Attitudes of physicians from 10 European countries on adherence and how treatment modalities in ABSSSI affect adherence: results from a Delphi survey

Attitudes of physicians from 10 European countries on adherence and how treatment modalities in... To explore the attitudes of European physicians on adherence and how treatment modalities impact adherence in complicated forms of soft skin and skin structure infections, now referred as acute bacterial skin and skin structures infections (ABSSSI). After literature review, a questionnaire was prepared. Topics focused on (1) the importance of adherence, (2) the importance of administration regimen on adherence, (3) the importance of drug selection on adherence, (4) the importance of complexity on choice of drug for treatment, (5) the role of adherence in drug resistance, and (6) the role of adherence in administration of long- acting antibiotics (ABs). The questionnaire was administered to 323 European infectious diseases specialists, of whom 74% responded. A modified Delphi method was used to obtain the highest consensus. Results varied by countries. We found a high degree of agreement of the importance of adherence in ABSSSI treatment. Experts agreed that complexity of patient’sconditions, drug selection, drug resistance, the type of regimen, and the number of infusions impact adherence. Two items linking oral switching and adherence did not reach consensus. Adherence for ABSSSI therapies appears a crucial factor for therapeutic management and reduces the risk of AB resistance. Among new treatment opportunities, long-acting agents, with their charac- teristics, may represent an interesting options. . . . . . Keywords Adherence Long-actingagents Skin/soft-tissueinfections Skinstructureinfections Intravenousroute Oralswitch Abbreviations IV Intravenous MRSA Methicillin-resistant Staphylococcus aureus ED Early discharge SSTI Skin and soft-tissue infections ES Early switch ABSSSI Acute bacterial skin and skin structure infections AB Antibiotic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10096-018-3264-0) contains supplementary material, which is available to authorized users. * Tom Stargardt Medicine Department, School of Medicine, Universidad tom.stargardt@uni–hamburg.de Complutense de Madrid, Madrid, Spain CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Hamburg Center for Health Economics, University of Hamburg, Madrid, Spain Esplanade 36, 20354 Hamburg, Germany Department of Experimental and Clinical Medicine, University of Department of General, Visceral, and Thoracic Surgery, Klinikum Florence, Florence, Italy Peine, Academic Hospital of Medical University Hannover, Hannover, Germany Microbiology and Virology Unit, Florence Careggi University Department of Clinical Microbiology and Infectious Diseases, Hospital, Florence, Italy Hospital General Universitario Gregorio Marañón, Madrid, Spain 4 9 Instituto de Investigación Sanitaria Gregorio Marañón, Department of Medicine and Surgery, Section of Infectious Diseases, Madrid, Spain University of Insubria, Varese, Italy 1612 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Introduction Delphi questionnaire preparation and administration Acute bacterial skin and skin structure infections (ABSSSI) We performed a literature review on the importance of adher- are one of the most frequent causes of hospitalization among ence in the management of ABSSSI and the impact of long- skin and soft-tissue infections (SSTIs) [1, 2]. Management of acting agents on adherence. In a first meeting, the authors of ABSSSI is complex and includes surgical procedures and an- this paper identified the topics to address and drafted the tibiotic (AB) treatment [1, 3]. Delphi questionnaire. Four external validators pre-tested the Adherence to medication is strictly associated with treat- questionnaire, and as a result, the following topics were ments’ efficacy [4–6]. It is not considered a major issue for prepared: hospitalized ABSSSI patients, usually treated via intravenous (IV) route, but it may impact on outpatient treatments. High 1. Importance of the adherence for the treatment of ABSSSI frequency of comorbidities, dose adjusting, and consider- 2. Importance of administration regimen for adherence in ations for drug interactions raise complexity in drug selection the treatment of ABSSSI and patient’s management [7]. Current treatments for ABSSSI 3. Impact of drug selection for the treatment of ABSSSI on often require multiple daily administrations, although in some adherence cases, once-a-day dosing may be applicable [8]. Since these 4. Importance of complexity on choice of drug for the treat- medications are often associated with gastrointestinal adverse ment of ABSSSI events, a low adherence, and poor clinical outcome can occur 5. Impact of drug resistance on the treatment of ABSSSI [6]. Furthermore, AB misuse, and length of treatment might 6. Long-acting antibiotic (AB) and adherence lead to drug resistance [5, 9]. Guidelines focusing on the issue of resistance frequently do not take into account variation in Each statement included three or more items. epidemiology of resistant pathogens, across countries [10]. Thereafter, the questionnaire was administered, via online Long-acting agents, which are characterized by a more fa- software, to 323 European experts, from the following countries: vorable administration regimen, have been launched in the Greece, Spain, Portugal, Russia, Bulgaria, Czech Republic, European markets [1, 11]. Their indications cover the major Austria, Romania, Poland, and Italy. The experts were chosen causes of ABSSSI, including MRSA. Among long-acting based on their practical experience in infectious diseases and agents, dalbavicin has demonstrated an efficacy and safety were invited to share comments on the topic. comparable to other similar agents in the treatment of Each expert expressed his/her level of agreement according ABSSSIs, both in hospital wards and outpatient’s settings to the following 5-point Likert scale: 1 = strongly disagree, [12]. Its long half-life might be considered definitive advan- 2 = disagree, 3 = agree, 4 = more than agree, and 5 = strongly tages for the therapeutic treatment of ABSSSI patients and in agree. An item achieved consensus, when the sum of items 1 terms of hospital cost-effectiveness [12]. and 2 (negative consensus) or 3, 4, and 5 (positive consensus) The importance of adherence, for patients with ABSSSI, was ≥ 66%. No consensus was reached, when the sum of the has not been addressed in therapeutic management guidelines, responses for a negative consensus or a positive consensus yet [7, 9, 13]. It is thus the aim of the present paper to explore was < 66%. Items 1 and 3, listed in topic 6, were purposely the attitudes of European physicians on adherence and how provided as internal controls, to evaluate the whole question- treatment modalities impact on adherence. naire reliability. Results Methods Information on the participants Delphi method Two hundred thirty-eight among 323 (74%) experts from ten A modified Delphi method was performed, aimed to reach the European countries participated in this survey. Most of the best estimate of consensus on unanswered questions [14]. As participants were infectious diseases specialists, while the re- usual, each expert freely, and anonymously, delivers his/her maining were clinical microbiologists, anesthesiologists, or- opinion; an administrator provides a summary of the experts’ thopedics, surgeons, or specialists in hygiene, pharmacology, answers and their rationale. Typically, the process ends when dermatology, cardiovascular diseases, and other specialties an agreement has been reached on all the discussed topics, (Table 1). through multiple rounds of discussions. Here, we decided Table 2 lists the number of participants from each country not to perform a second round, in favor of highlighting differ- with the following being the most numerous: Italy, Spain, ences across countries. Greece, and Romania. Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1613 Table 1 List of the Table 2 Distribution of the respondents, across the participating Specialties % medical specialties countries participating at the Infectious disease 61% Country Total Respondents % of respondents survey Microbiology 8% Austria 20 9 4% Anesthesiology/ICU 8% Bulgaria 7 5 2% Orthopedics 6% Czech Rep 30 21 9% Surgery/general surgery 5% Greece 34 31 13% Hygiene 2% Italy 82 58 24% Pharmacology 2% Poland 31 14 6% Dermatology 1% Portugal 28 18 8% Cardiovascular 1% Romania 28 28 12% Other field/department 8% Russia 4 1 0% Total 100% Spain 59 53 22% Total 323 238 100% Delphi survey: general results Number in italics indicates the total The results of the survey are listed in Table 3. The first topic important element in the choice of drug (item 1, 96% agreed). focused on the BImportance of adherence for the treatment of Moreover, drug-drug interaction (item 5, 100% agreed) and ABSSSI^ (Table 3, topic 1). According to the participants, the length of use of a catheter (item 2, 98%) were valued adherence to treatment exerts an important role in drug selec- affecting the complexity of the treatment. Complicated situa- tion (item 4, 93% agreed) and can influence the outcome of tions were found to increase the HCP time spent for the patient treatment (item 2, 99% agreed) and the chance of relapse and (item 4, 97% agreed). Finally, a prolonged use of IV devices recurrence of ABSSSI (item 5, 96% agreed). Moreover, it is a was judged crucial for the risk of super-infections (item 3, frequent issue encountered by the responding clinicians (item 98% agreed), and the main reason for an increase of length 1, 96% agreed) in their daily practice. of hospitalization (item 6, 99% agreed). The second topic regarded the Bimportance of administra- According to the experts, resistance to AB triggers relapse tion regimen for adherence in the treatment of ABSSSI^ and recurrence of ABSSSI (Table 3, topic 5, item 1, 97% (Table 3, topic 2). The number (item 1, 89% agreed) and the agreed), and increases the use of HCP resources (item 2, 99% length of infusions (item 3, 79% agreed) were considered agreed). Underexposure to treatment was considered a result important elements for adherence to treatment. In order to from lack of adherence (item 6, 95% agreed) and a source for keep patients adherent, the number of infusions (item 2, drug resistance (item 5, 97% agreed). Unsurprisingly, resistant 87% agreed) and their administration by healthcare profes- strains, such as MRSA, are frequently encountered in the ex- sionals (HCP) (item 7, 97% agreed) were also considered a pert’s clinical practice (item 4, 70% agreed) and were valued to burden. Oral switch may have a negative impact on adherence increase complexity of ABSSSI treatment (item 3, 98% agreed). (item 6, 69% agreed). Long-acting ABs for ABSSSI patients Last topic was on Blong-acting AB and adherence^ were considered useful in patients with severe renal impair- (Table 3, topic 6). One single infusion was considered to im- ment, if drug hemodialysis or dose adjustment are accessible prove adherence (item 1, 100% agreed), as opposite to multi- (item 4, 90% agreed). Item 5, the link between the existence of ple infusions (item 3, 89% disagreed). No agreement was an oral switch option and adherence, did not achieve consen- achieved on item 2, the link between switching to oral treat- sus (40% disagreed/60% agreed). ment and adherence (40% disagreed/57% agreed). Topic 3 focused on Bthe impact of drug selection for the treatment of ABSSSI on adherence^ (Table 3). Dose adjust- ment and therapeutic drug monitoring (TDM) increase thera- European diversity: description of the conflicting peutic management and affect adherence, according to the items experts (item 1, 87% agreed) especially in cases of comorbid- ities and polypharmacy (item 2, 90% agreed) and for the el- Among 31 proposed, the two items on oral switch-options and derly (item 3, 85% agreement). Multiple doses, dose adjust- their link to adherence remained with no consensus (topic 2, ment, and TDM were considered factors burdening the item 5; topic 6, item 2). Therefore, we decided to analyze the healthcare system (item 4, 97% agreed). conflicting results by country (Supplementary Information, Topic 4 was on Bimportance of complexity on choice of S.I., Table 1). Results for Austria (9 respondents), Bulgaria drug for the treatment of ABSSSI^ (Table 3). The experts (5), and Russia (1) have to be interpreted cautiously because considered the complexity of the treatment regimen, an of the low number of respondents. 1614 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Table 3 Topics addressed in our survey Topics Level of agreement Importance of the adherence for the treatment of ABSSSI Items 1. Adherence is very important in the treatment of ABSSSI in your daily clinical practice 4 6 47 84 98 4% 96% 2. Adherence can influence the clinical outcome of therapy 1 0 28 77 132 1% 99% 3. Lack of adherence is a major problem in the treatment of ABSSSI in your daily clinical 9 5486 5831 practice 26% 74% 4. The adherence has a major impact on drug selection 0 17 86 86 48 7% 93% 5. Lack of adherence has an impact on relapse and recurrence of ABSSSI and increases 010 58 102 68 resources use 4% 96% Importance of administration regimen for adherence in the treatment of ABSSSI Items 1. Multiple infusions are a problem for patients in terms of adherence 3 2494 6850 11% 89% 2. Multiple infusions are a problem for the healthcare professionals (HCP) in managing 3 2875 8943 patient adherence 13% 87% 3. Duration of infusion is a problem in managing patient adherence 7 4388 7228 21% 79% 4. I’ll be confident in using a long-acting antibiotic in patients with severe renal impairment 4 2195 8235 if the drug can be removed by hemodialysis or adjusted in its dose 10% 90% 5. Oral-switch option after discharge could lead to a decrease of adherence 10 86 86 37 18 40% 60% 6. Poor adherence due to oral-switch can delay the discharge 6 6786 6020 31% 69% 7. Easier administration regimen reduces resources use 1 6 68 89 74 3% 97% Impact of drug selection for the treatment of ABSSSI on adherence Items 1. The need for dose adjustment and TDM increases complexity of patient management and 7 2471 9145 thus reduces adherence 13% 87% 2. The need for dose adjustment is a major issue for adherence in patients with comorbidities 0 2471 9152 and polypharmacy 10% 90% 3. The need for dose adjustment is a major issue for adherence in elderly patients 0 3560 9845 15% 85% 4. Multiple dose administration, dose adjustment and TDM increase healthcare utilization 0 9 60 96 74 3% 97% Importance of complexity on choice of drug for the treatment of ABSSSI Items 1. Level of complexity of treatment is important for the choice of drug 1 9 79 88 61 4% 96% 2. The need for a peripheral or central venous catheter for a prolonged period can increase 1 3 30 89 115 complexity of treatment 2% 98% 3. The prolonged stay of intravenous devices for drug administration increase the risk for 1 3 14 62 157 super-infections 2% 98% 4. Higher complexity increases time the HCP spend for the patient 1 7 43 109 78 3% 97% Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1615 Table 3 (continued) Topics Level of agreement 5. Drug-drug interaction increase the complexity in management of patients 1 0 47 109 81 0% 100% 6. Super-infections increase the length of stay 0 3 10 54 171 1% 99% Impact of drug resistance on the treatment of ABSSSI Items 1. Resistance has an impact on relapse and on the recurrence of ABSSSI 0 9 48 77 105 3% 97% 2. ABSSSI due to resistant pathogen increases use of resources 0 3 31 79 125 1% 99% 3. ABSSSI due to resistant strain (e.g., MRSA) increase complexity of treatment 0 4 38 89 106 2% 98% 4. MRSA is a frequent cause of ABSSSI in my clinical practice 9 6469 7126 30% 70% 5. Under-exposure to treatment increases the risk of resistance selection 0 7 44 91 96 3% 97% 6. Under-exposure can be consequent to lack of adherence 011 61 92 74 5% 95% Long-acting AB and adherence Items 1. One single infusion to treat ABSSSI improves adherence 1 0 33 65 139 0% 100% 2. Switching to oral treatment for several days improves adherence 11 92 61 55 18 43% 57% 3. Multiple daily infusions improve adherence 54 157 14 10 3 89% 11% ABSSSI acute bacterial skin and skin structure infections, AB antibiotic, HCP healthcare professionals, MRSA methicillin-resistant Staphylococcus aureus, TDM therapeutic drug monitoring ForBOral-switch^optionafterdischargewhichcouldleadtoa has a more powerful impact in cases of prolonged, chronic, or decrease of adherence, experts in Austria, Greece, and Poland acute infections, such as ABSSSI [15]. achieved a positive consensus (S.I., Table 1, topic 2, item 5, 78, The aim of our survey was to explore the attitude of a panel of 74, and 79% agreed, respectively); no consensus was obtained infectious experts across ten European countries, on adherence for Bulgaria, Czech Republic, Italy, Spain, and Romania; and a andhowtreatmentmodalitiesimpactadherenceforABSSSItreat- negative consensus was reached from Russia and Portugal re- ments. A six-topic questionnaire and the Delphi method were spondents (S.I. Tables 1, 100 and 89% disagreed, respectively). used to obtain the most accurate expert’s opinion and consensus. For topic 6, item 2, Bswitching to oral treatment for several Interestingly, 61% of the participants were infectious dis- days improves adherence^, Bulgaria, Czech Republic, eases specialist (Table 1). It is important for us to highlight Portugal, Romania, and Russia reached a positive consensus recent findings demonstrating a crucial role for these special- (S.I., Table 1, topic 6, item 2, 80, 71, 72, 72, and 100% agreed, ists in the management of severe infections disease, including respectively); Italy, Greece, and Poland did not reach consen- ABSSSI. Indeed, it appears that the use of suitable guidelines sus; and Austrian respondents reached a negative consensus and infectious disease specialist represent an efficacious ap- (S.I., 78% disagreed). proach aimed at reducing the incidence of inappropriate ther- apies and increasing good outcome rates [16]. The participants fully agreed on the importance of adher- Discussion ence in ABSSSI treatment. Undeniably, poor adherence to treatments is a major determinant for therapeutic failure, be- Adherence to treatment represents a key factor for treatment ef- cause it can lead to lack of response, recurrence, and predis- ficacy, especially with antimicrobial drugs [5, 15]. Moreover, it poses to AB resistance [9]. 1616 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Administration regimen and drug selection for ABSSSI’s Drug selection requires evaluation of patient’scondition, treatment emerged as crucial factors for adherence. After initial dose adjusting, consideration of comorbidities, drug-drug in- treatment, patients may be switched to a suitable oral AB, or to teractions, and adherence [1, 5, 10]. In our survey, the partic- outpatient parenteral antibiotic therapy (OPAT) [2]. In general, ipants agreed on the importance of drug selection on adher- outpatient costs are lower, but treatments often require multiple ence, especially for elderly and in the presence of and long infusions, loading on the healthcare systems and HCP comorbidities. utilization [17]. However, OPAT has reached interesting suc- In our survey, clinicians strongly agreed on complexity on cess in several European countries, reducing the risks of choice of drug in particular ABSSSI cases, since length of hospital-related infections [6, 18]. Oral MRSA-active drugs treatment, hospital stays, an increased risk of IV-related infec- are included in guidelines for treatment of ABSSSI, in order tions, and onset of super-infections may occur [9]. These cir- to achieve an early switch (ES) and favoring early discharge cumstances represent a major difficulty for ES and conse- (ED) [1]. Recent trials have also supported the concomitant use quently for an ED [22, 26]. of oral antimicrobial therapies with incision and drainage, in Adherence emerged as an important factor also for less severe cases of ABSSSI [19, 20]. drug resistance. MRSA strains account for 16.7% of all Interestingly, the link between oral treatment and adher- S aureus isolate, being > 25% from Spain, Greece, Italy, ence after discharge (topic 2, item 5) and for several days and Portugal and > 50% in Romania (http://ecdc.europa. (topic 6, item 2) has produced conflicting answers, in our eu/en/healthtopics/antimicrobialresistance/database/Pages/ survey. A further analysis of the responses revealed that for map_reports.aspx). Treatment for SSTI/ABSSSI is topic 2-item 5, Portugal (and the single respondent from established; however, no epidemiological data for resis- Russia) provided a negative consensus. A positive consensus tance patterns and geographical regions are specified was obtained for this item from Austria, Poland, and Greece. [10]. Stewardship programs for ES and ED are being imple- A no consensus was obtained for Italy, Czech Republic, mented in European hospitals. Nevertheless, clinician miscon- Bulgaria, Spain, and Romania. ceptions, practical considerations, organizational factors, and The limited availability/accessibility of some oral ABs, espe- lack of awareness of IV to oral switch guidance might limit cially for the MRSA strains, could explain the responses obtain- their operation [22]. ed. Indeed, linezolid is the only available oral option in Romania The participants agreed on the positive impact of long- (www.anm.ro/anmdm/en/), while in Bulgaria are ampicillin, acting ABs on adherence. Oritavancin, dalbavancin, and levofloxacin, and clindamycin (www.bda.bg/en/). In Spain and tedizolid phosphate could represent an additional oppor- Italy, both linezolid and tedizolid are available; however, they tunity for ED of ABSSSI patients [9]. Vancomycin is a may be provided only in hospitals, and for a limited period standard choice for ABSSSI treatments, including MRSA outside hospital (www.aemps.gob.es/en/, www.aifa.gov.it). In infections [13]. However, it needs frequent drug monitor- Czech Republic, oral available ABs are penicillin, clindamycin, ing and is associated with risk of nephrotoxicity. cephalosporins (ceftaroline, cefuroxime, ceftazidime), and Moreover, new resistant strains have emerged in the re- linezolid; tedizolid is not marketed, yet (www.cepha.cz). cent years, limiting its use [27]. Oritavancin, dalbavancin, Physician and patient expectations should be added as variables and tedizolid offer more feasible treatments [8, 9, 28, 29], to an oral switch decision [1, 21, 22]. and no evidences for resistant strains have been reported, Regarding topic 6-item 2 statement, we found that respon- yet [28, 29]. In a recent retrospective analysis, long-acting dents from Bulgaria, Czech Republic, Portugal, Romania, and agents demonstrated a reduction in patient discomfort and Russia provided a positive consensus; Austria provided a neg- risks associated with frequent manipulation and also fa- ative consensus, and no consensus was reached by Greece, vored ED and the use of OPAT facilities [18]. Thus, a Italy, Poland, and Spain. Indeed, elderly patients or those with strong impact in terms of cost effectiveness for the use expected low adherence outside of hospital might have nega- of hospital resources, in favor to OPAT facilities might tively influenced clinician’s responses for this statement [22]. occur [30]. Furthermore, improved conditions might negatively influence This survey has limitations. First, questions related to adherence in these classes of patients. In addition, and in ac- oral treatment might have been subject to the re- cordance with our findings, Eckmann et al. reported a low rate sponder’s personal interpretation, given to the multiple of oral switching in Greece, Italy, and Poland and Spain (2, variables to take into consideration for oral switching, 4.7, and 4.7%, respectively), emerging a disagreeing scenario including healthcare systems policies, availability/ in ABSSSI management in these countries [21]. Since, long- accessibility of the oral AB, type of patient, and eco- acting agents dalbavancin and oritavancin, and tedizolid have nomic factors. Second, given the nature of experts anon- been proved to be statistically non-inferior to linezolid or to ymously giving their opinion, we lack information on vancomycin, followed by oral linezolid [1, 23–25], they might them, such as the hospitals or the units where the re- possess the potential for ED and ES to oral regimens [1]. sponders work. Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1617 Conclusions References Delphi panels are valuable tools to develop indicators for various 1. Russo A, Concia E, Cristini F, De Rosa FG, Esposito S, Menichetti F, Petrosillo N, Tumbarello M, Venditti M, Viale P, Viscoli C, diseases [14]. 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(2014) Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a Funding This work has been funded with an unrestricted grant by randomised, double-blind, phase 3, non-inferiority trial. Lancet Angelini. Infect Dis 14(8):696–705 9. Nathwani D, EckmannC,LawsonW,Solem CT,CormanS, Compliance with ethical standards Stephens JM, Macahilig C, Simoneau D, Chambers R, Li JZ, Haider S (2014) Influence of real-world characteristics on out- comes for patients with methicillin-resistant staphylococcal skin Ethical approval This article does not contain any studies with human and soft tissue infections: a multi-country medical chart review in participants or animals performed by any of the authors. Europe. BMC Infect Dis 14:476 10. 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Le infezioni in medicina : rivista periodica di eziologia, C, Li J, Charbonneau C, Baillon-Plot N, Haider S, Eckmann C epidemiologia, diagnostica, clinica e terapia delle patologie (2015) Implementing criteria-based early switch/early discharge infettive 21(4):270–278 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Microbiology Infectious Diseases Springer Journals

Attitudes of physicians from 10 European countries on adherence and how treatment modalities in ABSSSI affect adherence: results from a Delphi survey

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Biomedicine; Medical Microbiology; Internal Medicine
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0934-9723
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Abstract

To explore the attitudes of European physicians on adherence and how treatment modalities impact adherence in complicated forms of soft skin and skin structure infections, now referred as acute bacterial skin and skin structures infections (ABSSSI). After literature review, a questionnaire was prepared. Topics focused on (1) the importance of adherence, (2) the importance of administration regimen on adherence, (3) the importance of drug selection on adherence, (4) the importance of complexity on choice of drug for treatment, (5) the role of adherence in drug resistance, and (6) the role of adherence in administration of long- acting antibiotics (ABs). The questionnaire was administered to 323 European infectious diseases specialists, of whom 74% responded. A modified Delphi method was used to obtain the highest consensus. Results varied by countries. We found a high degree of agreement of the importance of adherence in ABSSSI treatment. Experts agreed that complexity of patient’sconditions, drug selection, drug resistance, the type of regimen, and the number of infusions impact adherence. Two items linking oral switching and adherence did not reach consensus. Adherence for ABSSSI therapies appears a crucial factor for therapeutic management and reduces the risk of AB resistance. Among new treatment opportunities, long-acting agents, with their charac- teristics, may represent an interesting options. . . . . . Keywords Adherence Long-actingagents Skin/soft-tissueinfections Skinstructureinfections Intravenousroute Oralswitch Abbreviations IV Intravenous MRSA Methicillin-resistant Staphylococcus aureus ED Early discharge SSTI Skin and soft-tissue infections ES Early switch ABSSSI Acute bacterial skin and skin structure infections AB Antibiotic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10096-018-3264-0) contains supplementary material, which is available to authorized users. * Tom Stargardt Medicine Department, School of Medicine, Universidad tom.stargardt@uni–hamburg.de Complutense de Madrid, Madrid, Spain CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Hamburg Center for Health Economics, University of Hamburg, Madrid, Spain Esplanade 36, 20354 Hamburg, Germany Department of Experimental and Clinical Medicine, University of Department of General, Visceral, and Thoracic Surgery, Klinikum Florence, Florence, Italy Peine, Academic Hospital of Medical University Hannover, Hannover, Germany Microbiology and Virology Unit, Florence Careggi University Department of Clinical Microbiology and Infectious Diseases, Hospital, Florence, Italy Hospital General Universitario Gregorio Marañón, Madrid, Spain 4 9 Instituto de Investigación Sanitaria Gregorio Marañón, Department of Medicine and Surgery, Section of Infectious Diseases, Madrid, Spain University of Insubria, Varese, Italy 1612 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Introduction Delphi questionnaire preparation and administration Acute bacterial skin and skin structure infections (ABSSSI) We performed a literature review on the importance of adher- are one of the most frequent causes of hospitalization among ence in the management of ABSSSI and the impact of long- skin and soft-tissue infections (SSTIs) [1, 2]. Management of acting agents on adherence. In a first meeting, the authors of ABSSSI is complex and includes surgical procedures and an- this paper identified the topics to address and drafted the tibiotic (AB) treatment [1, 3]. Delphi questionnaire. Four external validators pre-tested the Adherence to medication is strictly associated with treat- questionnaire, and as a result, the following topics were ments’ efficacy [4–6]. It is not considered a major issue for prepared: hospitalized ABSSSI patients, usually treated via intravenous (IV) route, but it may impact on outpatient treatments. High 1. Importance of the adherence for the treatment of ABSSSI frequency of comorbidities, dose adjusting, and consider- 2. Importance of administration regimen for adherence in ations for drug interactions raise complexity in drug selection the treatment of ABSSSI and patient’s management [7]. Current treatments for ABSSSI 3. Impact of drug selection for the treatment of ABSSSI on often require multiple daily administrations, although in some adherence cases, once-a-day dosing may be applicable [8]. Since these 4. Importance of complexity on choice of drug for the treat- medications are often associated with gastrointestinal adverse ment of ABSSSI events, a low adherence, and poor clinical outcome can occur 5. Impact of drug resistance on the treatment of ABSSSI [6]. Furthermore, AB misuse, and length of treatment might 6. Long-acting antibiotic (AB) and adherence lead to drug resistance [5, 9]. Guidelines focusing on the issue of resistance frequently do not take into account variation in Each statement included three or more items. epidemiology of resistant pathogens, across countries [10]. Thereafter, the questionnaire was administered, via online Long-acting agents, which are characterized by a more fa- software, to 323 European experts, from the following countries: vorable administration regimen, have been launched in the Greece, Spain, Portugal, Russia, Bulgaria, Czech Republic, European markets [1, 11]. Their indications cover the major Austria, Romania, Poland, and Italy. The experts were chosen causes of ABSSSI, including MRSA. Among long-acting based on their practical experience in infectious diseases and agents, dalbavicin has demonstrated an efficacy and safety were invited to share comments on the topic. comparable to other similar agents in the treatment of Each expert expressed his/her level of agreement according ABSSSIs, both in hospital wards and outpatient’s settings to the following 5-point Likert scale: 1 = strongly disagree, [12]. Its long half-life might be considered definitive advan- 2 = disagree, 3 = agree, 4 = more than agree, and 5 = strongly tages for the therapeutic treatment of ABSSSI patients and in agree. An item achieved consensus, when the sum of items 1 terms of hospital cost-effectiveness [12]. and 2 (negative consensus) or 3, 4, and 5 (positive consensus) The importance of adherence, for patients with ABSSSI, was ≥ 66%. No consensus was reached, when the sum of the has not been addressed in therapeutic management guidelines, responses for a negative consensus or a positive consensus yet [7, 9, 13]. It is thus the aim of the present paper to explore was < 66%. Items 1 and 3, listed in topic 6, were purposely the attitudes of European physicians on adherence and how provided as internal controls, to evaluate the whole question- treatment modalities impact on adherence. naire reliability. Results Methods Information on the participants Delphi method Two hundred thirty-eight among 323 (74%) experts from ten A modified Delphi method was performed, aimed to reach the European countries participated in this survey. Most of the best estimate of consensus on unanswered questions [14]. As participants were infectious diseases specialists, while the re- usual, each expert freely, and anonymously, delivers his/her maining were clinical microbiologists, anesthesiologists, or- opinion; an administrator provides a summary of the experts’ thopedics, surgeons, or specialists in hygiene, pharmacology, answers and their rationale. Typically, the process ends when dermatology, cardiovascular diseases, and other specialties an agreement has been reached on all the discussed topics, (Table 1). through multiple rounds of discussions. Here, we decided Table 2 lists the number of participants from each country not to perform a second round, in favor of highlighting differ- with the following being the most numerous: Italy, Spain, ences across countries. Greece, and Romania. Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1613 Table 1 List of the Table 2 Distribution of the respondents, across the participating Specialties % medical specialties countries participating at the Infectious disease 61% Country Total Respondents % of respondents survey Microbiology 8% Austria 20 9 4% Anesthesiology/ICU 8% Bulgaria 7 5 2% Orthopedics 6% Czech Rep 30 21 9% Surgery/general surgery 5% Greece 34 31 13% Hygiene 2% Italy 82 58 24% Pharmacology 2% Poland 31 14 6% Dermatology 1% Portugal 28 18 8% Cardiovascular 1% Romania 28 28 12% Other field/department 8% Russia 4 1 0% Total 100% Spain 59 53 22% Total 323 238 100% Delphi survey: general results Number in italics indicates the total The results of the survey are listed in Table 3. The first topic important element in the choice of drug (item 1, 96% agreed). focused on the BImportance of adherence for the treatment of Moreover, drug-drug interaction (item 5, 100% agreed) and ABSSSI^ (Table 3, topic 1). According to the participants, the length of use of a catheter (item 2, 98%) were valued adherence to treatment exerts an important role in drug selec- affecting the complexity of the treatment. Complicated situa- tion (item 4, 93% agreed) and can influence the outcome of tions were found to increase the HCP time spent for the patient treatment (item 2, 99% agreed) and the chance of relapse and (item 4, 97% agreed). Finally, a prolonged use of IV devices recurrence of ABSSSI (item 5, 96% agreed). Moreover, it is a was judged crucial for the risk of super-infections (item 3, frequent issue encountered by the responding clinicians (item 98% agreed), and the main reason for an increase of length 1, 96% agreed) in their daily practice. of hospitalization (item 6, 99% agreed). The second topic regarded the Bimportance of administra- According to the experts, resistance to AB triggers relapse tion regimen for adherence in the treatment of ABSSSI^ and recurrence of ABSSSI (Table 3, topic 5, item 1, 97% (Table 3, topic 2). The number (item 1, 89% agreed) and the agreed), and increases the use of HCP resources (item 2, 99% length of infusions (item 3, 79% agreed) were considered agreed). Underexposure to treatment was considered a result important elements for adherence to treatment. In order to from lack of adherence (item 6, 95% agreed) and a source for keep patients adherent, the number of infusions (item 2, drug resistance (item 5, 97% agreed). Unsurprisingly, resistant 87% agreed) and their administration by healthcare profes- strains, such as MRSA, are frequently encountered in the ex- sionals (HCP) (item 7, 97% agreed) were also considered a pert’s clinical practice (item 4, 70% agreed) and were valued to burden. Oral switch may have a negative impact on adherence increase complexity of ABSSSI treatment (item 3, 98% agreed). (item 6, 69% agreed). Long-acting ABs for ABSSSI patients Last topic was on Blong-acting AB and adherence^ were considered useful in patients with severe renal impair- (Table 3, topic 6). One single infusion was considered to im- ment, if drug hemodialysis or dose adjustment are accessible prove adherence (item 1, 100% agreed), as opposite to multi- (item 4, 90% agreed). Item 5, the link between the existence of ple infusions (item 3, 89% disagreed). No agreement was an oral switch option and adherence, did not achieve consen- achieved on item 2, the link between switching to oral treat- sus (40% disagreed/60% agreed). ment and adherence (40% disagreed/57% agreed). Topic 3 focused on Bthe impact of drug selection for the treatment of ABSSSI on adherence^ (Table 3). Dose adjust- ment and therapeutic drug monitoring (TDM) increase thera- European diversity: description of the conflicting peutic management and affect adherence, according to the items experts (item 1, 87% agreed) especially in cases of comorbid- ities and polypharmacy (item 2, 90% agreed) and for the el- Among 31 proposed, the two items on oral switch-options and derly (item 3, 85% agreement). Multiple doses, dose adjust- their link to adherence remained with no consensus (topic 2, ment, and TDM were considered factors burdening the item 5; topic 6, item 2). Therefore, we decided to analyze the healthcare system (item 4, 97% agreed). conflicting results by country (Supplementary Information, Topic 4 was on Bimportance of complexity on choice of S.I., Table 1). Results for Austria (9 respondents), Bulgaria drug for the treatment of ABSSSI^ (Table 3). The experts (5), and Russia (1) have to be interpreted cautiously because considered the complexity of the treatment regimen, an of the low number of respondents. 1614 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Table 3 Topics addressed in our survey Topics Level of agreement Importance of the adherence for the treatment of ABSSSI Items 1. Adherence is very important in the treatment of ABSSSI in your daily clinical practice 4 6 47 84 98 4% 96% 2. Adherence can influence the clinical outcome of therapy 1 0 28 77 132 1% 99% 3. Lack of adherence is a major problem in the treatment of ABSSSI in your daily clinical 9 5486 5831 practice 26% 74% 4. The adherence has a major impact on drug selection 0 17 86 86 48 7% 93% 5. Lack of adherence has an impact on relapse and recurrence of ABSSSI and increases 010 58 102 68 resources use 4% 96% Importance of administration regimen for adherence in the treatment of ABSSSI Items 1. Multiple infusions are a problem for patients in terms of adherence 3 2494 6850 11% 89% 2. Multiple infusions are a problem for the healthcare professionals (HCP) in managing 3 2875 8943 patient adherence 13% 87% 3. Duration of infusion is a problem in managing patient adherence 7 4388 7228 21% 79% 4. I’ll be confident in using a long-acting antibiotic in patients with severe renal impairment 4 2195 8235 if the drug can be removed by hemodialysis or adjusted in its dose 10% 90% 5. Oral-switch option after discharge could lead to a decrease of adherence 10 86 86 37 18 40% 60% 6. Poor adherence due to oral-switch can delay the discharge 6 6786 6020 31% 69% 7. Easier administration regimen reduces resources use 1 6 68 89 74 3% 97% Impact of drug selection for the treatment of ABSSSI on adherence Items 1. The need for dose adjustment and TDM increases complexity of patient management and 7 2471 9145 thus reduces adherence 13% 87% 2. The need for dose adjustment is a major issue for adherence in patients with comorbidities 0 2471 9152 and polypharmacy 10% 90% 3. The need for dose adjustment is a major issue for adherence in elderly patients 0 3560 9845 15% 85% 4. Multiple dose administration, dose adjustment and TDM increase healthcare utilization 0 9 60 96 74 3% 97% Importance of complexity on choice of drug for the treatment of ABSSSI Items 1. Level of complexity of treatment is important for the choice of drug 1 9 79 88 61 4% 96% 2. The need for a peripheral or central venous catheter for a prolonged period can increase 1 3 30 89 115 complexity of treatment 2% 98% 3. The prolonged stay of intravenous devices for drug administration increase the risk for 1 3 14 62 157 super-infections 2% 98% 4. Higher complexity increases time the HCP spend for the patient 1 7 43 109 78 3% 97% Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1615 Table 3 (continued) Topics Level of agreement 5. Drug-drug interaction increase the complexity in management of patients 1 0 47 109 81 0% 100% 6. Super-infections increase the length of stay 0 3 10 54 171 1% 99% Impact of drug resistance on the treatment of ABSSSI Items 1. Resistance has an impact on relapse and on the recurrence of ABSSSI 0 9 48 77 105 3% 97% 2. ABSSSI due to resistant pathogen increases use of resources 0 3 31 79 125 1% 99% 3. ABSSSI due to resistant strain (e.g., MRSA) increase complexity of treatment 0 4 38 89 106 2% 98% 4. MRSA is a frequent cause of ABSSSI in my clinical practice 9 6469 7126 30% 70% 5. Under-exposure to treatment increases the risk of resistance selection 0 7 44 91 96 3% 97% 6. Under-exposure can be consequent to lack of adherence 011 61 92 74 5% 95% Long-acting AB and adherence Items 1. One single infusion to treat ABSSSI improves adherence 1 0 33 65 139 0% 100% 2. Switching to oral treatment for several days improves adherence 11 92 61 55 18 43% 57% 3. Multiple daily infusions improve adherence 54 157 14 10 3 89% 11% ABSSSI acute bacterial skin and skin structure infections, AB antibiotic, HCP healthcare professionals, MRSA methicillin-resistant Staphylococcus aureus, TDM therapeutic drug monitoring ForBOral-switch^optionafterdischargewhichcouldleadtoa has a more powerful impact in cases of prolonged, chronic, or decrease of adherence, experts in Austria, Greece, and Poland acute infections, such as ABSSSI [15]. achieved a positive consensus (S.I., Table 1, topic 2, item 5, 78, The aim of our survey was to explore the attitude of a panel of 74, and 79% agreed, respectively); no consensus was obtained infectious experts across ten European countries, on adherence for Bulgaria, Czech Republic, Italy, Spain, and Romania; and a andhowtreatmentmodalitiesimpactadherenceforABSSSItreat- negative consensus was reached from Russia and Portugal re- ments. A six-topic questionnaire and the Delphi method were spondents (S.I. Tables 1, 100 and 89% disagreed, respectively). used to obtain the most accurate expert’s opinion and consensus. For topic 6, item 2, Bswitching to oral treatment for several Interestingly, 61% of the participants were infectious dis- days improves adherence^, Bulgaria, Czech Republic, eases specialist (Table 1). It is important for us to highlight Portugal, Romania, and Russia reached a positive consensus recent findings demonstrating a crucial role for these special- (S.I., Table 1, topic 6, item 2, 80, 71, 72, 72, and 100% agreed, ists in the management of severe infections disease, including respectively); Italy, Greece, and Poland did not reach consen- ABSSSI. Indeed, it appears that the use of suitable guidelines sus; and Austrian respondents reached a negative consensus and infectious disease specialist represent an efficacious ap- (S.I., 78% disagreed). proach aimed at reducing the incidence of inappropriate ther- apies and increasing good outcome rates [16]. The participants fully agreed on the importance of adher- Discussion ence in ABSSSI treatment. Undeniably, poor adherence to treatments is a major determinant for therapeutic failure, be- Adherence to treatment represents a key factor for treatment ef- cause it can lead to lack of response, recurrence, and predis- ficacy, especially with antimicrobial drugs [5, 15]. Moreover, it poses to AB resistance [9]. 1616 Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 Administration regimen and drug selection for ABSSSI’s Drug selection requires evaluation of patient’scondition, treatment emerged as crucial factors for adherence. After initial dose adjusting, consideration of comorbidities, drug-drug in- treatment, patients may be switched to a suitable oral AB, or to teractions, and adherence [1, 5, 10]. In our survey, the partic- outpatient parenteral antibiotic therapy (OPAT) [2]. In general, ipants agreed on the importance of drug selection on adher- outpatient costs are lower, but treatments often require multiple ence, especially for elderly and in the presence of and long infusions, loading on the healthcare systems and HCP comorbidities. utilization [17]. However, OPAT has reached interesting suc- In our survey, clinicians strongly agreed on complexity on cess in several European countries, reducing the risks of choice of drug in particular ABSSSI cases, since length of hospital-related infections [6, 18]. Oral MRSA-active drugs treatment, hospital stays, an increased risk of IV-related infec- are included in guidelines for treatment of ABSSSI, in order tions, and onset of super-infections may occur [9]. These cir- to achieve an early switch (ES) and favoring early discharge cumstances represent a major difficulty for ES and conse- (ED) [1]. Recent trials have also supported the concomitant use quently for an ED [22, 26]. of oral antimicrobial therapies with incision and drainage, in Adherence emerged as an important factor also for less severe cases of ABSSSI [19, 20]. drug resistance. MRSA strains account for 16.7% of all Interestingly, the link between oral treatment and adher- S aureus isolate, being > 25% from Spain, Greece, Italy, ence after discharge (topic 2, item 5) and for several days and Portugal and > 50% in Romania (http://ecdc.europa. (topic 6, item 2) has produced conflicting answers, in our eu/en/healthtopics/antimicrobialresistance/database/Pages/ survey. A further analysis of the responses revealed that for map_reports.aspx). Treatment for SSTI/ABSSSI is topic 2-item 5, Portugal (and the single respondent from established; however, no epidemiological data for resis- Russia) provided a negative consensus. A positive consensus tance patterns and geographical regions are specified was obtained for this item from Austria, Poland, and Greece. [10]. Stewardship programs for ES and ED are being imple- A no consensus was obtained for Italy, Czech Republic, mented in European hospitals. Nevertheless, clinician miscon- Bulgaria, Spain, and Romania. ceptions, practical considerations, organizational factors, and The limited availability/accessibility of some oral ABs, espe- lack of awareness of IV to oral switch guidance might limit cially for the MRSA strains, could explain the responses obtain- their operation [22]. ed. Indeed, linezolid is the only available oral option in Romania The participants agreed on the positive impact of long- (www.anm.ro/anmdm/en/), while in Bulgaria are ampicillin, acting ABs on adherence. Oritavancin, dalbavancin, and levofloxacin, and clindamycin (www.bda.bg/en/). In Spain and tedizolid phosphate could represent an additional oppor- Italy, both linezolid and tedizolid are available; however, they tunity for ED of ABSSSI patients [9]. Vancomycin is a may be provided only in hospitals, and for a limited period standard choice for ABSSSI treatments, including MRSA outside hospital (www.aemps.gob.es/en/, www.aifa.gov.it). In infections [13]. However, it needs frequent drug monitor- Czech Republic, oral available ABs are penicillin, clindamycin, ing and is associated with risk of nephrotoxicity. cephalosporins (ceftaroline, cefuroxime, ceftazidime), and Moreover, new resistant strains have emerged in the re- linezolid; tedizolid is not marketed, yet (www.cepha.cz). cent years, limiting its use [27]. Oritavancin, dalbavancin, Physician and patient expectations should be added as variables and tedizolid offer more feasible treatments [8, 9, 28, 29], to an oral switch decision [1, 21, 22]. and no evidences for resistant strains have been reported, Regarding topic 6-item 2 statement, we found that respon- yet [28, 29]. In a recent retrospective analysis, long-acting dents from Bulgaria, Czech Republic, Portugal, Romania, and agents demonstrated a reduction in patient discomfort and Russia provided a positive consensus; Austria provided a neg- risks associated with frequent manipulation and also fa- ative consensus, and no consensus was reached by Greece, vored ED and the use of OPAT facilities [18]. Thus, a Italy, Poland, and Spain. Indeed, elderly patients or those with strong impact in terms of cost effectiveness for the use expected low adherence outside of hospital might have nega- of hospital resources, in favor to OPAT facilities might tively influenced clinician’s responses for this statement [22]. occur [30]. Furthermore, improved conditions might negatively influence This survey has limitations. First, questions related to adherence in these classes of patients. In addition, and in ac- oral treatment might have been subject to the re- cordance with our findings, Eckmann et al. reported a low rate sponder’s personal interpretation, given to the multiple of oral switching in Greece, Italy, and Poland and Spain (2, variables to take into consideration for oral switching, 4.7, and 4.7%, respectively), emerging a disagreeing scenario including healthcare systems policies, availability/ in ABSSSI management in these countries [21]. Since, long- accessibility of the oral AB, type of patient, and eco- acting agents dalbavancin and oritavancin, and tedizolid have nomic factors. Second, given the nature of experts anon- been proved to be statistically non-inferior to linezolid or to ymously giving their opinion, we lack information on vancomycin, followed by oral linezolid [1, 23–25], they might them, such as the hospitals or the units where the re- possess the potential for ED and ES to oral regimens [1]. sponders work. Eur J Clin Microbiol Infect Dis (2018) 37:1611–1618 1617 Conclusions References Delphi panels are valuable tools to develop indicators for various 1. Russo A, Concia E, Cristini F, De Rosa FG, Esposito S, Menichetti F, Petrosillo N, Tumbarello M, Venditti M, Viale P, Viscoli C, diseases [14]. All participants have shown a high level of agree- Bassetti M (2016) Current and future trends in antibiotic therapy ment on the topics proposed, indicating the high quality and of acute bacterial skin and skin-structure infections. Clin Microbiol strength of the questionnaire. The number and variety of partic- Infect 22(Suppl 2):S27–S36 ipating specialists strongly empowered our survey. Moreover, it 2. Nathwani D, Dryden M, Garau J (2016) Early clinical assessment of response to treatment of skin and soft-tissue infections: how can offered interesting elements of discussion on health care settings it help clinicians? Perspectives from Europe. Int J Antimicrob and treatment modalities, across the participating countries. Agents 48(2):127–136 No studies have been performed addressing adherence for 3. Tran MC, Naumovski S, Goldstein EJ (2015) The times they are a- ABSSSI patients, either for standard or novel treatments. Our changin’: new antibacterials for skin and skin structure infections. survey, for the first time, has addressed this issue, finding a Am J Clin Dermatol 16(3):137–146 4. Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J general agreement, across 10 European countries specialists, Med 353(5):487–497 on the importance of adherence in drug selection, regimens 5. Vrijens B, Urquhart J (2005) Patient adherence to prescribed anti- and emerging resistance in ABSSSI. Further studies are need- microbial drug dosing regimens. J Antimicrob Chemother 55(5): ed to evaluate their impact on adherence regarding specific 616–627 ABSSSI treatments, hospital burdens, and IV-related infec- 6. Eells SJ, Nguyen M, Jung J, Macias-Gil R, May L, Miller LG (2016) The relationship between adherence to oral antibiotics and tions, in order to find treatment options contributing to im- post-discharge clinical outcomes among patients hospitalized with prove patient’s adherence on medication. Staphylococcus aureus skin infections. Antimicrob Agents Chemother 7. Dryden M, Andrasevic AT, Bassetti M, Bouza E, Chastre J, Acknowledgments The authors would like to thank all the participants Cornaglia G, Esposito S, French G, Giamarellou H, Gyssens IC, who responded to the questionnaire and Ethos s.r.l., for collection, anal- Nathwani D, Unal S, Voss A (2010) A European survey of antibi- ysis of the Delphi questionnaire results, and manuscript editing. otic management of methicillin-resistant Staphylococcus aureus in- fection: current clinical opinion and practice. Clin Microbiol Infect Author contributions EB, CE, PAG, GMR, and TS conceived, wrote, 16(Suppl 1):3–30 reviewed, and approved the final version of the manuscript. All authors 8. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P participated to the whole Delphi process. (2014) Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a Funding This work has been funded with an unrestricted grant by randomised, double-blind, phase 3, non-inferiority trial. Lancet Angelini. Infect Dis 14(8):696–705 9. Nathwani D, EckmannC,LawsonW,Solem CT,CormanS, Compliance with ethical standards Stephens JM, Macahilig C, Simoneau D, Chambers R, Li JZ, Haider S (2014) Influence of real-world characteristics on out- comes for patients with methicillin-resistant staphylococcal skin Ethical approval This article does not contain any studies with human and soft tissue infections: a multi-country medical chart review in participants or animals performed by any of the authors. Europe. BMC Infect Dis 14:476 10. Montravers P, Snauwaert A, Welsch C (2016) Current guidelines Informed consent Informed consent was obtained from all individual and recommendations for the management of skin and soft tissue participants included in the study. infections. Curr Opin Infect Dis 29(2):131–138 11. Anastasio PJ, Wolthoff P, Galli A, Fan W (2017) Single-dose Conflict of interest TS is a member of advisory boards for Novo Oritavancin compared to standard of care IV antibiotics for acute Nordisk, and Angelini and has received monetary compensation for par- bacterial skin and skin structure infection in the outpatient setting: a ticipating in an advisory board and conducting a training course for retrospective real-world study. Infect Dis Ther 6(1):115–128 Angelini, a manufacturer of dalbavancin. PAG is a member of advisory 12. Esposito S, Noviello S, Leone S (2015) Dalbavancin for the treat- boards for Novartis, MSD, Paratek, Gilead, Angelini, Biotest, and BD ment of acute bacterial skin and skin structure infections. Le and a member of the speakers’ bureau of MSD, Gilead, Biotest, Angelini. infezioni in medicina : rivista periodica di eziologia, epidemiologia, GMR has participated in advisory boards/speaker’s bureau for diagnostica, clinica e terapia delle patologie infettive 23(4):313–317 Accelerate, Achaogen, Angelini, Astra-Zeneca, Basilea, Biotest, 13. 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Journal

European Journal of Clinical Microbiology Infectious DiseasesSpringer Journals

Published: Jun 6, 2018

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