Introduction
Acute bacterial skin and skin structure infections (ABSSSI) are one of the most frequent causes of hospitalization among skin and soft-tissue infections (SSTIs) [
1,
2]. Management of ABSSSI is complex and includes surgical procedures and antibiotic (AB) treatment [
1,
3].
Adherence to medication is strictly associated with treatments’ efficacy [
4‐
6]. It is not considered a major issue for hospitalized ABSSSI patients, usually treated via intravenous (IV) route, but it may impact on outpatient treatments. High frequency of comorbidities, dose adjusting, and considerations for drug interactions raise complexity in drug selection and patient’s management [
7]. Current treatments for ABSSSI often require multiple daily administrations, although in some cases, once-a-day dosing may be applicable [
8]. Since these medications are often associated with gastrointestinal adverse events, a low adherence, and poor clinical outcome can occur [
6]. Furthermore, AB misuse, and length of treatment might lead to drug resistance [
5,
9]. Guidelines focusing on the issue of resistance frequently do not take into account variation in epidemiology of resistant pathogens, across countries [
10].
Long-acting agents, which are characterized by a more favorable administration regimen, have been launched in the European markets [
1,
11]. Their indications cover the major causes of ABSSSI, including MRSA. Among long-acting agents, dalbavicin has demonstrated an efficacy and safety comparable to other similar agents in the treatment of ABSSSIs, both in hospital wards and outpatient’s settings [
12]. Its long half-life might be considered definitive advantages for the therapeutic treatment of ABSSSI patients and in terms of hospital cost-effectiveness [
12].
The importance of adherence, for patients with ABSSSI, has not been addressed in therapeutic management guidelines, yet [
7,
9,
13]. It is thus the aim of the present paper to explore the attitudes of European physicians on adherence and how treatment modalities impact on adherence.
Discussion
Adherence to treatment represents a key factor for treatment efficacy, especially with antimicrobial drugs [
5,
15]. Moreover, it has a more powerful impact in cases of prolonged, chronic, or acute infections, such as ABSSSI [
15].
The aim of our survey was to explore the attitude of a panel of infectious experts across ten European countries, on adherence and how treatment modalities impact adherence for ABSSSI treatments. A six-topic questionnaire and the Delphi method were used to obtain the most accurate expert’s opinion and consensus.
Interestingly, 61% of the participants were infectious diseases specialist (Table
1). It is important for us to highlight recent findings demonstrating a crucial role for these specialists in the management of severe infections disease, including ABSSSI. Indeed, it appears that the use of suitable guidelines and infectious disease specialist represent an efficacious approach aimed at reducing the incidence of inappropriate therapies and increasing good outcome rates [
16].
The participants fully agreed on the importance of adherence in ABSSSI treatment. Undeniably, poor adherence to treatments is a major determinant for therapeutic failure, because it can lead to lack of response, recurrence, and predisposes to AB resistance [
9].
Administration regimen and drug selection for ABSSSI’s treatment emerged as crucial factors for adherence. After initial treatment, patients may be switched to a suitable oral AB, or to outpatient parenteral antibiotic therapy (OPAT) [
2]. In general, outpatient costs are lower, but treatments often require multiple and long infusions, loading on the healthcare systems and HCP utilization [
17]. However, OPAT has reached interesting success in several European countries, reducing the risks of hospital-related infections [
6,
18]. Oral MRSA-active drugs are included in guidelines for treatment of ABSSSI, in order to achieve an early switch (ES) and favoring early discharge (ED) [
1]. Recent trials have also supported the concomitant use of oral antimicrobial therapies with incision and drainage, in less severe cases of ABSSSI [
19,
20].
Interestingly, the link between oral treatment and adherence after discharge (topic 2, item 5) and for several days (topic 6, item 2) has produced conflicting answers, in our survey. A further analysis of the responses revealed that for topic 2-item 5, Portugal (and the single respondent from Russia) provided a negative consensus. A positive consensus was obtained for this item from Austria, Poland, and Greece. A no consensus was obtained for Italy, Czech Republic, Bulgaria, Spain, and Romania.
The limited availability/accessibility of some oral ABs, especially for the MRSA strains, could explain the responses obtained. Indeed, linezolid is the only available oral option in Romania (
www.anm.ro/anmdm/en/), while in Bulgaria are ampicillin, levofloxacin, and clindamycin (
www.bda.bg/en/). In Spain and Italy, both linezolid and tedizolid are available; however, they may be provided only in hospitals, and for a limited period outside hospital (
www.aemps.gob.es/en/,
www.aifa.gov.it). In Czech Republic, oral available ABs are penicillin, clindamycin, cephalosporins (ceftaroline, cefuroxime, ceftazidime), and linezolid; tedizolid is not marketed, yet (
www.cepha.cz). Physician and patient expectations should be added as variables to an oral switch decision [
1,
21,
22].
Regarding topic 6-item 2 statement, we found that respondents from Bulgaria, Czech Republic, Portugal, Romania, and Russia provided a positive consensus; Austria provided a negative consensus, and no consensus was reached by Greece, Italy, Poland, and Spain. Indeed, elderly patients or those with expected low adherence outside of hospital might have negatively influenced clinician’s responses for this statement [
22]. Furthermore, improved conditions might negatively influence adherence in these classes of patients. In addition, and in accordance with our findings, Eckmann et al. reported a low rate of oral switching in Greece, Italy, and Poland and Spain (2, 4.7, and 4.7%, respectively), emerging a disagreeing scenario in ABSSSI management in these countries [
21]. Since, long-acting agents dalbavancin and oritavancin, and tedizolid have been proved to be statistically non-inferior to linezolid or to vancomycin, followed by oral linezolid [
1,
23‐
25], they might possess the potential for ED and ES to oral regimens [
1].
Drug selection requires evaluation of patient’s condition, dose adjusting, consideration of comorbidities, drug-drug interactions, and adherence [
1,
5,
10]. In our survey, the participants agreed on the importance of drug selection on adherence, especially for elderly and in the presence of comorbidities.
In our survey, clinicians strongly agreed on complexity on choice of drug in particular ABSSSI cases, since length of treatment, hospital stays, an increased risk of IV-related infections, and onset of super-infections may occur [
9]. These circumstances represent a major difficulty for ES and consequently for an ED [
22,
26].
Adherence emerged as an important factor also for drug resistance. MRSA strains account for 16.7% of all S aureus isolate, being > 25% from Spain, Greece, Italy, and Portugal and > 50% in Romania (
http://ecdc.europa.eu/en/healthtopics/antimicrobialresistance/database/Pages/map_reports.aspx). Treatment for SSTI/ABSSSI is established; however, no epidemiological data for resistance patterns and geographical regions are specified [
10]. Stewardship programs for ES and ED are being implemented in European hospitals. Nevertheless, clinician misconceptions, practical considerations, organizational factors, and lack of awareness of IV to oral switch guidance might limit their operation [
22].
The participants agreed on the positive impact of long-acting ABs on adherence. Oritavancin, dalbavancin, and tedizolid phosphate could represent an additional opportunity for ED of ABSSSI patients [
9]. Vancomycin is a standard choice for ABSSSI treatments, including MRSA infections [
13]. However, it needs frequent drug monitoring and is associated with risk of nephrotoxicity. Moreover, new resistant strains have emerged in the recent years, limiting its use [
27]. Oritavancin, dalbavancin, and tedizolid offer more feasible treatments [
8,
9,
28,
29], and no evidences for resistant strains have been reported, yet [
28,
29]. In a recent retrospective analysis, long-acting agents demonstrated a reduction in patient discomfort and risks associated with frequent manipulation and also favored ED and the use of OPAT facilities [
18]. Thus, a strong impact in terms of cost effectiveness for the use of hospital resources, in favor to OPAT facilities might occur [
30].
This survey has limitations. First, questions related to oral treatment might have been subject to the responder’s personal interpretation, given to the multiple variables to take into consideration for oral switching, including healthcare systems policies, availability/accessibility of the oral AB, type of patient, and economic factors. Second, given the nature of experts anonymously giving their opinion, we lack information on them, such as the hospitals or the units where the responders work.
Compliance with ethical standards