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ORIGINAL ARTICLE

Comparison of adherence between twice- and thrice-daily regimens of oral amoxicillin/clavulanic acid
CARL LLOR,1 CAROLINA BAYONA,2 SILVIA HERNNDEZ,3 ANA MORAGAS3 AND MARC MIRAVITLLES4
Primary Care Centre Jaume I and University Rovira i Virgili, Tarragona, 2Primary Care Centre Valls Urb, Valls, 3Primary Care Centre Jaume I, Tarragona, and 4The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBER of Respiratory Diseases, Hospital Clnic Barcelona, Spain
1

ABSTRACT
Background and objective: Few studies have analysed adherence with antibiotic treatment in patients with respiratory tract infections. The aim of this study was to compare the compliance of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of patients taking the standard formulation thrice daily. Methods: Patients with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections were included. Adherence was assessed by electronic monitoring, which recorded every opening of the patients bottle of pills. The outcome variables were compliance with taking the medication, taking the correct dose and with timing of the dose. Results: A total of 240 patients were enrolled (167 in the thrice-daily group and 73 in the twice-daily group). The percentage of doses taken was greater with the twice-daily regimen (84.5 22.8%) than with the thrice-daily regimen (72.7 20.1%; P < 0.001). Forty patients in the twice-daily group opened the container every 12 6 h during at least 80% of the course (54.8%), while only 19.6% of the patients assigned to the thrice-daily formulation did so every 8 4 h (P < 0.001). The percentage of patients who opened the container a satisfactory number of times per day was signicantly higher among those taking the twice-daily regimen on days three, four, ve, six and seven. Moreover, the thrice-daily group more frequently forgot to take the afternoon dose. Conclusions: The rate of compliance with amoxicillin/clavulanic acid therapy was very low. However, compliance with the new formulation that is taken twice-daily was signicantly better.

SUMMARY AT A GLANCE
Compliance with amoxicillin/clavulanic acid therapy among patients with community-acquired infections was very low and was signicantly lower among those using the standard thricedaily formulation than among those using the new pharmacokinetically enhanced twice-daily formulation.

Key words: amoxicillin-potassium clavulanate combination, drug administration schedule, micro-electricalmechanical system, patient compliance, respiratory tract infection.

INTRODUCTION
Many studies have been performed to investigate therapeutic adherence in patients with chronic diseases; however, adherence in patients with acute infections has not been investigated.1 Poor adherence with antibiotic regimens has been identied as a major cause of treatment failure and poor clinical outcomes.2 In addition, therapeutic non-compliance may lead to storage of antibiotics at home with a greater likelihood of self-medication and a vicious cycle that favours the emergence of bacterial resistance.3 Adherence with a drug regimen may be dened as the degree to which the patient accepts the advice given by a doctor or health professional regarding the pharmacological treatment that has been prescribed. The term adherence is intended to be non-judgmental, that is, a statement of fact rather than ascribing blame to the prescriber, patient or treatment.4 The recommendations are adhered to by the patient, based on a reasoned decision, without the connotations of subservience that this term may imply for the patient.4 Based on the evidence from studies of therapeutic adherence in patients with respiratory tract infections, the factors that most inuence patients to take their medications inappropriately are the number of daily doses and the duration of treatment.5,6
Respirology (2012) 17, 687692 doi: 10.1111/j.1440-1843.2012.02159.x

Correspondence: Carl Llor, Primary Healthcare Centre Jaume I, c. Felip Pedrell, 45-47, 43005 Tarragona, Spain. Email: carles.llor@urv.cat Conict of interest statement: The MEMS containers were provided through a grant from GlaxoSmithKline. The authors declare that they did not receive any direct economical support for undertaking this study. Received 13 October 2011; invited to revise 17 November 2011; revised 30 November 2011; accepted 15 December 2011 (Associate Editor: Marcos Restrepo). 2012 The Authors Respirology 2012 Asian Pacic Society of Respirology

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A new, pharmacokinetically enhanced bilayer formulation of the b-lactam antibiotic, amoxicillinclavulanic acid taken at a dose of 2000/125 mg twice daily, has been available in Spain since 2004.7 This enhanced formulation has been shown to be at least as effective as oral amoxicillin/clavulanic acid at different doses, when administered twice daily for 7 days, to treat adult patients with communityacquired respiratory tract infections; however, adherence with these two formulations has not been investigated in previous trials.811 Different methods are used to measure adherence. These can be separated into direct and indirect methods.4 The former involve monitoring of drug concentrations in patients. This method is costly, and despite providing knowledge of the true compliance of the patient, it only measures adherence in the hours preceding the medical appointment rather than over the whole therapeutic course. Indirect methods evaluate adherence based on information provided by the patients through measurement of events or circumstances that are probably or indirectly related to adherence. These methods are usually simple, economical and are most commonly used when a large population is being studied. The main limitation is that the information is normally provided by the patients themselves or their relatives, and is therefore not very objective, although this depends on the type of indirect method that is implemented. In general, these methods overestimate the true adherence. However, of all the indirect methods, the most precise is that based on electronic monitoring using pill containers with caps that record how many times per day the patients open their bottles. This has also proven to be the best method when evaluating adherence with antibiotic therapy.4 In the present study, we compared therapeutic adherence in patients treated with the pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid, taken twice daily, with that of patients taking the conventional formulation thrice daily in a primary care setting and with the utilization of electronic monitoring.

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lation of amoxicillin/clavulanic acid, taken at a dose of 2000/125 mg twice daily, became available and was included in the study. This paper reports the results of a comparison of compliance between these two formulations of the same antibiotic. Because this was a non-randomized, observational study performed during usual clinical practice, the choice of antibiotic was left to the attending physician. Patients were treated with one of two formulations of amoxicillin/clavulanic acid, the pharmacokinetically enhanced formulation (2000/125 mg taken twice daily for 7 days) or the standard oral formulation (500/125 mg taken thrice daily for 8 days). Adherence was assessed using the electronic Medication Event Monitoring System 6 (Aardex Ltd, Zug, Switzerland), with container caps that recorded how many times per day the patients opened their pill containers. The study was designed and conducted according to the guidelines applicable to observational studies. Before initiation of the study, the Spanish health authorities were informed and gave approval for the study. Spanish legislation at the time the study was conducted did not require that approval be obtained from the institutional review board for observational studies. However, the patients gave informed consent to participate in a study on the rational use of antibiotics. They were provided with complete information about the study and their participation, but were not informed at that time about the future assessment of adherence, so as to avoid bias in interpretation of the results. When the patients returned to the clinic, adherence was evaluated, they were fully informed about the results, and permission was obtained to include the anonymous data in the present report. All data entered into the database were encoded so as to ensure condentiality. The data recorded in the microprocessors was transferred to a computer and then processed using PowerView version 1.3.2. software (Aardex Ltd). Multiple openings of the container within a period of <15 min were not counted.

Parameters for assessing adherence

METHODS
Study design
A prospective, observational study was performed to evaluate compliance with antibiotic treatment in ve general medicine outpatient clinics between 2003 and 2008. Patients aged 18 years or older, with uncomplicated acute illness of <7 days duration, presenting to the primary care practice with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections, were recruited. Patients who had received previous treatment with antibiotics, those with indications for hospitalization, those with any other condition necessitating the aid of other persons for administration of drugs, and those with hypersensitivities to b-lactam antibiotics or clavulanic acid were excluded. The study protocol has been described in detail elsewhere.6 One year after initiation of the study, the new pharmacokinetically enhanced formuRespirology (2012) 17, 687692

Three different outcome measures were taken into account: 1. Compliance with taking the medication: the number of times the container was opened during the course of treatment calculated as a percentage based on the total number of pills in the containers.12 The percentage of patients who opened the container at least 80% of the required number of times was also calculated. 2. Compliance with taking the correct dose: calculated as the number of days on which the patient opened the container a satisfactory number of times at least twice a day for patients treated with the pharmacokinetically enhanced formulation and at least thrice a day for those assigned to the standard formulation of amoxicillin/clavulanic acid. 3. Compliance with recommended timing of medication during at least 80% of the antibiotic course, as indicated by whether opening of the container coin 2012 The Authors Respirology 2012 Asian Pacic Society of Respirology

Adherence with two coamox formulations

Table 1 Baseline characteristics of the patients included in the study, according to antibiotic therapy received 1000/62.5 mg, 28 tablets, 7 days (2 tablets/12 h)
73 53 (72.6) 9 (12.3) 11 (15.1) 55.1 (18.9) 32 (43,8) 29 (39.7) 15 (20.8) 10 (13.9)

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Formulation
n Type of infection, n (%) Respiratory tract infection Pharyngitis Dental infection Age, mean (SD) Male gender, n (%) Smokers, n (%) Comorbidity, n (%) High blood pressure Diabetes mellitus

500/125 mg, 24 tablets, 8 days (1 tablet/8 h)

167 89 (53.3) 54 (32.3) 24 (14.4) 49.3 (20.5) 77 (46.1) 51 (30.5) 36 (21.6) 21 (12.6)

Total
240 142 (59.2) 63 (26.3) 35 (14.7) 51.1 (20.2) 109 (45.4) 80 (33.3) 51 (21.3) 31 (13.0)

P value

0.004 0.051 0.779 0.182 0.900 0.835

SD, standard deviation.

cided with the recommended time intervals of 8 4 h during at least 80% of the thrice-daily course of the standard regimen and 12 6 h during at least 80% of the twice-daily course of the pharmacokinetically enhanced formulation. The rate of clinical failure was not an outcome of this study; however, information on the need for a second course of antibiotics, during or at the end of treatment, was also recorded.

Statistical analysis
Descriptive analysis of the data was performed before application of non-parametric MannWhitney tests to compare mean values and Fishers exact test to compare categorical variables, with differences being considered statistically signicant when the P-value was <0.05.

RESULTS
A total of 240 patients were recruited. Of these, 167 (69.6%) received the standard formulation of the antibiotic, and 73 (30.4%) received the new pharmacokinetically enhanced formulation. At the second visit, all patients gave permission for inclusion of data on adherence. The mean age for all patients was 51.1 years (standard deviation 20.2), with 131 being females (54.6%). A total of 142 patients presented with lower respiratory tract infections (59.2%). There were no statistically signicant differences in these parameters between the patients assigned to the two groups, although patients assigned to the new twice-daily formulation of the antibiotic were slightly older than those assigned to the standard thrice-daily formulation (Table 1). There were six antibiotic treatment failures (2.5%) requiring a change in antimicrobial treatment: three with the enhanced formulation and three with the conventional formulation. Ten patients demonstrated non-adherence, with six or less openings of the container, all due to digestive intolerance.
2012 The Authors Respirology 2012 Asian Pacic Society of Respirology

Fourteen patients opened the containers more than once at intervals of <15 min. Table 2 shows the main results for compliance with the different antibiotic regimens. The percentage of doses taken was greater for patients using the twice-daily formulation (84.5%, standard deviation 22.8) than for those using the thrice-daily regimen (72.7%, standard deviation 20.1; P < 0.001). Fifty-three patients assigned to the twice-daily antibiotic regimen (72.6%) took at least 80% of the required number of doses, which was a signicantly higher percentage than that observed among patients taking the thrice-daily antibiotic regimen (79 patients, 47.3%; P < 0.001). There were no statistically signicant differences in adherence in relation to age, gender or any comorbid condition. The percentage of patients who opened the container a satisfactory number of times throughout the course of treatment was signicantly higher for those using the twicedaily formulation on days three (82.2% vs 66.5%; P < 0.05), four (76.7% vs 51.8%; P < 0.01), ve (73.9% vs 42.8%; P < 0.001), six (68.5% vs 33.7%; P < 0.001) and seven (52.1% vs 28.3%; P < 0.001) (Fig. 1). The dose most often forgotten by patients assigned to the thrice-daily antibiotic regimen was the afternoon dose after the second day, which accounted for 47.1% of the forgotten doses, followed by the evening dose (27.8%) and the morning dose (25.1%) (Fig. 2). The patients assigned to the twice-daily antibiotic regimen also showed the best compliance with respect to timing of the doses, with 40 (54.8%) of these patients taking the antibiotic every 12 6 h as compared with 19.8% of patients taking the standard formulation of amoxicillin/clavulanic acid thrice daily every 8 4 h (P < 0.001) (Fig. 3).

DISCUSSION
This study demonstrated that there was a low degree of compliance with amoxicillin/clavulanic acid antibiotic treatment among patients attending outpatient clinics with different types of community-acquired
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Table 2 Compliance with taking the two formulations of amoxicillin/clavulanic acid and with the recommended interval between doses 1000/62.5 mg, 28 tablets, 7 days (2 tablets/12 h)
73 11.8 (3.2) 84.5 (22.8) 215 53 (72.6) 40 (54.8)

Formulation
n Number of openings, mean (SD) Percentage of doses taken (SD) Range of openings More than 80% of doses taken, n (%) Good compliance with timing of the interval between doses, n (%)

500/125 mg, 24 tablets, 8 days (1 tablet/8 h)

167 17.4 (4.8) 72.7 (20.1) 124 79 (47.3) 33 (19.8)

Total
240 15.7 (5.1) 76.3 (21.6) 124 132 (55.0) 73 (30.4)

P value
<0.001 <0.001 NA <0.001 <0.001

Openings of the container coincided with the recommended time intervals of 8 4 h during at least 80% of the thrice-daily standard course of amoxicillin/clavulanic acid or 12 6 h during at least 80% of the course of pharmacokinetically enhanced amoxicillin/clavulanic acid. NA, not available; SD, standard deviation.

Figure 1 The percentages of patients who opened the Medication Event Monitoring System containers a satisfactory number of times at least twice a day (b.i.d.) among patients who took the pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid (2000/125 mg) and at least three times a day (t.i.d.) among those assigned to the standard formulation of amoxicillin/clavulanic acid (500/125 mg). Not all the patients began taking the antibiotic on the morning of the rst day. NS, not signicant. ( ), 2000/125 mg b.i.d. 7 days; ( ), 500/125 mg t.i.d. 8 days.

Figure 2 Adherence with the standard regimen of amoxicillin/clavulanic acid (500/125 mg) taken thrice daily. Bars show the percentage of patients forgetting to open the Medication Event Monitoring System container according to the time of day. Not all the patients began taking the antibiotic on the morning of the rst day. ( ), morning; ( ), afternoon; ( ), evening.

infections, especially when the antibiotics were administered thrice daily. Before discussing the results of this study, some limitations should be considered. First, our objective was not to evaluate the effectiveness of the treatments, although six cases of treatment failure requiring a change in antibiotic treatment were reported (three in each group). Interestingly, there was no relationship between poor compliance and clinical failure (data not shown). Second, this was not a randomized study, and the physicians were free to use either of the antibiotic formulations; however, the clinical characteristics of the two groups of patients were very similar and
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should not have signicantly inuenced the differences in compliance that were observed. Third, the diagnosis was based on clinical criteria; therefore, it could not be guaranteed that all the patients actually had bacterial infections. However, this applied equally to patients in both treatment arms and should not have been directly related to compliance with treatment. Lastly, it could not be veried that every time the container was opened, the medication was actually taken. Neither could it be ensured that when patients took the new pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid, they took two tablets simultaneously. Nonetheless, we believe that the electronic method used in this study and the fact that patients were not informed as to the real objective of the study until the second visit undoubtedly constituted the greatest strengths of this work. Moreover, we believe that with regard to adherence, this method best simulates the circumstances of real medication intake by the patients. This may explain why 14 patients opened their containers on repeated occasions at intervals of less than 15 min. On most
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Adherence with two coamox formulations

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maximum therapeutic effect.15 For example, the bacteriological efcacy of the b-lactam antibiotics correlates with the amount of time for which the concentration of unbound drug exceeds the minimum inhibitory concentration. A prolonged time interval between doses not only results in reduced efcacy but also contributes to the emergence of antibiotic-resistant pathogens.16,17 Furthermore, when b-lactam antibiotic concentrations are below the minimum inhibitory concentration for more than 40% of the between-dose time interval, therapeutic failure is more likely.18 This type of therapeutic failure was not observed in the present study probably because patients with mild or moderate infections were included, and the number of patients was clearly insufcient for comparisons of clinical efcacy between the treatment arms. However, the results may have been different if patients with potentially severe infections were included. In the present study, only one-fth of the patients assigned to the standard thrice-daily regimen of amoxicillin/clavulanic acid took their medication every 8 h. When the interval between doses is longer than 12 h, it cannot be guaranteed that the antibiotic concentration remains above the minimum inhibitory concentration for at least 40% of the time, and therapeutic efcacy may therefore be reduced. With the twice-daily regimen, a little more than half the patients showed good interval compliance when this was dened as opening of the container every 12 6 h. In another study involving the use of electronic monitors, Favre et al.19 also found that patients usually opened the containers the recommended number of times when using twicedaily antibiotic therapy, but only 32.6% of patients did so with an interval between doses of 12 1 h. Patients usually stop taking their medication when they begin to feel better. If we are to improve adherence with antibiotic treatment, we must take patient behaviour into account.20,21 Based on the results of this study, one strategy would be to consider using regimens that are easier for patients, such as the new pharmacokinetically enhanced twice-daily formulation of amoxicillin/clavulanic acid instead of the standard thrice-daily formulation, which more often results in missed doses.

Figure 3 Compliance with taking of antibiotic therapy and good compliance with recommended timing of doses during at least 80% of the antibiotic course. Bars indicate overall adherence among patients taking either formulation of amoxicillin/clavulanic acid (see text). b.i.d., twice daily; t.i.d., thrice daily. ( ), >80 doses taken; ( ), good compliance.

occasions, this indicated repeated activation by patients investigating an unfamiliar opening mechanism, particularly when taking the initial doses. This study was initiated in 2003, with the standard formulation of amoxicillin/clavulanic acid (500/ 125 mg three times a day).6 The new formulation of amoxicillin/clavulanic acid was not launched in Spain until 2004 and was therefore unavailable when the study was initiated. Due to the lack of direct comparisons of compliance with different formulations of the same antibiotic, we decided to analyse the data for patients who were prescribed with these two different formulations. This type of data is not available for phase III efcacy studies because such studies do not simulate everyday clinical practice. Few studies have analysed adherence with antibiotic regimens, and even fewer have used electronic monitoring. Garau et al.13 observed similar rates of adherence when comparing use of the same two antibiotic regimens for treatment of community-acquired pneumonia (89.9% with the pharmacokinetically enhanced and 86.3% with the conventional formulation of amoxicillin/clavulanic acid), although the patients were requested to return the unused medication at the end-of-therapy visit. Compliance was analysed by counting the unused tablets, and the different method used in that study, together with the greater severity of disease, may largely explain the differences in adherence rates when compared with the present study. In an exhaustive review of studies of compliance, Urquhart observed large differences between twice-daily and thrice-daily regimens.14 This may be related to the fact that patients who still work while they are unwell may nd it difcult to take their medication during work hours. In most clinical situations, particularly those involving antibiotic therapy, the time interval between doses is extremely important. In most cases, the pharmacokinetics of the drug necessitates that it not be taken later than recommended to ensure
2012 The Authors Respirology 2012 Asian Pacic Society of Respirology

ACKNOWLEDGEMENTS
We thank the patients who participated in this study. The MEMS containers were provided through a grant from GlaxoSmithKline. The authors declare that they did not receive any direct nancial support for undertaking this study.

REFERENCES
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12 Cals JW. Comment on: the higher the number of daily doses of antibiotic treatment in lower respiratory tract infection the worse the compliance. J. Antimicrob. Chemother. 2009; 63: 10834. 13 Garau J, Twynholm M, Garcia-Mendez E et al. Oral pharmacokinetically enhanced co-amoxiclav 2000/125 mg, twice daily, compared with co-amoxiclav 875/125 mg, three times daily, in the treatment of community-acquired pneumonia in European adults. J. Antimicrob. Chemother. 2003; 52: 82636. 14 Urquhart J. Ascertaining how much compliance is enough with outpatient antibiotic regimens. Postgrad. Med. J. 1992; 68(Suppl. 3): S6978. 15 Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 1998; 26: 110. 16 Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. J. Chemother. 1997; 9(Suppl. 3): 3844. 17 Thomas JK, Forrest A, Bhavnani SM et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob. Agents Chemother. 1998; 42: 5217. 18 Andes D. Pharmacokinetic and pharmacodynamic properties of antimicrobials in the therapy of respiratory tract infections. Curr. Opin. Infect. Dis. 2001; 14: 16572. 19 Favre O, Delacrtaz E, Badan M et al. Relationship between the prescribers instructions and compliance with antibiotherapy in outpatients treated for an acute infectious disease. J. Clin. Pharmacol. 1997; 37: 1758. 20 Hawkings NJ, Cutler CC, Wood F. Antibiotics in the community: a typology of user behaviours. Patient Educ. Couns. 2008; 73: 14652. 21 Murio C, Soler X, Prez M et al. Acute exacerbations of chronic obstructive pulmonary disease in primary care in Spain: the EPOCAP study. Ther. Adv. Respir. Dis. 2010; 4: 21523.

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2012 The Authors Respirology 2012 Asian Pacic Society of Respirology