key: cord-0955707-q4nl9t3d
authors: Fernández‐Urrusuno, Rocío; Meseguer Barros, Carmen Marina; Anaya‐Ordóñez, Sonia; Borrego Izquierdo, Yolanda; Lallana‐Álvarez, María Jesús; Madridejos, Rosa; Tejón, Esther Marco; Sánchez, Raquel Prieto; Pérez Rodríguez, Olatz; García Gil, María; Escudero Vilaplana, Belén; Riádigos, Genma M. Silva; López‐Fando, M. Sagrario Pardo; Olmo Quintana, Vicente; Pina Gadea, M. Belén; García Alvarez, Angel; Martorell, M. Llüisa Sastre; Jiménez Arce, Jorge I.; Aguilella Vizcaíno, Rafael; Pérez Martín, Joaquín; Alzueta Isturiz, Natalia
title: Patients receiving a high burden of antibiotics in the community in Spain: a cross‐sectional study
date: 2020-12-19
journal: Pharmacol Res Perspect
DOI: 10.1002/prp2.692
sha: a6fab1c0d47233261c0d3d1984a1ad62d3600ad3
doc_id: 955707
cord_uid: q4nl9t3d

Some patients in the community receive a high burden of antibiotics. We aimed at describing the characteristics of these patients, antibiotics used, and conditions for which they received antibiotics. We carried out a cross‐sectional study. Setting: Thirty Health Primary Care Areas from 12 regions in Spain, covering 5,960,191 inhabitants. Patients having at least 30 packages of antibacterials for systemic use dispensed in 2017 were considered. Main outcome measures: Prevalence of antibiotic use, conditions for which antibiotics were prescribed, clinical characteristics of patients, comorbidities, concomitant treatments, and microbiological isolates. Patient’s average age was 70 years; 52% were men; 60% smokers/ex‐smokers; 54% obese. Overall, 93% of patients had, at least, one chronic condition, and four comorbidities on average. Most common comorbidities were cardiovascular and/or hypertension (67%), respiratory diseases (62%), neurological/mental conditions (32%), diabetes (23%), and urological diseases (21%); 29% were immunosuppressed, 10% were dead at the time of data collection. Patients received three antibiotic treatments per year, mainly fluoroquinolones (28%), macrolides (21%), penicillins (19%), or cephalosporins (12%). Most frequently treated conditions were lower respiratory tract (infections or prophylaxis) (48%), urinary (27%), and skin/soft tissue infections (11%). Thirty‐five percent have been guided by a microbiological diagnosis, being Pseudomonas aeruginosa (30%) and Escherichia coli (16%) the most frequent isolates. In conclusion, high antibiotic consumers in the community were basically elder, with multimorbidity and polymedication. They frequently received broad‐spectrum antibiotics for long periods of time. The approach to infections in high consumers should be differentiated from healthy patients receiving antibiotics occasionally.

Antimicrobial resistance is a growing problem, widely recognized as a major threat to public health. [1] [2] [3] [4] In general practice, there is a major concern that some common infections are becoming increasingly difficult to be treated, and those infections caused by antibiotic-resistant bacteria may take longer to be resolved. 5 Primary Care is responsible for most of the antibiotics prescriptions in human health. [6] [7] [8] [9] There is a high prevalence of infectious diseases in this setting, 10 and two thirds of patients treated for infectious diseases receive antibiotic therapy. 2, 6, 7 This leads to 25-30% of the population receiving antibiotics annually. 11, 12 Not all patients in the community receive the same burden of antibiotics. 13, 14 While some patients receive antibiotics occasionally, others receive antimicrobial treatments on a continuous or cyclic manner for prolonged periods of time, in the context of infectious diseases with indication of long-term treatments, recurrent infections or for prophylactic purposes. 13 These patients are more susceptible to infections by multidrug resistant bacteria, [15] [16] [17] leading to more frequent use of broad-spectrum antibiotics. This limits the possibility of treating future infections in the ambulatory setting. 18 Improving the appropriate use of antibiotics has become an increasing priority for Health Services. The establishment of powerful interventions, preferably integrated into antimicrobial stewardship programs (ASP), is essential. 19, 20 It is a priority to identify which patients receive a high burden of antibiotics in the community, and which of them could benefit from interventions aimed to improving the use of antibiotic. At this time, when global attention is focused on the SARS-CoV-2 pandemic, it is necessary not to forget the importance of maintaining ASP interventions since optimizing the use of antibiotics should not cease to be a priority. 21 Furthermore, given the higher rates of inpatient utilization of broad-spectrum antibiotics during the pandemic, a higher spread of bacterial resistance could be expected. 22 The objective of this work was to characterize the patients who receive a high burden of antibiotics in the community, the antibiotics used, and clinical conditions for which patients are treated. Our results will serve to design interventions aimed at optimizing antibiotic prescribing in these patients.

A descriptive cross-sectional study was carried out in Primary Care, covering a total population of 5 960 191 inhabitants. The study setting comprised 30 Healthcare Areas from 12 of the 17 regions in Spain (Table S1 ). The Spanish National Healthcare System is organized in Health Areas. A Health Area is an administrative district that clusters a group of Primary Care centers and professionals under its organizational and functional dependency. Primary Care provides essential care for the entire population. Furthermore, each Health Area has one or more referral hospitals for hospital care. were men; 60% smokers/ex-smokers; 54% obese. Overall, 93% of patients had, at least, one chronic condition, and four comorbidities on average. Most common comorbidities were cardiovascular and/or hypertension (67%), respiratory diseases (62%), neurological/mental conditions (32%), diabetes (23%), and urological diseases (21%); 29% were immunosuppressed, 10% were dead at the time of data collection. Patients received three antibiotic treatments per year, mainly fluoroquinolones (28%), macrolides (21%), penicillins (19%), or cephalosporins (12%). Most frequently treated conditions were lower respiratory tract (infections or prophylaxis) (48%), urinary (27%), and skin/soft tissue infections (11%). Thirty-five percent have been guided by a microbiological diagnosis, being Pseudomonas aeruginosa (30%) and Escherichia coli (16%) the most frequent isolates. In conclusion, high antibiotic consumers in the community were basically elder, with multimorbidity and polymedication. They frequently received broad-spectrum antibiotics for long periods of time. The approach to infections in high consumers should be differentiated from healthy patients receiving antibiotics occasionally.

ambulatory Care, antibiotic prescribing, antimicrobial stewardship programs, infection, outpatients

The unit of analysis was the patient, identified by the use of his personal social insurance system card number. Inclusion criteria for high consumers were as follows: all patients assigned to Primary Care centers from the study areas, having at least 30 packages of antibacterial agents for systemic use (J01, according to the WHO Anatomical Therapeutic Chemical classification system 23 ) dispensed from January to December 2017.

Patients were identified through databases from computerized pharmacy records of reimbursed and dispensed drugs, from their The following variables, defined at the population level, were calculated: prevalence of antibiotic use (that is the percentage of the population that consumes antibiotics during the year), the average number of antibiotic prescriptions per patient, and the average number of days with antibiotic per patient. Variables collected at the patient level were as follows: age, gender, smoking behavior (smoke now or former smoker), obesity, or high body mass index (BMI; obesity: BMI>30 kg/m 2 ), residence in nursing home or in long-term care facilities, urinary incontinence, bedridden, number and type of underlying chronic health conditions (Table S2 ), condition that caused antimicrobial treatment, hospital admissions, death, type of antibiotic prescribed, number of antibiotic treatments received, antibiotic days, concomitant treatments (Table S3) , prescriber medical specialty, type of sample for microbiological testing, and microbiological isolates.

A descriptive analysis of the data was carried out to determine the prevalence and profile of high antibiotic consumers. Summary statistics were computed using frequencies and percentages for categorical variables and median (50th percentile), and interquartile range (25-75th percentiles) for continuous variables with asymmetric distribution. Confidence intervals were calculated at 95% (95% CI). STATA Corp. V12 was used for statistical analysis. 

We have identified 1,876,927 patients with antibiotics prescribed during the study period. The prevalence of antibiotic use was 31%.

Among these patients, 1,162 were high consumers according to the criteria established in this study, and 889 met the inclusion criteria.

Characteristics of high consumers are described in Table 1 . Median age was 70 (58-80) years; 52% were men; around 60% were smokers or ex-smokers; 54% were obese.

Overall, 93% of patients had at least one of the analyzed comorbidities while 92% were receiving concomitant chronic treatments (Table 1) . Most common comorbid conditions were chronic respiratory disease, cardiovascular (60%; 67% considering those with hypertension), neurological/mental, diabetes, urological disease, and 29% were immunosuppressed. High consumers had four chronic conditions on average, 53% were admitted, at least once, during the year of the study, and 10% were dead at the time of data collection (Table 1) .

For their pathologies, patients received a median of five concomitant chronic treatments (Table 1) . Treatments most commonly prescribed were proton pump inhibitors (PPI), corticoids, antihypertensives, bronchodilators, analgesics, benzodiazepines, lipid-lowering agents, antidepressants, and antidiabetics.

Patients received a total of 3,226 antibiotic treatments during the study period. Half of the patients (51%) received antibiotics for the entire annual period: 24% received them in a single antibiotic course and 76% received several courses (18% received two courses; 17% received three courses; 13% received four courses, and 28% Regarding the therapeutic group, fluoroquinolones was the most prescribed antibiotic group, followed by macrolides, penicillins, and cephalosporins (Table 2) . When analyzed by antibiotic agents, azithromycin, amoxicillin-clavulanate, levofloxacin, and ciprofloxacin were the most prescribed antibiotics ( Table 2 ).

The absence of a diagnosis in clinical records was detected for Based on records, antibiotics were mainly used to treat infections, with 21% treatments used with prophylactic purposes.

Prophylaxis of lower respiratory infections accounted for 69% of all established prophylaxis.

Specific diagnosis for which antibiotics were used can be observed in Table 3 . Lower urinary tract infections (UTIs) were the most treated condition (21%), followed by chronic obstructive pulmonary disease (COPD) exacerbations (11%), and overinfected bronchiectasis (11%) ( Table 3 ).

The distribution of antibiotics by condition is described in 

and Community Medicine (50% of the total), followed by specialists in Pneumology (25%), Internal Medicine (8%), and Urology (6%).

These four professional groups accounted for 88% of prescriptions.

A total of 1,074 samples were recorded for microbiological assessment, that is, 35% of antibiotic treatments would have been guided by a microbiological diagnosis: 49% corresponded to bronchial exudates, followed by urine cultures (32%), and skin exudates (13%) ( 

This observational study shows that patients who receive a high burden of antimicrobials in the community are, basically, older adults with multiple chronic conditions and polymedication. The studied population had a high prevalence of comorbidities, a high management from hospital care and hospital admissions (53% patients), as well as a high risk of dying (10% exitus).

In our study, prevalence of hypertension, asthma, CODP, neurological and mental disorders, diabetes, malignancies, or chronic renal failure were more frequent than that reported for general population receiving antibiotics in the community. 11, 23 COPD and asthma were about 10 times more frequent in the study patients than in general population receiving antibiotics in the community in Spain, 11 and the prevalence of hypertension, heart diseases, and diabetes was three times higher. 11 It should be emphasized the high percentage of patients with chronic renal failure among high consumers (12%).

Other aspects besides comorbidities such as smoking behavior, overweight/obesity, or polypharmacy, common conditions in patients in our study, might be associated with antibiotic prescribing decisions. In relation to concomitant medication, PPI, NSAIDs, or corticosteroids which may contribute to increase susceptibility to infections were frequently used by the study patients. Around 60% of high antibiotic consumers in our study received corticosteroids.

This has been previously shown to be a better predictor of antibiotic prescribing than comorbidities themselves. 13 Lower respiratory tract, urinary tract, and skin and soft tissue infections or prophylaxis justified most antibiotic treatments in high consumers. However, there are great differences between the conditions in these patients and those treated in general population:

antibiotic use for the treatment of exacerbations of COPD and bronchiectasis, which represent a 2% of the use of antibiotics by general population in the community, 25 accounted for 34% of treatments in high consumers. By contrast, upper respiratory tract infections, which represent the 53% of infections treated with antibiotics in the ambulatory setting, 25 represented a 4% of infections treated in high consumers. In addition, prophylactic treatments, very scarce in healthy population, accounted for 21% of all treatments in high consumers, and expose these patients to antibiotics for prolonged periods of time, in a continuous or a cyclic manner.

Regarding the antibiotics prescribed, fluoroquinolones, macrolides, cephalosporins, or co-trimoxazole which represent a low prescription in the community in Spain (10%, 6%, 3%, and 0.3%, respectively) 25 accounted for 28%, 21%, 12%, and 5%, respectively, in high consumers ( Table 2 ). The profile of antibiotic use was very heterogeneous by condition ( Figure 1 ). The most notorious result was the relatively high use of fluoroquinolones and cephalosporins, two groups of antibiotics associated with the selection for resistant bacteria, for the treatment of all kind of infectious diseases, and the wide use of macrolides for the prophylaxis of lower respiratory tract infections.

The high prevalence of Pseudomonas aeruginosa and multidrug-resistant bacteria in these patients would justify these treatments, but at the same time, this makes the patients increasingly susceptible to infections by multidrug-resistant microorganisms. 15, 17 In addition, the use of long-term macrolides for immunomodulatory purposes is a common practice, 26 although the appropriateness of both the indication and the duration of treatments should be tested.

Comorbidity is a main driver of prescribing in high consumers.

The higher the comorbidity, the more antibiotic prescriptions patients received. 12, 27, 28 Rates of antibiotic prescribing to patients with asthma and COPD are 1.6-and 3-fold, respectively, higher than rates in general population, and patients with heart failure, peripheral arterial disease, diabetes, or coronary artery disease are prescribed 47-69% more antibiotics than individuals without these conditions. 12 Despite the great advances in the prevention, diagnosis, and treatment of infectious diseases, these continue to cause great morbidity and mortality in people with chronic conditions. (13) Pseudomonas aeruginosa 34 (13) Enterococcus faecalis 27 (10) Proteus mirabilis 26 (10) Skin exudate 135 (13) 120 (13) Pseudomonas aeruginosa 32 (27) Staphylococcus aureus 26 (22) Escherichia coli 16 (13) Proteus mirabilis 11 (9) Other 64 (6) 86 (10) Several limitations of the study should be pointed out. First, antibiotic prescribing data were exclusively collected from the computerized pharmacy records of dispensed drugs from Regional Public In conclusion, a high prevalence of aged patients with high-risk comorbidities among practices could account for legitimate medical reasons of higher antibiotic prescribing rates, and higher prescription of broad-spectrum antibiotics in the ambulatory setting. The approach to infections and antibiotic use by these patients should be carried out from both health-care settings, since these patients are with high management from hospital care and frequent hospital admissions.

Further studies should be addressed to determine whether high consumers are prescribed antibiotics appropriately or whether the excessive antibiotic use by these patients could be decreased or avoided. 

ON has received funding for conference attendance from Novartis and Mundipharma, and VO from Novonordisk and Lilly. VO has participated as an author of a book sponsored by Pfizer, and received training course enrollment by Amgen. The other authors declare that they have no conflict of interests to disclose. 

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Rocío Fernández-Urrusuno https://orcid. org/0000-0002-6261-6869

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