DIAGN MICROBIOLINFECT DIS 1992;15:103S-109S
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Factors Affecting Nonadherence with Antibiotics Robert Sanson-Fisher, Jennifer Bowman, and Susan Armstrong
Nonadherence with antibiotic therapy has profound implications both for patient health and the health care system that bears the financial casts incurred. Significant levels of nonadherence with antibiotic prescriptions have been demonstrated. Of the many proposed variables involved, those that are potentially modifiable relate to aspects of the doctor-patient interaction and drug regimen. Despite the potential for intervention with these variables, there have been very few methodologically sound studies examining their effect on adherence with either medications generally or antibiotics specifically. Only two
studies were located that had tested the effectiveness of reduced complexity of antibiotic dosage schedules. The results suggest that the less complex the schedule, the greater is the adherence. Both practitioners and patients must be encouraged to use and accept simpler dosage schedules, preferably once-daily schedules wherever possible. The paucity of well-controlled studies to date highlights the need for further research evaluating intervention strategies that utilize variations in dosage schedule and elements of the doctor-patient interaction to improve adherence with antibiotic medications.
INTRODUCTION
no account can be taken for such factors as losses occurred in storage, transit, and as a result of noncompliance. The uncertainties of the data notwithstanding, antibiotics are clearly one of the most commonly used therapeutic drugs throughout the world--often accounting for 15%--30% of drug expenditures, the largest share of any therapeutic drug group (Col and O'Connor, 1987). h~ an Australian study of the prescribing habits of general practice trainees, data suggest that a drug of some kind was prescribed in - 5 5 % of all consultations, and that 29% of all drugs prescribed were antibiotics (NSW Family Medicine Programme, Evaluation Group, unpublished data). In total, 21% of all patients were prescribed an antibiotic.
Nonadherence with drug therapy has profound implications both for patient health and the health care system that bears the financial costs incurred as a resuit. Antibiotics are effective and widely used drugs and, as such, they provide an excellent opportunity for studying--and, if possible, modifying--the mechanisms that appear to be involved in noncompliance.
A N T I B I O T I C S ARE C O M M O N L Y U S E D It is difficult to obtain reliable data on the actual amounts of antibiotics consumed. The availability of antibiotics can be estimated based on sales, production, and trade data. Such estimates, however, do not represent a measure of actual consumption, as From the .~'~isciplineof BehaviouralSciencein Relation to Medicine, Faculty of Medicine, Universityof Newcastle, Newcastle, NSW, Australia. Additional copie-~of this supplement are availablefrom Roussel UCLAF, Domaine Th~rapeutiqueAntibioth~rapie,35 Boulevarddes lnvalides, 75007Paris, France. Received 8 October 1991;revised and accepted 20 December 1991. © 1992ElsevierSciencePublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893]92/$5.00
NONADHERENCE IN TAKING ANTIBIOTICS: CONSEQUENCES AND COSTS Adherence to treatment is essential for most successful medical treatments. Nonadhe~ence is therefore a serious medical problem. With regard to antibiotics specifically, the effectiveness of therapy can be considered dependent on a n u m b e r of key factors, including the correct diagnosis being made by the practitioner, prescription of the most effective
1048
form of treatment, the effectiveness of the chosen medication, and patient adherence to the course of medication. This article is concerned with the latter factor, discussing its measurement, the variables that have been found to be related to adherence, and the strategies that can be used to reduce the levels of nonadherence. In taking antibiotics, there is considerable scope for a patient to deviate from the prescribed schedule. Nonadherence can occur in four ways: complete omission of doses; errors in quantity of dose-taking too little or too much; errors in the time of dose administration; and premature discontinuation of the prescribed course of treatment. A recent international survey of both practitioners and patients regarding antibiotic treatment provides some interesting information regarding the issue of nonadherence. In each of five countries (France, Germany, Italy, the United Kingdom, and Spain), 150 patients who had used antibiotics within the previous 3 months completed a telephone interview, and 100 general practitioners took part in faceto-face interviews. The data collected in this interview indicated that practitioners recognized the occurrence of nonadherence to be common, and perceived its effects to be potentially serious. Furthermore, 55% of the practitioners surveyed believed that the rate of patient nonadherence to antl~oiotic treatment was "high" (Groupe MV2, 1991). The negative consequences that can arise for individuals as a result of nonadherence to antibiotics include therapeutic failure, the development of microorganisms resistant to that particular drug, specific drug reactions, and inappropriate selfmedication at a later date (Hamilton-Miller, 1984; Hussar, 1987). While there is little data relating directly to antibiotics, self-medication has been reported to be commonplace in the USA, Great Britain, and Australia (Hussar, 1987). One Australian survey reported that self-medication accounted for -60% of all drug treatment (Wade, 1976), and Hayes et al. (1976) found that a significant degree of drug "hoarding" occurred within Australian homes. Significant financial costs are also incurred by the health care system as a result of nonadherence. It has been estimated that 25% of hospital admissions in Australia are due to people not adhering to pre• ious treatment instructions (Ley, 1984), and that the wastage of unused medications adds up to $200 million per annum (~$156 million US) to the Australian health bill (Senate Standing Committee on Social Welfare, 1981). In the United States, it has been estimated that the total cost of nonadherence with regimens for ten common drug classes is $396$792 million dollars (Ley, 1988).
R. Sanson-Fisher et al.
M E A S U R E M E N T OF N O N A D H E R E N C E IN TAKING ANTIBIOTICS A number of methods are available to clinicians as a means of estimating the degree of their patients' adherence with taking a medication as directed; they include both direct and indirect measures.
Direct Measures: Physical Assays of Blood Plasma or Urine Assays can be used to determine the quantity of medication in blood plasma or urine. This method is acknowledged to be the most rigorous evidence that can be obtained about nonadherence (Walther, et al. 1978; Sackett, 1979; Richens and Warringten, 1979)----being relatively unaffected by human judgment. However, several pragmatic problems are associated with its use: (a) The technology must he available to assay the drug of interest. (b) The expense involved may be substantial, prohibiting the use of this method for large studies. (c) The facilities for assay must be located close to the research site, so that specimens can be stored under appropriate conditions. (d) The request to patients may seem intrusive, with resulting reluctance ot patients to participate. In addition, problems can arise with the existence of individual differences in absorption and excretion rates, and through the possibility of patients being able to build up the appropriate levels of medication by taking the right doses only for a day or two before a sample is taken for assay (Cockburn, 1986).
Indirect Measures: Pill Counts Pill counts represent a simple, inexpensive, and easily implemented alternative to direct measures of adherence. A count is made of the medication remaining in the patient's tablet dispenser after a specified time period, and this quantity is compared with the amount that should be present if total adherence had occurred. A ratio is computed that describes the deviation from the prescribed dose, providing a quantitative assessment of adherence. There are difficulties associated with the use of this method, however: the investigator must know how much medication was dispensed initially, the patient must present all remaining tablets at the time of counting, and patients may hide tablets or throw them away if they know adherence is to be assessed. In addition, this method usually assesses only the amount of medication consumed, and provides no evidence on the scheduling of the doses. Mechanical devices have been used to assess adherence in a number of clinical and analogue studies, recording when a medication container is opened (Ley, 1988; Cramer
Factors for Nonadherence with Antibiotics
et al., 1989). The chief advantage of such devices is that they allow the accurate timing of doses, although not necessarily the actual taking of medication.
Indirect Measures: Judgment by Health Professionals The chief advantage of this method is that the patient is not involved, thus minimizing the potential reactive effects. However, there are clearly likely to be problems with the accuracy of physicians' reporting. Physicians have been found to overestimate adherence~believing that patients follow instructions more closely than they actually do (Gilbert et al., 1980; Norrell, 1981). It is likely that the practitioners surveyed in the international study referred to earlier (Groupe MV2, 1991), even though one-half considered the rate of nonadherence to be high, nevertheless underestimated its real magnitude.
10SS
influence treatment outcome---so that it is not possible to assume a causal relationship between adherence and outcome. (b) Patients on multiple medications may adhere with some and not with others, and yet display a clinical improvement. (c) If taking medications on a long-term basis, patients may discontinue treatment altogether for a period of time and display no apparent change in their condition. In summary, given the various problems associated with each strategy, it is clear that the use of multiple measures may provide the best indication of patient adherence behavior. However, as there are substantial costs involved with most measures, a more feasible approach for practitioners to employ in detecting the nonadherent patient may be to (a) monitor the treatment goals, and focus attention on patients who, despite vigorous treatment, have failed to reach their treatment target; and (b) use a nonthreatening interview of patients to identify actual or potential nonadherers.
Indirect Measures: Patient Self-Report This is a frequently used measure of adherence, being relatively simple and inexpensive, and enabling an in-depth study of the types of errors made and the reason for them. The inherent disadvantage with this method, however, is its reliance on the patient reporling accurately. Agreement between patient selfreport and other measures of adherence is often poor, with p~tients generally reporting a higher degree of adherence than indicated by other measures (Park and Lipman, 1964; Gordis et al., 1969; Roth and Caron, 1978). It has been suggested that variability in the patient's daily behavior may account for most reporting errors, rather than patients deliberately lying (Dunbar, 1979; Gordis, 1979). Data from the international patient survey (Groupe MV2, 1991), where the patients involved had been prescribed an antibiotic within the last 3 months, indicated that, in total, only 20% of patients reported having forgotten to take an antibiotic within that time period. Sixteen percent of the patients surveyed reported that they had ceased taking a course of antibiotic treatment before the end. Both of these figures must be treated with some skepticism.
Indirect Measures: Therapeutic Effect The argument for this measure of adherence is that, given an effective treatment for a condition, those who are more adherent will on average respond better to treatment. The disadvantages of this method, however, are readily apparent, and are such that it would not be advisable to use this method alone in estimating adherence: (a) Many other factors may
EXTENT A N D C L I N I C A L S I G N I F I C A N C E OF N O N A D H E R E N C E IN T A K I N G ANTIBIOTICS An important methodologic issue arises for the researcher and clinician in utilizing any of these direct or indirect measures of adherence: that of defining a cutoff point for the definition of "adherence" and "nonadherence." Adherence can be viewed as a continuous measure. For most practical and research purposes, however, a categorical definition is more appropriate. It may be determined by a pill count, for instance, that a patient has taken only 80% of the prescribed medication and so, in an absolute sense, could be defreed as nonadherent. However, such an absolute measure of nonadherence may have little meaning if there is no therapeutic difference between 80% and 100% adherence. To have clinical significance, adherence may need to be defined as having taken 50% of the tablets. In previous research, the criteria used for categorizing patients as adherent or otherwise have often not been clearly defined (Dunbar, 1979; Marsten, 1979; Cummings et al., 1984). This has been particularly true for studies that have examined adherence with antibiotic regimens where the operational definition of nonadherence has ranged from deviations of 15% (Unterhalter, 1979; Ettinger and Freeman, 1981) to 33% (Bergman and Werner, 1965) from the prescribed dose. This degree of variation makes it difficult to compare rates of nonadherence in different studies, and limits the ability to generalize from resuits.
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R. Sanson-Fisher et al.
Although the operational definition of nonadherence varies across investigations, reviewers appear to agree that at least some 30% of patients in most studies fail to follow advice ((;ilium and Barsky, 1974; Eraker et al., 1984). Ley (1982) summarized the results of a number of reviews reporting percentages of patients judged to be nonadherent with medications, producing the figures reported in Table 1. In all three reviews, the proportion of patients judged to be nonadherent in taking antibiotic medications was ~50%, a figure generally higher than rates of nonadherence for other types of medication such as antihypertensives and medications for tuberculosis and psychiatric disorders. However, there is a lack of recent data. h~ the 1976 review by Ley, for instance, data were derived from investigations reported in 1969 or earlier. A more recent study by Cockburn et al. (1987a), defining nonadherence as ---20% deviation from the prescribed dosage, found 27% of general practice patients to be nonadherent in taking short-course oral antibiotics.
DETERMINANTS OF NONADHERENCE A range of factors have been associ-a(ed with levels of medication adherence. It is useful to categorize them as those that are potentially modifiable, and those that are not, as shown in Table 2. N o n m o d i f i a b l e Factors: Characteristics of Patient, Practitioner, or Illness Characteristics of the individual practitioner or patient that may influence adherence are usually unmodifiable. Evidence of the impact of such variables on adherence is often contradictory, with some studies showing that some factors such as the age (Weintraub et al., 1973), sex (Davis, 1968), and socioeconomic status (Davis, 1968; Drury et al., 1976) of the patient affects adherence, while others do not support these conclusions. SL.nilarly, variables related to the particular illness, such as whether it was a
TABLE I
psychiatric or nonpsychiatric complaint and the severity of the disease, have been related to adherence in some studies. Again, however, the findings are inconsistent (Haynes, 1979).
Modifiable Factors: Doctor-Patient Interaction and Dosage Regimen Doctor-Patient Interaction
Many aspects of the doctor-patient interaction--including the content and manner in which information is communicated to the patient (Sharpe and Mikeal, 1974; Kincey et al., 1975; Ley, 197"/), the patient's health beliefs (Becket and Maiman, 1975; Becket et al., 1979; Ley, 1988), and the level of satisfaction with the consultation (Becket and Maiman, 1980; Eraker et al., 1984)----have been related to adherence with medication use. Despite the evident potential for modifying these kinds of factors, very few methodologically rigorous intervention studies have attempted to improve adherence. A computer-base literaO-re search for the period 1980-1990, inclusive, identified only 13 studies attempting to modify factors relating to the doctor-patient interaction in order to improve adherence with taking antibiotic medications. Many of these studies are methodologically weak, involving small subject numbers or lacking suitable control groups, and so provide no convincing conclusions. The existing research does, however, suggest that a clinician's use of the following strategies in consultations where antibiotics are prescribed may increase adherence to treatment: identifying and correcting inappropriate patient beliefs and attitudes, giving clear (written) treatment instructions, tailoring the regimen to the patient's daily routine, using reminders, utilizing family support, providing information about missed doses and adverse side effects, checking the patient's understanding of instructions, and monitoring their adherence (Cockbum et al., 1988). To insure that the patient's beliefs and attitudes are likely to lead to adherence, it is suggested that the practitioner should explore the patient's under-
Prevalence of Nonadherence (%)
Medication Type
Ley (1976)
Food and Drug Administration (1979)
Barofsky (1980)
Antibiotics Psychiatric Antihypertensive Antitubercuiosis Other medications
49 39 -38 48
48 42 43 42 54
52 42 61 43 46
From ~ (1982).
Factors for Nonadherence with Ap.~lbiotics
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TABLE 2 Factors Related to Adherence Nonmodifiable
Modifiable
Patient's age, sex, and socioeconomic status Doctor's age and years of prac',ice
Patient's health, beliefs Information provided to patients: content and manner of communication Patient's satisfaction with 1he consultation Drug regimen: dosage
Severity and history of illness Nature of the illness
standing and perceptions concerning the diagnosis and cause of symptoms, the long-term consequences of the disease, any barriers to taking the medication, and the benefits to be derived from adhering to the treatment. A great deal of information is often given in a consultation, and research has shown that much of it is poorly attended to or recalled by patients (Ley, 1977). Although results have not always been consistent, several studies have indicated that the more patients understand about their illness and treatment, the more likely they are to be adherent (Sharpe and Mikeal, 1974; Kincey et al., 1975). To enhance recall and therefore adherence, clinicians can employ the following techniques: present treatment instructions clearly and simply, use concrete specific advice, stress the importance of the advice, repeat important components of the advice, use explicit categorization (where the instructions are divided into categories that the clinician outlines to the patient before then proceeding to give information about each in turn), check the patient's understanding by asking the patient ~o repeat salient details of the information, and write down the instructions for the patient--preferably on a specially designed card or sheet. Tailoring the regimen to the patient's daily routine refers to identifying specific events within the patient's usual daily activities around which to anchor the regimen. For instance, for a particular patient on a twice-daily schedule, it may be appropriate for the clinician to advise that the medication be taken in the morning and evening just before ~he patient brushes his or her teeth, and that the medication container be left near the toothbrush holder as a reminder. The regularity of events for any particular patient should not be assumed. For instance, it will not be sufficient for a clinician to issue the instruction "Take one tablet three times a day with meals" if the patient routinely eats only two meals a day. Providing reminders could consist of a sticker or magnet for'the refrigerator, medication calendars, or encouraging family support. A simple adherence-aiding strategy that makes
intuitive sense is to inform the patient of what to do if a tablet is forgotten. A recent survey of Australian general practice patients prescribed antibiotics (involving 56 doctors and 201 patients) found that no doctor provided the patient with this information (Cockburn et al., 1987c). The international survey of patients who had been recently prescribed antibiotics indicated a great deal of variation in patient reports of their behavior when a dose was forgotten; most (46%) just skipped the missed dose without making treatment any longer (Groupe MV2, 1991). Side effects that are unexpected are more likely to result in a negative perception of the value of medication than those that are expected (Madden, 1973). Therefore, adequately informing patients of possible side effects at the time the medication is prescribed may reduce the likelihood that, if side effects are subsequently experienced, the medication will be perceived negatively as a result. Maintenance of a more positive view of the antibiotic treatment is likely to in turn reinforce adherence. And finally, it is important that a practitioner continue to monitor a patient's adherence in an ongoing fashion. Nearly all studies that have continued to monitor adherence after an effective adherence-aiding strategy has beer. withdrawn document a deterioration in adherence back toward its prior low level. This deterioration is often very rapid. In the case of antibiotic prescribing, therefore, it is important for a clinician to check adherence and to use techniques to enhance it, even though the clinician may have previously given the same patient similar information.
DosageRegimen Another potentially modifiable variable associated with adherence is th~ drug regimen. A number of studies have shown that the complexity of the regimen as indicated by the frequency of the dose, the number of tablets prescribed daily, and the length of time for which the medication is prescribed, is negatively rela~.ed to adherence (Gatley, 1968; Hulka et al., 1976). Pullar et al. (1988) examined the adherence of diabetic patients taking oral hypoglyce-
108S
mic drugs prescribed once, twice, or three times daily. Measurement using both pill count and a pharmacologic indicator (phenobarbital) found that adherence with a once-daffy regimen was best, and that both once- and twice-daily regimens were superior to dosing three times a day. Eisen et al. (1990) assessed the medication adherence of patients receiving hypertensive medications by using pill containers that electronically recorded the time and date of medication removal. They found that adherence improved significantly as prescribed dose frequency decreased: from 59.0% on a three-times-daily regimen to 83.6% on a once-daffy regimen. In relation to antibiotics, there has been scant research investigating the possible relationship between dosage complexity and adherence. From the literature search conducted for 1980-1990, five studies were located that investigated the effect on adherence of manipulating some aspect of the drug regimen-only two of which considered the actual dosage schedule. Both of these studies were conducted as randomized controlled trials. The study by Cheung et al. (1988) compared the effect of administering two different antibiotics, one taken twice daffy and the other four times daffy, on therapeutic outcome and patient adherence. Adherence was assessed by pill count and by using a mechanical box device. Patients taking the four-times-daffy treatment showed a higher level of nonadherence (~66%) as measured by box openings, than those ta~:.ing the twice-daily treatment (~33%). Cockburn et al. (1987b) tested the effect of decreasing the complexity of an antibiotic regimen on adherence, and also looked at the effect of written information and behavioral tailoring on adherence. The provision of information and tailoring strategies were found to make no significant improvement to
R. Sanson-Fisher et al.
adherence rates. However, dosage schedules of increasing complexity were shown to result in significantly higher levels of nonadherence--measured both in an absolute sense and at a level thought to be clinically significant (>20% deviation from the prescribed dose). In addition, there was a significant positive association between complexity and a patient's reported difficulty with fitting tablet taking into the daffy routine. The recent international survey regarding antibiotic treatment provides some interesting information on the perceptions of both doctors and patients regarding dosage schedules and adherence (Groupe MV2, 1991). The majority of doctors (86%) did recognize that the number of doses per day was important to patient adherence. Despite the available literature to the contrary, many doctors (52%) indicated that a twice-daffy dosage was the "ideal" regimen for maximizing patient adherence. These findings reflect a need for further practitioner education regarding the potential adherence-aiding benefits of a once-daily antibiotic dosage schedule. If it were shown to be effective and acceptable, almost all doctors (93%) indicated that they would prescribe an antibiotic with a once-daffy dosage schedule. The survey of patients revealed that very few patients are currently prescribed antibiotics with oncedaffy schedules: the greatest proportion (54%) had taken their last antibiotic treatment three times daily. When asked to express a preference, the greater majority expressed a preference for once (32%)- or twice (41%)-daily regimens. As in the case of the practitioner sample, if patients' concerns about efficacy and possible side effects were answered, the great m~-iority (86%) would be happy to use a once-a-day antibiotic.
REFERENCES Backer IVIH,Maiman LA (1975) Sociobehavioral determi-
nants of compliance with health and medical care recommendations. Med Care 13:10-24. Backer MH, Maiman LA (1980) Strategies for enhancing patient compliance. ] Commun Health 6:113-135. Becket MH, Main'tan LA, Kirscht JP, Haefner DP, Drachman RH, Taylor DW (1979) Patient perception and compliance: recent studies of the health belief model. In Compliance in Health Care. Eds, RB Haynes, DW Taylor, and DL SackeR. Baltimore: John Hopkins Press, pp 78109. Bergman AB, Wemer RJ (1965) Failure of children to receive penicillin by mouth. N Engl ] Med 268:1334--1338. Cheung R, Sullens CM, Seal D, Dickins J, Nicholson PW, Deshmukh AA, Denham MJ, Dobbs SM (1988) The paradox of using a 7 day antibacterial course to treat urinary tract infections in the community. Br J Clin Pharmaco126:391-398.
Cockburn J (1986) Variables related to antibiotic compliance in general practice patients: the application ofbehavioural science methodologies. Doctoral dissertation, University of Newcastle, NSW. Cockburn J, Gibberd RW, Reid AL, Sanson-Fisher RW (1987a) Determinants of non-compliance with shortterm antibiotic regimens. Br Med ] Clin Res 295:814-818. Cockburn J, Reid AL, Bowman JA, Senson-Fisher RW (1987"o)Effects of intervention on antibiotic compliance in patients in general practice. Meal J Aust 147:324-328. Cockburn J, Reid AL, Sanson-Fisher RW (1987c) The process and content of general practice consultations that involve prescription of antibiotic agents. Med J Aust 147:321--324. Cockbum J, Redman 5, Sanson-Fisher RW (1988) Compliance aiding strategies: a guide for the busy practitioner. Aust Prescriber 11:52-54. Col NT, O'Connor RW (1987) Estimating worldwide cur-
Factors for N o n a d h e r e n c e with Antibiotics
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Hussar DA (1987) Importance of patient compliance in rent antibiotic usage: report of Task Force 1. Rev Infect effective antimicrobiai therapy. Pediatr Infect Dis 6:971Dis 9:$232-243. 975. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, OuelKincey J, Bradshaw P, Ley P (1975) Patients' satisfaction lette VL (1989) How often is medication taken as preand reported acceptance of advice in general practice. scribed? A novel assessment technique. J Am Med Assoc J R CoU Gen Pract 25:558-566. 261:3273-3277. Ley P (1977) Psychological studies of doctor-patient comCui~.mings KM, Kirscht JP, Backer MH, Levin NW (1984) munication. In Contributions to Medical Psychology, voi Construct validity comparisons of three methods for 1. Ed, S Rachman. Oxford: Pergamon, pp 9-42. measuring patient compliance. Health Serv Res 19:103116. Ley P (1982) Satisfaction, compliance and communication. Br ] Clin Pharmacol 21:241-2,54. Davis MS (1968) Variations in patients' compliance with doctors' advice: an empirical analysis of patterns of Ley P (1984) Reducing non-compliance: a comparison of communication. Am J Publ Health 58:274--288. behavioural and other techniques. Presented at the conference of the Australian Behaviour Modification Drury V, Wade O, Woalfe E (1976) Following advice in Association, Perth. general practice. J R Coil Gen Pract 26:712-718. Ley P (1988) Communicating with Patients: Improving ComDunbar J (1979) Issues in assessment. In New Directions in munication, Satisfactionand Complinnce. New York: Croom Patient Compliance. Ed, SJ Cohen. Boston: DC Health, Helm. pp 41-57. Madden EF (1973) Evaluation of outpatient pharmacy Eisen 5A, Miller DK, Woodward RS, ~pitznagel E, Przycounselling. J Am Pharm Assoc 13:437. beck TR (1990) The effect of prescribed daily dose freMarsten MV (1979) Compliance with medical regimens: a quency on patient medication compliance. Arch Intern review of the literature. Nurs ires 19:312-323. Med 150:1881-1884. NorreU SE (1981) Accuracy of patient interviews and esEraker SA, Kirscht JP, Becker MH (1984) Understanding timates by clinical staff in determining medication com,~nd improving patient compliance. Ann Intern Med pliance. Soc Sci Med 15E:57-61. 100:258-268. Park LC, Lipman RS (1964) A comparison of patient dosEttinger PRA, Freeman GK (1981) General practice comage deviation reports with pill counts. Psychopharmapliance study: is it worth being a personal doctor? Br cologica 6:299-302. Med ] 282:1192-1194. Pullar T, Birtwell AJ, Wiles PG, Hay A, Feel}, MP (1988) Gatley MS (1968) To be taken as directed. ] R Coil Gen Use of a pharmacologic indicator to compare compliPract 16:39-44. ance with tablets prescribed to be taken once, twice, or Gilbert JR, Evans CE, Haynes RB, Tugwell P (1980) Prethree times daily. Clin Pharmacol Ther 44:540-545. dicting compliance with a regimen of digoxin therapy Richens A, Warringten S (1979) When should plasma drug in family practice. Can Med Assoc J 123:119-122. levels be monitored? Drugs 17:488-500. Gillum FR, Barsky AJ (1974) Diagnosis and management Roth HP, Caron HS (1978) Accuracy of doctors" estimates of patient non-compliance. J Am Med Assoc 228:1563and patients" statements on adherence to a drug regi1567. men. Clin Pharmacol Ther 23:361-370. Gordis L, Markowitz M, Lillienfield AM (1969) The inacSeckett DL (1979) A compliance practicum for the busy curacy of using interviews to estimate patient reliability practitioner. In Compliancein Health Care. Eds, RB Haynes, in taking medications at home. Med Care 7:49-54. DW Taylor, and DL Sackett. Baltimore: John Hopkins Gordis L (1979) Conceptual and methodologic problems University Press, pp 286-294. in measuring patient compliance. In Compliance in Health Senate Standing Committee on Social Welfare (1981) AnCare. Eds, RB Haynes, DW Taylor, and DL Sackett. other side to the drug debate: a medicated society? Baltimore: John Hopkins University Press, pp 25-45. Parliamentary paper 98. Canberra: Australian Government Publishing Service. Groupe MV2 (1991) Stud}, on a once a day dosing oral antibiotic: quantitative phasis, patients (report no. 1) Sharpe TR, Mikeal RL (1974) Patient compliance with anand quantitative phasis doctors. Paris, France. tibiotic regimens. Am J Hosp Pharm 31:479-484. Hamilton-Miller JMT (1984) Use and abuse of antibiotics. Unterhalter B (1979) Compliance with western medical Br ] Clin Pharmaco118:469-474. treatment in a group of black ambulatory hospital .patients. ,S0c$ci ivied 13A:621--631. Hayes P, Hickey K, Lovell S, Dugdale AE (1976) The storage of drugs in homes. Med ] Aust 1:235--236. Wade DN (1976) The background pattern of drug usage in AustraRa. Clin Pharmacol Ther 19:651-656. Haynes RB (1979) Determinants of compliance: the disease Walther H, Meyer FP, Quednow I3, Leuschner U, Kohler and the mechanics of treatment. In Compliance in Health E, Horenburg I (1978) Dosage monitoring throJ_ighmeaCare. Eds, RB Haynes, DW Taylor, and DL SackeR. surement of serum level: a task of clinical pharmacolBaltimore: John Hopkins University Press, pp 49-62. ogy. Int J Clin Pharmacol Biopharm 16:387--390. Hulka BS, Cassel JC, Kupper LL, Burdette JA (1976) ComWeintraub M, Au WY, Lasagna L (1973) Compliance as a munications, compliance and concordance between determinant of serum digoxin concentration. J Am Med physit~ans and patients with prescribed medications. Assac 224:~1- ~-ff,5. Am j Pubi Health 66:847-853.
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Factors Affecting Nonadherence with Antibiotics Robert Sanson-Fisher, Jennifer Bowman, and Susan Armstrong
Nonadherence with antibiotic therapy has profound implications both for patient health and the health care system that bears the financial casts incurred. Significant levels of nonadherence with antibiotic prescriptions have been demonstrated. Of the many proposed variables involved, those that are potentially modifiable relate to aspects of the doctor-patient interaction and drug regimen. Despite the potential for intervention with these variables, there have been very few methodologically sound studies examining their effect on adherence with either medications generally or antibiotics specifically. Only two
studies were located that had tested the effectiveness of reduced complexity of antibiotic dosage schedules. The results suggest that the less complex the schedule, the greater is the adherence. Both practitioners and patients must be encouraged to use and accept simpler dosage schedules, preferably once-daily schedules wherever possible. The paucity of well-controlled studies to date highlights the need for further research evaluating intervention strategies that utilize variations in dosage schedule and elements of the doctor-patient interaction to improve adherence with antibiotic medications.
INTRODUCTION
no account can be taken for such factors as losses occurred in storage, transit, and as a result of noncompliance. The uncertainties of the data notwithstanding, antibiotics are clearly one of the most commonly used therapeutic drugs throughout the world--often accounting for 15%--30% of drug expenditures, the largest share of any therapeutic drug group (Col and O'Connor, 1987). h~ an Australian study of the prescribing habits of general practice trainees, data suggest that a drug of some kind was prescribed in - 5 5 % of all consultations, and that 29% of all drugs prescribed were antibiotics (NSW Family Medicine Programme, Evaluation Group, unpublished data). In total, 21% of all patients were prescribed an antibiotic.
Nonadherence with drug therapy has profound implications both for patient health and the health care system that bears the financial costs incurred as a resuit. Antibiotics are effective and widely used drugs and, as such, they provide an excellent opportunity for studying--and, if possible, modifying--the mechanisms that appear to be involved in noncompliance.
A N T I B I O T I C S ARE C O M M O N L Y U S E D It is difficult to obtain reliable data on the actual amounts of antibiotics consumed. The availability of antibiotics can be estimated based on sales, production, and trade data. Such estimates, however, do not represent a measure of actual consumption, as From the .~'~isciplineof BehaviouralSciencein Relation to Medicine, Faculty of Medicine, Universityof Newcastle, Newcastle, NSW, Australia. Additional copie-~of this supplement are availablefrom Roussel UCLAF, Domaine Th~rapeutiqueAntibioth~rapie,35 Boulevarddes lnvalides, 75007Paris, France. Received 8 October 1991;revised and accepted 20 December 1991. © 1992ElsevierSciencePublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893]92/$5.00
NONADHERENCE IN TAKING ANTIBIOTICS: CONSEQUENCES AND COSTS Adherence to treatment is essential for most successful medical treatments. Nonadhe~ence is therefore a serious medical problem. With regard to antibiotics specifically, the effectiveness of therapy can be considered dependent on a n u m b e r of key factors, including the correct diagnosis being made by the practitioner, prescription of the most effective
1048
form of treatment, the effectiveness of the chosen medication, and patient adherence to the course of medication. This article is concerned with the latter factor, discussing its measurement, the variables that have been found to be related to adherence, and the strategies that can be used to reduce the levels of nonadherence. In taking antibiotics, there is considerable scope for a patient to deviate from the prescribed schedule. Nonadherence can occur in four ways: complete omission of doses; errors in quantity of dose-taking too little or too much; errors in the time of dose administration; and premature discontinuation of the prescribed course of treatment. A recent international survey of both practitioners and patients regarding antibiotic treatment provides some interesting information regarding the issue of nonadherence. In each of five countries (France, Germany, Italy, the United Kingdom, and Spain), 150 patients who had used antibiotics within the previous 3 months completed a telephone interview, and 100 general practitioners took part in faceto-face interviews. The data collected in this interview indicated that practitioners recognized the occurrence of nonadherence to be common, and perceived its effects to be potentially serious. Furthermore, 55% of the practitioners surveyed believed that the rate of patient nonadherence to antl~oiotic treatment was "high" (Groupe MV2, 1991). The negative consequences that can arise for individuals as a result of nonadherence to antibiotics include therapeutic failure, the development of microorganisms resistant to that particular drug, specific drug reactions, and inappropriate selfmedication at a later date (Hamilton-Miller, 1984; Hussar, 1987). While there is little data relating directly to antibiotics, self-medication has been reported to be commonplace in the USA, Great Britain, and Australia (Hussar, 1987). One Australian survey reported that self-medication accounted for -60% of all drug treatment (Wade, 1976), and Hayes et al. (1976) found that a significant degree of drug "hoarding" occurred within Australian homes. Significant financial costs are also incurred by the health care system as a result of nonadherence. It has been estimated that 25% of hospital admissions in Australia are due to people not adhering to pre• ious treatment instructions (Ley, 1984), and that the wastage of unused medications adds up to $200 million per annum (~$156 million US) to the Australian health bill (Senate Standing Committee on Social Welfare, 1981). In the United States, it has been estimated that the total cost of nonadherence with regimens for ten common drug classes is $396$792 million dollars (Ley, 1988).
R. Sanson-Fisher et al.
M E A S U R E M E N T OF N O N A D H E R E N C E IN TAKING ANTIBIOTICS A number of methods are available to clinicians as a means of estimating the degree of their patients' adherence with taking a medication as directed; they include both direct and indirect measures.
Direct Measures: Physical Assays of Blood Plasma or Urine Assays can be used to determine the quantity of medication in blood plasma or urine. This method is acknowledged to be the most rigorous evidence that can be obtained about nonadherence (Walther, et al. 1978; Sackett, 1979; Richens and Warringten, 1979)----being relatively unaffected by human judgment. However, several pragmatic problems are associated with its use: (a) The technology must he available to assay the drug of interest. (b) The expense involved may be substantial, prohibiting the use of this method for large studies. (c) The facilities for assay must be located close to the research site, so that specimens can be stored under appropriate conditions. (d) The request to patients may seem intrusive, with resulting reluctance ot patients to participate. In addition, problems can arise with the existence of individual differences in absorption and excretion rates, and through the possibility of patients being able to build up the appropriate levels of medication by taking the right doses only for a day or two before a sample is taken for assay (Cockburn, 1986).
Indirect Measures: Pill Counts Pill counts represent a simple, inexpensive, and easily implemented alternative to direct measures of adherence. A count is made of the medication remaining in the patient's tablet dispenser after a specified time period, and this quantity is compared with the amount that should be present if total adherence had occurred. A ratio is computed that describes the deviation from the prescribed dose, providing a quantitative assessment of adherence. There are difficulties associated with the use of this method, however: the investigator must know how much medication was dispensed initially, the patient must present all remaining tablets at the time of counting, and patients may hide tablets or throw them away if they know adherence is to be assessed. In addition, this method usually assesses only the amount of medication consumed, and provides no evidence on the scheduling of the doses. Mechanical devices have been used to assess adherence in a number of clinical and analogue studies, recording when a medication container is opened (Ley, 1988; Cramer
Factors for Nonadherence with Antibiotics
et al., 1989). The chief advantage of such devices is that they allow the accurate timing of doses, although not necessarily the actual taking of medication.
Indirect Measures: Judgment by Health Professionals The chief advantage of this method is that the patient is not involved, thus minimizing the potential reactive effects. However, there are clearly likely to be problems with the accuracy of physicians' reporting. Physicians have been found to overestimate adherence~believing that patients follow instructions more closely than they actually do (Gilbert et al., 1980; Norrell, 1981). It is likely that the practitioners surveyed in the international study referred to earlier (Groupe MV2, 1991), even though one-half considered the rate of nonadherence to be high, nevertheless underestimated its real magnitude.
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influence treatment outcome---so that it is not possible to assume a causal relationship between adherence and outcome. (b) Patients on multiple medications may adhere with some and not with others, and yet display a clinical improvement. (c) If taking medications on a long-term basis, patients may discontinue treatment altogether for a period of time and display no apparent change in their condition. In summary, given the various problems associated with each strategy, it is clear that the use of multiple measures may provide the best indication of patient adherence behavior. However, as there are substantial costs involved with most measures, a more feasible approach for practitioners to employ in detecting the nonadherent patient may be to (a) monitor the treatment goals, and focus attention on patients who, despite vigorous treatment, have failed to reach their treatment target; and (b) use a nonthreatening interview of patients to identify actual or potential nonadherers.
Indirect Measures: Patient Self-Report This is a frequently used measure of adherence, being relatively simple and inexpensive, and enabling an in-depth study of the types of errors made and the reason for them. The inherent disadvantage with this method, however, is its reliance on the patient reporling accurately. Agreement between patient selfreport and other measures of adherence is often poor, with p~tients generally reporting a higher degree of adherence than indicated by other measures (Park and Lipman, 1964; Gordis et al., 1969; Roth and Caron, 1978). It has been suggested that variability in the patient's daily behavior may account for most reporting errors, rather than patients deliberately lying (Dunbar, 1979; Gordis, 1979). Data from the international patient survey (Groupe MV2, 1991), where the patients involved had been prescribed an antibiotic within the last 3 months, indicated that, in total, only 20% of patients reported having forgotten to take an antibiotic within that time period. Sixteen percent of the patients surveyed reported that they had ceased taking a course of antibiotic treatment before the end. Both of these figures must be treated with some skepticism.
Indirect Measures: Therapeutic Effect The argument for this measure of adherence is that, given an effective treatment for a condition, those who are more adherent will on average respond better to treatment. The disadvantages of this method, however, are readily apparent, and are such that it would not be advisable to use this method alone in estimating adherence: (a) Many other factors may
EXTENT A N D C L I N I C A L S I G N I F I C A N C E OF N O N A D H E R E N C E IN T A K I N G ANTIBIOTICS An important methodologic issue arises for the researcher and clinician in utilizing any of these direct or indirect measures of adherence: that of defining a cutoff point for the definition of "adherence" and "nonadherence." Adherence can be viewed as a continuous measure. For most practical and research purposes, however, a categorical definition is more appropriate. It may be determined by a pill count, for instance, that a patient has taken only 80% of the prescribed medication and so, in an absolute sense, could be defreed as nonadherent. However, such an absolute measure of nonadherence may have little meaning if there is no therapeutic difference between 80% and 100% adherence. To have clinical significance, adherence may need to be defined as having taken 50% of the tablets. In previous research, the criteria used for categorizing patients as adherent or otherwise have often not been clearly defined (Dunbar, 1979; Marsten, 1979; Cummings et al., 1984). This has been particularly true for studies that have examined adherence with antibiotic regimens where the operational definition of nonadherence has ranged from deviations of 15% (Unterhalter, 1979; Ettinger and Freeman, 1981) to 33% (Bergman and Werner, 1965) from the prescribed dose. This degree of variation makes it difficult to compare rates of nonadherence in different studies, and limits the ability to generalize from resuits.
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Although the operational definition of nonadherence varies across investigations, reviewers appear to agree that at least some 30% of patients in most studies fail to follow advice ((;ilium and Barsky, 1974; Eraker et al., 1984). Ley (1982) summarized the results of a number of reviews reporting percentages of patients judged to be nonadherent with medications, producing the figures reported in Table 1. In all three reviews, the proportion of patients judged to be nonadherent in taking antibiotic medications was ~50%, a figure generally higher than rates of nonadherence for other types of medication such as antihypertensives and medications for tuberculosis and psychiatric disorders. However, there is a lack of recent data. h~ the 1976 review by Ley, for instance, data were derived from investigations reported in 1969 or earlier. A more recent study by Cockburn et al. (1987a), defining nonadherence as ---20% deviation from the prescribed dosage, found 27% of general practice patients to be nonadherent in taking short-course oral antibiotics.
DETERMINANTS OF NONADHERENCE A range of factors have been associ-a(ed with levels of medication adherence. It is useful to categorize them as those that are potentially modifiable, and those that are not, as shown in Table 2. N o n m o d i f i a b l e Factors: Characteristics of Patient, Practitioner, or Illness Characteristics of the individual practitioner or patient that may influence adherence are usually unmodifiable. Evidence of the impact of such variables on adherence is often contradictory, with some studies showing that some factors such as the age (Weintraub et al., 1973), sex (Davis, 1968), and socioeconomic status (Davis, 1968; Drury et al., 1976) of the patient affects adherence, while others do not support these conclusions. SL.nilarly, variables related to the particular illness, such as whether it was a
TABLE I
psychiatric or nonpsychiatric complaint and the severity of the disease, have been related to adherence in some studies. Again, however, the findings are inconsistent (Haynes, 1979).
Modifiable Factors: Doctor-Patient Interaction and Dosage Regimen Doctor-Patient Interaction
Many aspects of the doctor-patient interaction--including the content and manner in which information is communicated to the patient (Sharpe and Mikeal, 1974; Kincey et al., 1975; Ley, 197"/), the patient's health beliefs (Becket and Maiman, 1975; Becket et al., 1979; Ley, 1988), and the level of satisfaction with the consultation (Becket and Maiman, 1980; Eraker et al., 1984)----have been related to adherence with medication use. Despite the evident potential for modifying these kinds of factors, very few methodologically rigorous intervention studies have attempted to improve adherence. A computer-base literaO-re search for the period 1980-1990, inclusive, identified only 13 studies attempting to modify factors relating to the doctor-patient interaction in order to improve adherence with taking antibiotic medications. Many of these studies are methodologically weak, involving small subject numbers or lacking suitable control groups, and so provide no convincing conclusions. The existing research does, however, suggest that a clinician's use of the following strategies in consultations where antibiotics are prescribed may increase adherence to treatment: identifying and correcting inappropriate patient beliefs and attitudes, giving clear (written) treatment instructions, tailoring the regimen to the patient's daily routine, using reminders, utilizing family support, providing information about missed doses and adverse side effects, checking the patient's understanding of instructions, and monitoring their adherence (Cockbum et al., 1988). To insure that the patient's beliefs and attitudes are likely to lead to adherence, it is suggested that the practitioner should explore the patient's under-
Prevalence of Nonadherence (%)
Medication Type
Ley (1976)
Food and Drug Administration (1979)
Barofsky (1980)
Antibiotics Psychiatric Antihypertensive Antitubercuiosis Other medications
49 39 -38 48
48 42 43 42 54
52 42 61 43 46
From ~ (1982).
Factors for Nonadherence with Ap.~lbiotics
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TABLE 2 Factors Related to Adherence Nonmodifiable
Modifiable
Patient's age, sex, and socioeconomic status Doctor's age and years of prac',ice
Patient's health, beliefs Information provided to patients: content and manner of communication Patient's satisfaction with 1he consultation Drug regimen: dosage
Severity and history of illness Nature of the illness
standing and perceptions concerning the diagnosis and cause of symptoms, the long-term consequences of the disease, any barriers to taking the medication, and the benefits to be derived from adhering to the treatment. A great deal of information is often given in a consultation, and research has shown that much of it is poorly attended to or recalled by patients (Ley, 1977). Although results have not always been consistent, several studies have indicated that the more patients understand about their illness and treatment, the more likely they are to be adherent (Sharpe and Mikeal, 1974; Kincey et al., 1975). To enhance recall and therefore adherence, clinicians can employ the following techniques: present treatment instructions clearly and simply, use concrete specific advice, stress the importance of the advice, repeat important components of the advice, use explicit categorization (where the instructions are divided into categories that the clinician outlines to the patient before then proceeding to give information about each in turn), check the patient's understanding by asking the patient ~o repeat salient details of the information, and write down the instructions for the patient--preferably on a specially designed card or sheet. Tailoring the regimen to the patient's daily routine refers to identifying specific events within the patient's usual daily activities around which to anchor the regimen. For instance, for a particular patient on a twice-daily schedule, it may be appropriate for the clinician to advise that the medication be taken in the morning and evening just before ~he patient brushes his or her teeth, and that the medication container be left near the toothbrush holder as a reminder. The regularity of events for any particular patient should not be assumed. For instance, it will not be sufficient for a clinician to issue the instruction "Take one tablet three times a day with meals" if the patient routinely eats only two meals a day. Providing reminders could consist of a sticker or magnet for'the refrigerator, medication calendars, or encouraging family support. A simple adherence-aiding strategy that makes
intuitive sense is to inform the patient of what to do if a tablet is forgotten. A recent survey of Australian general practice patients prescribed antibiotics (involving 56 doctors and 201 patients) found that no doctor provided the patient with this information (Cockburn et al., 1987c). The international survey of patients who had been recently prescribed antibiotics indicated a great deal of variation in patient reports of their behavior when a dose was forgotten; most (46%) just skipped the missed dose without making treatment any longer (Groupe MV2, 1991). Side effects that are unexpected are more likely to result in a negative perception of the value of medication than those that are expected (Madden, 1973). Therefore, adequately informing patients of possible side effects at the time the medication is prescribed may reduce the likelihood that, if side effects are subsequently experienced, the medication will be perceived negatively as a result. Maintenance of a more positive view of the antibiotic treatment is likely to in turn reinforce adherence. And finally, it is important that a practitioner continue to monitor a patient's adherence in an ongoing fashion. Nearly all studies that have continued to monitor adherence after an effective adherence-aiding strategy has beer. withdrawn document a deterioration in adherence back toward its prior low level. This deterioration is often very rapid. In the case of antibiotic prescribing, therefore, it is important for a clinician to check adherence and to use techniques to enhance it, even though the clinician may have previously given the same patient similar information.
DosageRegimen Another potentially modifiable variable associated with adherence is th~ drug regimen. A number of studies have shown that the complexity of the regimen as indicated by the frequency of the dose, the number of tablets prescribed daily, and the length of time for which the medication is prescribed, is negatively rela~.ed to adherence (Gatley, 1968; Hulka et al., 1976). Pullar et al. (1988) examined the adherence of diabetic patients taking oral hypoglyce-
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mic drugs prescribed once, twice, or three times daily. Measurement using both pill count and a pharmacologic indicator (phenobarbital) found that adherence with a once-daffy regimen was best, and that both once- and twice-daily regimens were superior to dosing three times a day. Eisen et al. (1990) assessed the medication adherence of patients receiving hypertensive medications by using pill containers that electronically recorded the time and date of medication removal. They found that adherence improved significantly as prescribed dose frequency decreased: from 59.0% on a three-times-daily regimen to 83.6% on a once-daffy regimen. In relation to antibiotics, there has been scant research investigating the possible relationship between dosage complexity and adherence. From the literature search conducted for 1980-1990, five studies were located that investigated the effect on adherence of manipulating some aspect of the drug regimen-only two of which considered the actual dosage schedule. Both of these studies were conducted as randomized controlled trials. The study by Cheung et al. (1988) compared the effect of administering two different antibiotics, one taken twice daffy and the other four times daffy, on therapeutic outcome and patient adherence. Adherence was assessed by pill count and by using a mechanical box device. Patients taking the four-times-daffy treatment showed a higher level of nonadherence (~66%) as measured by box openings, than those ta~:.ing the twice-daily treatment (~33%). Cockburn et al. (1987b) tested the effect of decreasing the complexity of an antibiotic regimen on adherence, and also looked at the effect of written information and behavioral tailoring on adherence. The provision of information and tailoring strategies were found to make no significant improvement to
R. Sanson-Fisher et al.
adherence rates. However, dosage schedules of increasing complexity were shown to result in significantly higher levels of nonadherence--measured both in an absolute sense and at a level thought to be clinically significant (>20% deviation from the prescribed dose). In addition, there was a significant positive association between complexity and a patient's reported difficulty with fitting tablet taking into the daffy routine. The recent international survey regarding antibiotic treatment provides some interesting information on the perceptions of both doctors and patients regarding dosage schedules and adherence (Groupe MV2, 1991). The majority of doctors (86%) did recognize that the number of doses per day was important to patient adherence. Despite the available literature to the contrary, many doctors (52%) indicated that a twice-daffy dosage was the "ideal" regimen for maximizing patient adherence. These findings reflect a need for further practitioner education regarding the potential adherence-aiding benefits of a once-daily antibiotic dosage schedule. If it were shown to be effective and acceptable, almost all doctors (93%) indicated that they would prescribe an antibiotic with a once-daffy dosage schedule. The survey of patients revealed that very few patients are currently prescribed antibiotics with oncedaffy schedules: the greatest proportion (54%) had taken their last antibiotic treatment three times daily. When asked to express a preference, the greater majority expressed a preference for once (32%)- or twice (41%)-daily regimens. As in the case of the practitioner sample, if patients' concerns about efficacy and possible side effects were answered, the great m~-iority (86%) would be happy to use a once-a-day antibiotic.
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