack of knowledge of appropriate choice of antimicrobials may be factors such as limited access to updated, unbiased information especially regarding local antibiotic resistance patterns, and the availability of treatment guidelines that provide a cost-effective approach to common clinical syndromes using available antibiotics. It is not uncommon for drug company sales representatives and the commercially oriented publications they provide to be the main sources of information for many prescribers.[22]
Real time monitoring of antimicrobial resistance and ongoing feedback to the prescribers in a community is very important. Medical care costs and lack of affordable culture and sensitivity tests often limits the availability of patient specific information. Under such circumstances empiric therapy of real or perceived "treatable" infections with broad spectrum agents is common. Additionally, prescribing just to be safe increases when there is diagnostic uncertainty, lack of prescriber knowledge regarding optimal diagnostic approaches, lack of opportunity for patient follow-up, and/or fear of possible litigation.[19],[23] Diagnostic uncertainty can be viewed as having two components - an uncertainty of whether a patient has a bacterial infection or not and/or if a bacterial infection, the uncertainty of what antibiotic to use. It is important to acknowledge that even in the hands of the best clinician there will be patient case scenarios associated with a "diagnostic uncertainty" and in situations where the potential consequences of misdiagnosis are great such as a patient with suspected meningitis, empiric antibiotic use is unavoidable and understandable. In sharp contrast is the "diagnostic uncertainty" of an "otitis media" where the consequences of a delayed diagnosis are minimal.
Cultural and Economic factors. In some cultural settings, antimicrobials given by injection are considered more efficacious than oral formulations. This tends to be associated with the over prescribing of broad-spectrum injectable agents when a narrow spectrum oral agent would be more appropriate. Gumodoka et al reported that one in four patients in their medical districts received antimicrobials by injection and that approximately 70% of these injections were unnecessary.[24] Prescribers may fear the potential loss of future patients and revenue if they do not respond to perceived demands for antimicrobials.[25] In focus group studies, prescribers expressed concern that, if they did not prescribe antimicrobials, patients would seek other sources of care where they could obtain antimicrobials. Furthermore, in some countries, prescribers profit from both prescribing and dispensing antimicrobials, so that it is in their financial interest to prescribe antimicrobials even when they are not clinically indicated. Additional profit is sometimes gained by recommending newer and more expensive antimicrobials in preference to older and cheaper agents. In countries where physicians are poorly paid, pharmaceutical companies have been known to pay commissions to prescribers who use their products.[26]
Patient characteristics
When a parent or child has received an antibiotic prescription for an illness in the past, that experience engenders expectations that the same therapy is required should such symptoms recur.[27] Parental expectation is often cited as a reason for antibiotic prescriptions.[28] However, at least one study shows that physicians' perceptions of parents' expectations are not always correct.[29] In this study while physicians were significantly more likely to inappropriately prescribe if they believed a parent desired antimicrobials, there was poor agreement between actual pre-visit expectations reported by parents and physician-perceived expectations. Actual parental expectations did not have an effect on the decision to prescribe after controlling for covariates. Of interest, this study found that when physicians thought a parent wanted an antimicrobial, otitis media and sinusitis were both significantly more likely to be diagnosed. Additionally, studies have also shown that misconceptions regarding antibiotic use are widespread among patients and parents.[30],[32],[32]
In a study by Macfarlane et al the authors assessed patients' views and expectations when they consult their general practitioners in the UK with acute lower respiratory symptoms and the influence these have on management.[33] They found that most patients think their symptoms are caused by infection, think an antibiotic will help, and want antibiotics. Three quarters of previously well adults in this study consulting with the symptoms of an acute lower respiratory tract illness received antibiotics even though their general practitioners assessed that antibiotics were definitely indicated in only a fifth of such cases. Patients' expectations and views and doctors' concern that the patient may otherwise reconsult had a powerful effect on doctors' decision to prescribe. Patients who did not receive an antibiotic that they wanted were more likely to be dissatisfied and reconsulted twice as frequently. In a survey of 3610 patients conducted by Branthwaite and Pechθre,[34] over 50% of interviewees believed that antimicrobials should be prescribed for all respiratory tract infections with the exception of the common cold. It was noted that 81% of patients expected to see a definite improvement in their respiratory symptoms after three days and that 87% believed that feeling better was a good reason for cessation of antimicrobial therapy. Most of these patients also believed that any remaining antimicrobials could be saved for use at a later time.
These and other patient misconceptions combined with access to antimicrobials without a prescription in many countries creates the perfect environment for injudicious use of antibiotics. In a Brazilian study, it was determined that the three most common types of medication used by villagers were antimicrobials, analgesics and vitamins. The majority of antimicrobials were prescribed by a pharmacy attendant or were purchased by the patient without prescription[35] despite having prescription-only legal status. In addition to obvious uncertainty as to whether the patient has an illness that will benefit from antimicrobial treatment, self-medicated antimicrobials are often inadequately dosed[36] or may not contain adequate amounts of active drug, especially if they are counterfeit drugs.[37] Patients may shop by brand name of antibiotics not realizing that different brand name products may contain the same antibiotic. Specific patient demand caused one pharmacy in South India to stock more than 25 of the 100 or so brands of co-trimoxazole.[38] In countries with such free access to antibiotics there is often unregulated growth of companies that manufacture these products. This raises concern about the quality of many antibiotic products and ultimately the impact this would have on the problem of antimicrobial resistance.
Direct-to-consumer advertising allows pharmaceutical manufacturers to market medicines directly to the public via television, radio, print media and the Internet. Where permitted, this practice has "the potential to stimulate demand by playing on the consumer's relative lack of sophistication about the evidence supporting the use of one treatment over another".[39]
Poor adherence to medication doses and duration of therapy is a well recognized cause of resistance. This is especially so with illness requiring long term therapy such as tuberculosis and HIV. Adding to the complexity of the problem is the fact that in many countries most of the patients pay out of pocket for medical treatment. It is not unusual for patients to buy "aliquots" of medications based on what they can afford and to skip doses or take inadequate doses when feeling well or when short on money.
Interventions to promote judicious use of antibiotics
A number of interventions have been tried to promote judicious use of antibiotics around the world. The applicability of these interventions differs not only based on the clinical setting of antibiotic use i.e. management of acute infections in an outpatient setting vs. inpatient setting vs. treatment of chronic infections, but also on a number of other factors such as site characteristics (private practice vs. academic setting), available resources (such as electronic data management and electronic prescriptions) and patient characteristics (literacy, cultural beliefs, socio-economic status). No single intervention is likely to have a significant impact by itself and a combined approach using multiple interventions is necessary. Additionally, while the enormity of the problem and the degree to which it has become pervasive in society, especially in some countries may be daunting, every effort that is made to promote judicious antibiotic use will have some benefit. A list of ideas and interventions is provided below realizing that not all of them may be practical or applicable to every country or clinic setting. This list includes some recommendations made as part of the WHO Global strategy for containment of antimicrobial resistance (http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf), a review of interventions reported successful in various studies and authors opinion. The WHO Global strategy for containment of antimicrobial resistance is a comprehensive source of information regarding judicious antibiotic use and other measures to address the problem of antimicrobial resistance. Readers are encouraged to browse the cited WHO Global Strategy link to get complete details on this topic. Based on existing resources, feasible options should be considered.
Interventions directed to patients and the non-medical community:
1. Education: Physicians have cited patient/parent pressure as one of the factors that influences their antibiotic prescribing practice. For this and other reasons educating patients and the general public is critical to the efforts to promote judicious antibiotic use. Educational messages should be directed on the following themes:
a. Education regarding common diseases and the role of antibiotics (where they work and where they do not)
b. Efforts to increase awareness of antibiotic resistance and its impact on individuals and the society.
c. Education to discourage self-initiation of treatment and encourage appropriate and informed health care seeking behavior. Education on suitable alternatives to antimicrobials for relief of symptoms should be provided where applicable.
d. Education to promote adherence to the prescribed treatment.
As with any other public health related intervention creative use of locally available and applicable resources that take into account patient literacy should be done to effectively impart education related to the above mentioned themes. These messages can be delivered by the media, in clinic waiting rooms,[40] during prescriber-patient interaction and during dispenser-patient interaction. Based on patient literacy, information leaflets can be provided.[41] A number of websites provide patient education material and evidence based recommendations on antibiotic use. Examples of such resources from US based organizations are the Center for Disease Control and Prevention (www.cdc.org) and Alliance for the Prudent Use of Antibiotics (http://www.tufts.edu/med/apua/). Among other things the CDC website provides the template for a "prescription pad" that can be used in patients with a viral illness. Such information can be used to create patient information material in regional languages with the message modified where necessary to fit the local culture and beliefs. Some drug resistant bacteria i.e. "super bugs" have caught the media attention and this limelight should be used to present information regarding judicious antibiotic use to the community. In addition to the media, information can be provided at community health events and through local community leaders as part of other public health messages that increase overall health awareness in the community.
2. Incentives and reassurance: Patients seek reassurance, symptomatic relief (often a quick fix) and especially when paying 'out of pocket' for the medical services they expect something concrete out of the visit to justify the money or time they have spent to access care. Keeping this in mind, some interventions that can be considered, include:
a. The use of delayed prescribing techniques.[19] A strategy of providing the patient with a prescription for an antibiotic but asking that the prescription not be filled unless symptoms do not get better within a few days has been successfully used in one study.[41]
b. Some physicians say that they promise a free return visit if the patient feels that a re-consultation is necessary because they did not receive antimicrobials.[19] Another approach (if the resources are available) is to arrange for the office staff such as a nurse to make a follow-up phone call to the patient. This can potentially decrease the insecurity felt by a patient/parent when leaving the clinic without an antibiotic prescription.
c. Suitable alternatives to antimicrobials for relief of symptoms should be provided where applicable.
d. From acute care to comprehensive care: For patients with poor access to health care, visits for acute illnesses are the window of opportunity for the physician to provide health-related education, immunizations, and treatment of common illnesses such as anemia and helminthiasis.
Interventions directed to the prescribers and dispensers of antibiotics:
1. Education: While the need for ongoing education of all clinical care providers regarding judicious use of antibiotics is widely accepted the question of "who should do it" and "how should it be done in preferably an evidence based manner" needs to be answered based on local health care and political infrastructure. While it is important to provide this information as part of all clinical provider training programs (medical schools, pharmacy schools etc), based on information we presented earlier the value of continuing medical education for practicing physicians cannot be over emphasized. As with patient education, multiple avenues to disseminate information have to be identified. These include printed materials (journals, periodicals, newsletters), continuing medical education (CME) activities (meetings, conferences, online access), and point of care services (pop up prompts triggered by electronic prescribing).[42] Previous studies have shown that didactic sessions alone do not help.[43],[44],[45] Educational outreach or "academic detailing", which consists of brief, targeted, face-to-face educational visits to clinicians by specially trained staff,[44];[46] is successful but may not be practical or cost-effective in many countries. Engaging local opinion leaders in the process of disseminating targeted educational messages to their peer group has been shown to be another successful strategy.[40],[47]
2. Affordable, reliable microbiology laboratory services: Reliable culture and antimicrobial susceptibility studies are critical to optimizing antimicrobial use in the hospitals and the community. Access to such services is often unaffordable or under utilized in developing countries. Diagnostic uncertainty as described before (does the patient have a bacterial infection and if so what empiric antibiotic to use) is often cited as a reason for over prescribing and broad-spectrum antibiotic use. Availability of low cost microbiology facilities for individual patient care is desirable but in many countries is not always feasible. Especially in such settings, systematic collection of reliable and comparable antimicrobial resistance data by regional government and private laboratories and dissemination of this information on a regular basis to prescribers in the community is very important.
3. Clinical care guidelines: Clinical care guidelines can address both forms of diagnostic uncertainty. Access to updated regionally appropriate treatment guidelines for common infections facilitates evidence based standard of care.[48] These guidelines should be based on existing antibiotic resistance patterns. In 1998 the CDC and the American Academy of Pediatrics published evidence based principles to define judicious antimicrobial use for pediatric upper respiratory tract infections that account for majority of outpatient antimicrobial use in the United States.[49] Dissemination of such guidelines using multiple methods including CME activities, academic detailing, local opinion leaders and others will optimize the impact of these guidelines.
4. Education for "other" clinical care providers: In many countries including India the presence of non-physician providers with no formal training who continue to provide health care services to a large section of society is well recognized. These providers persist because of cultural, financial or lack of affordable alternative reasons. Recognizing the logistical difficulties of removing such "non-traditional" providers and dispensers, taking steps to provide them with drug and disease related education, including judicious antibiotic use may reduce antibiotic misuse.
5.Hospital therapeutic committees and antibiotic audits: While the major contributor to the overall volume of antimicrobial overuse may be outpatient prescribing, measures to address judicious antibiotic use in the hospitals are also important. Besides the overall benefits of promoting judicious antibiotic use, hospital based interventions may affect the prescribing habits of not only trainees but community physicians with admitting privileges. The beneficial role of hospital therapeutic committees in the promotion of rational prescribing habits, monitoring of drug usage and cost containment is well established in developed countries.[50] There is paucity of literature about the feasibility and effectiveness of such committees in developing nations. Such committees are responsible for development of written policies and guidelines for appropriate antimicrobial usage in the hospital, based on local resistance surveillance data. They assist in selection and provision of appropriate antimicrobials in the pharmacy after consideration of local clinical needs. Additionally they define an antimicrobial utilization review program, with audit and feedback on a regular basis to providers, and promotion of active surveillance of the nature and amount of antimicrobial use in the hospital. Despite the logistical challenges of creating and empowering such committees in hospitals where a culture of complete physician autonomy exists the potential benefits of having such a self regulating committee should be explored.
Interventions directed to Governments and other policy makers: It is beyond the scope of this article to go into the nuances of some of the suggested interventions and how they would be applied based on the unique political healthcare infrastructure and societal circumstances of each country. For example, a crackdown on antibiotic dispensing to make these available only with a prescription without looking into the feasibility of patients to access a "prescription provider" or the ability to authenticate the credentials of the person who writes the prescription is unlikely to be effective and may have other undesirable ripple effects including breeding corruption. In many countries overall or region specific (for e.g. in rural areas) lack of trained health care providers combined with poverty, low literacy rate and out of pocket expenses for medical care have allowed untrained prescribers of antibiotics to flourish. It is also not unheard of for the drug dispensers and pharmacies to offer "free medical advice" including suggestions about antimicrobials. Understanding these problems and suggesting a remedy to them is not easy and requires government initiative and policy changes.
The importance of taking the essence of each of the recommendations and distilling them into practical, regionally appropriate actions cannot be overemphasized.
1. Governments and physician organizations should provide funding and resources to educate patients, prescribers and dispensers as delineated in the previous paragraphs.
2. Governments should develop and enforce regulations limiting over-the-counter purchase of antimicrobials.
3. Governments should develop and enforce regulations to ensure the quality of antibiotics that are available in the market.
4. Governments and physician organizations should link professional registration requirements for prescribers and dispensers to requirements for training and continuing education.
5. Government schemes should subsidize the creation of affordable microbiology laboratory services.
6. Governments and physician organizations should provide funding and collaboration to optimize antimicrobial resistance surveillance.
7. Government schemes should subsidize the cost of certain preferred antimicrobials and/or provide free access to them through specific centers. This is especially important for medications used for chronic illnesses such as tuberculosis and HIV.
8. Governments should control and monitor pharmaceutical company promotional activities and direct-to-consumer advertising and limit these to only those that have educational benefit.
Conclusion
Many parts of the world have witnessed a change in society's views about smoking, diet and obesity - a similar level of awareness and motivation is needed in regards to antibiotic use. Measures to improve the use of antibiotics are not limited to addressing this problem alone but are far overreaching. In a way the interventions discussed earlier go towards creating a society of informed consumers who receive rationale health care. While the goal is far from being reached, a reader who makes it to the end of this review article is encouraged to pause for a moment, reflect on his practice and decide what he as an individual can do to address this problem.
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