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Articles: Supplement Article

Noncompliance in Current Antibiotic Practice

Kardas, Przemyslaw MD, PhD

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Infectious Diseases in Clinical Practice: July 2006 - Volume 14 - Issue 4 - p S11-S14
doi: 10.1097/01.idc.0000230544.11499.8b
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Abstract

BASIC DEFINITION OF COMPLIANCE

Noncompliance is a phenomenon well known to every practitioner. A frequently cited definition describes it as the extent to which the time history of drug administration corresponds to the prescribed regimen.1 Most commonly, it is perceived as a problem occurring during chronic treatment. Indeed, approximately half of patients treated for chronic conditions comply only partially or do not comply at all. Low compliance is not only a feature of chronic treatment but is also frequent during the treatment of acute conditions, such as acute infections.

Some authors suggest that compliance implies obedience to a directive, rather than a mutually agreed course of action. Therefore, they suggest that adherence is a more appropriate term because it implies that the patient will adhere to a mutually accepted therapeutic plan, in what more or less equates to a concept of modern patient management.2 However, in the case of antibiotic treatment, this approach does not seem to apply so rigidly. According to widely accepted guidelines, doctors are expected to prescribe antibiotics for the treatment of certain infections, and even the duration of such treatment is clearly described in some cases. In this instance, the doctor is ultimately responsible for both therapy plan and outcome; thus, for both medical and legal reasons, there is a limited scope for negotiations with patients. Therefore, as long as antibiotic treatment seems to be the most appropriate treatment, compliance is the term that is deemed most suitable.

PREVALENCE OF NONCOMPLIANCE WITH ANTIBIOTICS

Most antibiotic consumption is in response to community-acquired infections and takes place in an outpatient setting. In these circumstances, patient compliance becomes an important issue. Recently performed meta-analysis revealed overall noncompliance in 37.8% of outpatients taking antibiotics.3 Even this number may be underestimated, as most of the studies conducted in this field were based on less precise, subjective assessment techniques, such as questionnaire studies, patient diaries, and others. With more objective measurement, noncompliance was found to be much more prevalent, reaching 70% in cases of electronic measurement. Nevertheless, even the above-mentioned one third of patients who are noncompliant with antibiotic treatment is unacceptable, and requires our urgent attention.

REASONS FOR NONCOMPLIANCE WITH ANTIBIOTICS

High prevalence of noncompliance with antibiotics might be surprising. Poor compliance in chronic conditions can be partly explained by the number that are typically asymptomatic. This is clearly not the case with acute infections; patients suffering from malaise, cough, high temperature, and other troublesome infection symptoms are apparently very interested in effective treatment and consequently are usually the last to develop noncompliance. Nevertheless, lack of adherence seems to be a rule not an exception in this patient group. Therefore, examining the reasons for such behavior is fully justified.

Factors affecting compliance may be divided into patient, doctor, treatment, and healthcare system related. The most frequent reasons for nonadherence with antibiotic treatment are listed in Table 1,4-6 of which some are quite predictable. For example, it is a universal rule that the more frequent the regimen, the lower the compliance. Other factors, such as some patients' beliefs, are frequent obstacles for compliance and are not so easily predictable for physicians. Some of the more extreme beliefs were revealed in a survey undertaken recently in Taiwan, where more than 40% of residents claimed that it is harmful to follow physicians' directions when taking antibiotics, and as many as 92.6% thought that taking less antibiotics then prescribed is more healthy.7

TABLE 1
TABLE 1:
Frequent Causes of Noncompliance With Antibiotics4-6

PATTERNS OF NONCOMPLIANCE WITH ANTIBIOTICS

Patterns of noncompliance with antibiotics are numerous. The most frequent ones are listed in Table 2; however, not all of them are of equal importance. For example, in clinical practice, prematurely stopping the therapy is of particular concern.

TABLE 2
TABLE 2:
Most Important Patterns of Noncompliance With Antibiotics6

According to the results of an international survey, not completing treatment seems to be a frequent phenomenon, present in approximately 31% of patients treated with antibiotics (range, from 10% in UK to 47% in Thailand).4 The most frequent (87%) reasons for not completing a treatment course given by patients is simply "getting better."5 Indeed, in a recent study, as many as 46.7% of surveyed Greeks claimed to discontinue therapy once their symptoms subside.8

Another pattern of noncompliance is unconscious single-dose omission. Its importance comes from the fact that the more doses are missed, the more likely is the possibility of poor outcome and emergence of resistance. This frequent behavior may serve to explain the large discrepancy between compliance values observed after subjective and objective assessment, such as the ones obtained for Chlamydia trachomatis treatment with doxycycline, in which interviews and electronic measurements revealed 90% and 16% compliance, respectively.9

With regard to antibiotic treatment, it is also the dose timing (ie, keeping the correct time for subsequent dose intake and interdose intervals), which seems to be important. Indeed, even the patients taking the correct number of prescribed doses may reveal noncompliance in terms of timing. A study assessing a twice-daily (BD) antibiotic regimen found taking compliance was nearly perfect (99.6%), whereas timing compliance was significantly lower (32.6%).10

THE CONSEQUENCES OF NONCOMPLIANCE WITH ANTIBIOTICS

Although it is difficult to give 1 universal answer to the question of how much of prescribed antibiotic doses should be taken to achieve positive outcome, certain levels of compliance are necessary for both clinical success and bacterial eradication. When this threshold is not achieved, negative consequences of noncompliance are likely to appear. They include a number of outcomes of varying degrees of severity: treatment failure, recurrent diseases and complications, need for additional consultations, tests and treatment (including hospital admissions), and, last but not least, even death. All these outcomes are directly or indirectly connected with a rise in costs. This list is more or less typical of nonadherence in every field of medicine, whereas in the case of antibiotics, 1 extra consequence of low compliance must also be taken into consideration. This consequence is bacterial resistance, which may emerge on both an individual and a population level. Although overcompliance is much less prevalent than undercompliance, it can also result in negative consequences, such as emergence of adverse effects, superinfections, and a rise in costs.

The effect of compliance on outcome has clearly been demonstrated in a study of long-term antibiotic treatment.11 In this study, the urinary tract infection recurrence rate in compliant children was established to be 3.0 episodes/yr, whereas in a partially compliant group, it was 4.8 episodes/yr and in a noncompliant one, 7.2 episodes/yr. Recently, 2 large trials successfully demonstrated a link between compliance and outcome in cases of acute respiratory tract infections (RTIs).12,13 In both studies, while assessing short-course amoxicillin treatment of pneumonia in children, noncompliance was found to be the most important risk factor for treatment failure (with odds ratios of 4.5 and 11.6, respectively). These results support the conclusion of a meta-analysis on the relation of medication adherence and cost, which found the impact of noncompliance on outcome to be always negative.14

Although the impact of nonadherence on the cost in the above-mentioned meta-analysis was found to range from negative to positive, one may expect that this was due to the inclusion of studies assessing the effect of compliance on outcome in relatively expensive treatments with delayed and not so obvious results, such as lipid-lowering treatment. In the case of acute antibiotic treatment in outpatient settings, the cost of medication is not so high, but both the chance and the cost of possible consequences, such as noncompliance, are of great importance. For example, a decrease from 100% to 60% compliance in C. trachomatis treatment decreases the cure rate from 98% to 90% and increases costs from $29 to $115.15 There is still a lack of precise data to support the link between nonadherence with antibiotic regimens and both outcome measures and cost, but one may develop an opinion by taking into consideration an average cost of treatment failure in children with RTIs, which was established at approximately $220 for drugs and visits only.16 Moreover, in cases of noncompliance with antibiotics, sources of extra costs are numerous and include increased out-of-pocket and healthcare system costs for office visits, tests, hospitalizations, and additional treatment, as well as direct and indirect additional costs, such as transportation costs, lost productivity, and lower quality of life. The possible burden of costs connected with noncompliance with antibiotic treatment can be derived from the 40 million penicillin prescriptions occurring per year due to ambulatory care visits made to physician offices in the United States.17

HOW TO AVOID AND MANAGE NONCOMPLIANCE WITH ANTIBIOTICS

A number of studies have confirmed that even in cases of acute antibiotic treatment, physicians are unable to predict which patients will comply and which will not.18 Similarly, with tuberculosis treatment, the sensitivity of prediction of nonadherence was 24% for doctor and 19% for nurse assessment, even for those with extensive experience with tuberculosis treatment.19 In such circumstances, the conclusion seems to be straightforward-everyone taking antibiotics should be assessed and comprehensive methods aimed at improving compliance with acute antibiotic treatment should be introduced and widely used. Unfortunately, physicians seldom use techniques that prove effective in the improvement of patient compliance.20 On the other hand, a number of such methods are easily applicable and inexpensive and hence make them a good candidate for mass use.

Patient education seems to be an obligatory step in maximizing patient compliance, although it is not sufficient on its own to ensure compliance, because patients who are fully aware of the consequences still tend to reveal noncompliance. Examples of this phenomenon include transplant rejection (which occurs mainly due to noncompliance) and patients treated with antibiotic therapy within clinical trials. Conversely, one could hardly imagine why patients would follow instructions to complete a course of antibiotic treatment if they were not informed of the possible consequences of noncompliance. Therefore, patients should be educated about the need for compliance in the completion of a course of antibiotics. Topics to be included in any educational program are the risks associated with misuse of antibiotics and, conversely, the benefits associated with effective treatment for both the patient and the community. Patients should also be educated not to expect an antibiotic for every infection they develop but, when they are prescribed one, to take the medication as directed. Finally, there is growing evidence that empowering patients through the implementation of patient-centered healthcare strategies, such as shared decision making in conjunction with educational initiatives, will help to change attitude and behavior and improve the completion of appropriate antimicrobial therapy.21

An important precondition for successful management of antibiotic compliance is to take into consideration that noncompliant behavior in patients develops both consciously and nonconsciously. Consequently, the more user-friendly the medication, the better the compliance. For example, in this case, user-friendly means short-course antibiotic therapy with infrequent dosing, a convenient dosage form, and minimal adverse effects.

Patient compliance drops dramatically with time-the longer the treatment course, the lower the compliance. In a study assessing penicillin treatment of streptococcal infections with a simple method of pill count, 44%, 29%, and 18% of patients were found to be compliant at days 3, 6, and 9, respectively, although the course was typically designed for 10 days.22 More detailed electronic measurement could prove a constant decrease in compliance levels in time starting from day 3 of treatment (Fig. 1).23 Therefore, shorter courses of antibiotics may be expected to maximize patient compliance and help to contain antimicrobial resistance.24

FIGURE 1
FIGURE 1:
The effect of treatment duration on patient compliance with antibiotic in acute bacterial exacerbation of chronic bronchitis: after an initial delay of therapy start, compliance reaches its maximum on day 3 and subsequently drops down in both once-daily (OD) and twice-daily (BD) clarithromycin group.23

Compliance and resistance are the main reasons why new short-course treatment options are now being tested worldwide. In addition, patients also find short-course, once-daily (OD) treatment an attractive option that best meets their expectations.24 A European survey of patients' attitudes to antibiotic use has proved that more than 80% of patients expect clinical improvement after 3 days of antibiotic treatment.5

Compliance, in general, and particularly single-dose omission are strongly connected with regimen complexity-the more frequent the doses, the poorer the adherence.26 Nowadays, most antibiotics are available in OD and BD formulations, which, one might assume, are easy to adhere to. Nevertheless, careful study of the results of electronic monitoring can reveal significant differences between these 2 regimens, being in favor of OD regimen in terms of both dosing and timing. In a study that has assessed compliance in cases of acute bacterial exacerbation of chronic bronchitis, the overall compliances were 93.7% and 81.3% for OD and BD groups, respectively (P < 0.0001), and correct interdose intervals were 74.4% and 56.4%, respectively (P < 0.001) (Fig. 2).23

FIGURE 2
FIGURE 2:
The effect of the number of daily doses on patient compliance with antibiotic in acute bacterial exacerbation of chronic bronchitis.23

Recently, a single, oral, high-dose therapy with azithromycin in RTIs was postulated as a novel method of overcoming the compliance problem with the simplest possible outpatient regimen, which reduces both the duration and the number of daily doses to the minimum.27 Such an ultimately simple regimen fits patients' expectations best and may be expected to minimize the extent of noncompliance.

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