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Antibiotic treatment duration in diverticulitis, complicated urinary tract infection, and endocarditis: a retrospective, single-center study

  • Author Footnotes
    # Contributed equally.
    Nicolas Eduard Frei
    Footnotes
    # Contributed equally.
    Affiliations
    Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
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  • Author Footnotes
    # Contributed equally.
    Sarah Dräger
    Footnotes
    # Contributed equally.
    Affiliations
    Division of Internal Medicine, University Hospital Basel, Basel, Switzerland

    Department of Clinical Research, University Basel, Basel, Switzerland
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  • Maja Weisser
    Affiliations
    Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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  • Michael Osthoff
    Correspondence
    Corresponding author at: Michael Osthoff, Division of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland, Tel: +41 61 32 86828; Fax: +41-61-265-4722.
    Affiliations
    Division of Internal Medicine, University Hospital Basel, Basel, Switzerland

    Department of Clinical Research, University Basel, Basel, Switzerland
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  • Author Footnotes
    # Contributed equally.
Open AccessPublished:September 20, 2022DOI:https://doi.org/10.1016/j.ijid.2022.09.025

      Highlights

      • Antibiotic treatment duration was assessed in diverticulitis, urinary tract infection, and endocarditis.
      • The treatment duration in diverticulitis and urinary tract infections exceeded recommendations in >50%.
      • Longer treatment duration was associated with a lack of pathogen identification.
      • Postdischarge treatment contributed significantly to the prolonged duration.
      • Substantial opportunities exist to improve antibiotic prescribing in Switzerland.

      Abstract

      Objectives

      Despite the availability of international guidelines advocating shorter treatment durations, nonadherence to them is common. We assessed duration of antibiotic treatment for diverticulitis, complicated urinary tract infection (UTI), and endocarditis.

      Methods

      Medical records of patients hospitalized with the previously stated diseases in 2017 and 2018 were randomly selected at a Swiss tertiary care hospital. The appropriateness of antibiotic treatment duration was assessed according to international and local guidelines.

      Results

      A total of 243 patients were included in the study: 100 with diverticulitis, 200 with complicated UTI, and 43 with endocarditis. The dherence to local and international guidelines was 11% and 18% in diverticulitis, 39% and 40% in complicated UTI, and 84% and 86% in endocarditis, respectively. Nonadherence was primarily due to the prolonged treatment in diverticulitis and complicated UTI with a median duration of antibiotic treatment of 11 days (interquartile range 10-13) and 14 days (interquartile range 10-15), respectively. When pooling diverticulitis and complicated UTI cases, the identification of a pathogen in any microbiological sample was associated with an improved adherence to local guidelines in addition to hospitalization in a medical ward and infectious diseases consultation.

      Conclusion

      Prolonged courses of antibiotic treatment were common and the treatment adherence to guidelines were poor in diverticulitis, moderate in complicated UTI, and excellent in endocarditis.

      Keywords

      Introduction

      Antibiotic resistance was declared as one of the top 10 public health threats worldwide by the World Health Organization in 2019 (
      World Health Organization
      ). Infections with resistant bacteria are associated with considerable morbidity and mortality (
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      Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis.
      ). The inappropriate use and overuse of antibiotics, such as a longer duration of antibiotic treatment (DAT) than recommended, may increase the risk of antimicrobial resistance development (
      • Barnsteiner S
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      Antimicrobial resistance and antibiotic consumption in intensive care units, Switzerland, 2009 to 2018.
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      Adverse events associated with prolonged antibiotic use.
      ;
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      Optimizing drug exposure to minimize selection of antibiotic resistance.
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      • Hampton N
      • Kollef MH
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      Duration of exposure to antipseudomonal beta-lactam antibiotics in the critically ill and development of new resistance.
      ), drug-related adverse events, and Clostridioides difficile infection (
      • Stevens V
      • Dumyati G
      • Fine LS
      • Fisher SG
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      Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection.
      ;
      • Tamma PD
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      • Li DX
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      Association of adverse events with antibiotic use in hospitalized patients.
      ). In 30-50% of patients who are hospitalized, antibiotics are prescribed due to suspected or proven infection (
      • Gürtler N
      • Erba A
      • Giehl C
      • Tschudin-Sutter S
      • Bassetti S
      • Osthoff M.
      Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
      ;
      • Magill SS
      • Edwards JR
      • Beldavs ZG
      • Dumyati G
      • Janelle SJ
      • Kainer MA
      • et al.
      Prevalence of antimicrobial use in US acute care hospitals, May–September 2011.
      ), including urinary tract infections (UTIs) and pneumonia. However, one-third of antibiotic prescriptions are inappropriate (
      • Gürtler N
      • Erba A
      • Giehl C
      • Tschudin-Sutter S
      • Bassetti S
      • Osthoff M.
      Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
      ). Antimicrobial stewardship (AMS) programs apply important tools to improve antibiotic prescription practices, including the implementation of clinical guidelines, educational programs, formulary restrictions, decision support tools, and antimicrobial resistance surveillance (
      • Cunha CB.
      Antimicrobial stewardship programs: principles and practice.
      ).
      Shortening DAT has been shown to be effective and safe in several diseases, including intra-abdominal infections (
      • Daniels L
      • Ünlü Ç
      • de Korte N
      • van Dieren S
      • Stockmann HB
      • Vrouenraets BC
      • et al.
      Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis.
      ;
      • DeCesare L
      • Xu TQ
      • Saclarides C
      • Coughlin JM
      • Chivukula SV
      • Woodfin A
      • et al.
      Trends in antibiotic duration for complicated intra-abdominal infections: adaptation to current guidelines.
      ;
      • Sawyer RG
      • Claridge JA
      • Nathens AB
      • Rotstein OD
      • Duane TM
      • Evans HL
      • et al.
      Trial of short-course antimicrobial therapy for intraabdominal infection.
      ), pyelonephritis, and urosepsis (
      • Drekonja DM
      • Trautner B
      • Amundson C
      • Kuskowski M
      • Johnson JR.
      Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ;
      • Eliakim-Raz N
      • Yahav D
      • Paul M
      • Leibovici L.
      Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Molina J
      • Montero-Mateos E
      • Praena-Segovia J
      • León-Jiménez E
      • Natera C
      • López-Cortés LE
      • et al.
      Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial.
      ;
      • Sandberg T
      • Skoog G
      • Hermansson AB
      • Kahlmeter G
      • Kuylenstierna N
      • Lannergård A
      • et al.
      Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.
      ;
      • Smith BJ
      • Heriot G
      • Buising K.
      Antibiotic treatment of common infections: more evidence to support shorter durations.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ;
      • Yahav D
      • Franceschini E
      • Koppel F
      • Turjeman A
      • Babich T
      • Bitterman R
      • et al.
      Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial.
      ). The translation of these results into clinical practice may strongly impact the total amount of antibiotics administered. In endocarditis, guidelines recommend the consultation of an infectious diseases (ID) specialist to assist in the management of antibiotic therapy, especially in patients with Staphylococcus aureus infections (
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • Fowler VG
      • Tleyjeh IM
      • Rybak MJ
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ).
      The data on guideline adherence in ID in Switzerland are scarce. Considering the recommendations for shorter antibiotic treatments in several infections and the lack of available data, this study aimed to evaluate the adherence to international and local guidelines concerning the antibiotic treatment duration in patients with diverticulitis, complicated UTI, and endocarditis and to identify parameters associated with nonadherence that might be targeted in future AMS interventions.

      Material and methods

      This is a single-center, observational, quality-control study that was conducted at the University Hospital Basel, a 750-bed academic, tertiary care center in Switzerland. The study protocol was approved by the ethics committee of northwest and central Switzerland (EKNZ 2019-00185) with a waiver for written informed consent. However, patients were excluded if the hospital general research consent for the use of routinely obtained personal and medical data has been previously declined. Patient, clinical, laboratory, and microbiological data were extracted from the electronic medical records of the hospital information system and the microbiological laboratory system.

      Patient characteristics

      The patients who were hospitalized due to diverticulitis, pyelonephritis/urosepsis, or endocarditis in 2017 and 2018 were identified from the local hospital information system using the International Classification of Disease, Tenth Revision codes (main or secondary diagnosis): diverticulitis: K57.03*; pyelonephritis and other UTI: N10.0, N30.0, N39.0; endocarditis: I33.0, I33.9; and sepsis (A40.*, A41.*) as the main diagnosis plus one of the infections mentioned previously as a secondary diagnosis (*including all subcategories in that number). Diverticulitis was categorized into complicated and uncomplicated diverticulitis according to the classification of diverticular disease (Schreyer et al., 2015). The urogenital infections (pyelonephritis, urosepsis, and complicated UTI) are summarized under the term of “complicated UTI.”
      The patients were randomly selected from an extracted patient list. The patients were excluded in case of any of the following: antibiotic treatment mainly administered in another hospital, additional and simultaneous infections in the case of complicated UTI and diverticulitis (e.g., osteomyelitis) that required longer treatment durations, incomplete or missing documentation of administered antibiotic treatment, in-hospital death without definitive statement regarding DAT, and the decision for end-of-life care. The patients were defined as immunocompromised if they met at least one of the following criteria: treatment with corticosteroids (prednisone equivalent of >10 mg per day for ≥4 weeks), biologicals (e.g., tumor necrosis factor-α-inhibitors), immunosuppressive drugs (e.g., calcineurin inhibitors, mammalian target of rapamycin inhibitors), HIV infection Centers for Disease Control and Prevention category C, liver cirrhosis, chemotherapy within the preceding 4 weeks, presence of neutropenia (<0.5 g/l), primary immunodeficiency, asplenia, and solid organ or hematologic stem cell transplantation.

      Definition of appropriate antibiotic treatment duration

      The appropriateness was judged according to available international guidelines until 2019 and according to local guidelines (https://webedition.sanfordguide.com/en/weissbuch; updated at least once every 2 years). In addition, evidence from randomized controlled trials and recommendations in reviews published in high-ranking medical journals were considered. For uncomplicated diverticulitis, antibiotic therapy was still recommended in the guidelines during the studied time frame. The recommended treatment durations are shown in Table 1.
      Table 1Treatment duration recommendations according to local and international guidelines (complemented by evidence from randomized controlled trials and expert opinions published in review articles).
      DiagnosisInternational guidelines complemented by evidence from randomized, controlled trials and recommendations in review articlesLocal guidelines
      local guidelines are incorporated into the Sanford Guide (“infektioStandards”) and accessible online (https://webedition.sanfordguide.com/en/weissbuch).
      Diverticulitis
      Uncomplicated, mild to moderate4-7 days (
      • Sawyer RG
      • Claridge JA
      • Nathens AB
      • Rotstein OD
      • Duane TM
      • Evans HL
      • et al.
      Trial of short-course antimicrobial therapy for intraabdominal infection.
      ;
      • Solomkin JS
      • Mazuski JE
      • Bradley JS
      • Rodvold KA
      • Goldstein EJ
      • Baron EJ
      • et al.
      Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.
      ;
      • Wenzel RP
      • Edmond MB.
      Antibiotics for abdominal sepsis.
      ;
      • Young-Fadok TM
      Diverticulitis.
      )
      4-7 days
      Complicated e.g. with positive blood culture, drained abscess7-10 days (
      • Sawyer RG
      • Claridge JA
      • Nathens AB
      • Rotstein OD
      • Duane TM
      • Evans HL
      • et al.
      Trial of short-course antimicrobial therapy for intraabdominal infection.
      ;
      • Solomkin JS
      • Mazuski JE
      • Bradley JS
      • Rodvold KA
      • Goldstein EJ
      • Baron EJ
      • et al.
      Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ;
      • Young-Fadok TM
      Diverticulitis.
      )
      7-14 days
      Urinary tract infection
      Pyelonephritis and complicated urinary tract infection5-14 days according to antibiotic
      e.g. trimethoprim/sulfamethoxazole, ciprofloxacin.
      , sex and risk factors
      pregnancy, obstruction, chronic kidney disease, male sex, immunosuppression, kidney stones, anatomic/ functional urinary tract abnormality.
      (
      • Drekonja DM
      • Trautner B
      • Amundson C
      • Kuskowski M
      • Johnson JR.
      Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ;
      • Gupta K
      • Hooton TM
      • Naber KG
      • Wullt B
      • Colgan R
      • Miller LG
      • et al.
      International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
      ;
      • Johnson JR
      • Russo TA.
      Acute pyelonephritis in adults.
      ;
      • Stamm WE
      • McKevitt M
      • Counts GW.
      Acute renal infection in women: treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks. A randomized trial.
      )
      7-14 days according to antibiotic
      e.g. trimethoprim/sulfamethoxazole, ciprofloxacin.
      , sex and risk factors
      pregnancy, obstruction, chronic kidney disease, male sex, immunosuppression, kidney stones, anatomic/ functional urinary tract abnormality.
      Urosepsis7-14 days according to risk factors
      pregnancy, obstruction, chronic kidney disease, male sex, immunosuppression, kidney stones, anatomic/ functional urinary tract abnormality.
      (
      • Eliakim-Raz N
      • Yahav D
      • Paul M
      • Leibovici L.
      Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      )
      7-14 days according to risk factors
      local guidelines are incorporated into the Sanford Guide (“infektioStandards”) and accessible online (https://webedition.sanfordguide.com/en/weissbuch).
      Endocarditis
      Native valve endocarditis2-4 weeks (
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • Fowler VG
      • Tleyjeh IM
      • Rybak MJ
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ;
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • Bongiorni MG
      • Casalta JP
      • Del Zotti F
      • et al.
      2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ;
      • Hoen B
      • Duval X.
      Clinical practice. Infective endocarditis.
      )
      Prosthetic valve ecndocarditis6 weeks (
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • Fowler VG
      • Tleyjeh IM
      • Rybak MJ
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ;
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • Bongiorni MG
      • Casalta JP
      • Del Zotti F
      • et al.
      2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ;
      • Hoen B
      • Duval X.
      Clinical practice. Infective endocarditis.
      )
      a e.g. trimethoprim/sulfamethoxazole, ciprofloxacin.
      b pregnancy, obstruction, chronic kidney disease, male sex, immunosuppression, kidney stones, anatomic/ functional urinary tract abnormality.
      c local guidelines are incorporated into the Sanford Guide (“infektioStandards”) and accessible online (https://webedition.sanfordguide.com/en/weissbuch).
      Every day with at least 50% of the total daily antibiotic dosage administered was considered as a treatment day. DAT was determined according to the prescriptions and the notes in the medical records. The possibility and appropriateness of switching from intravenous to oral antibiotic treatment were judged according to the study published by
      • Mertz D
      • Koller M
      • Haller P
      • Lampert ML
      • Plagge H
      • Hug B
      • et al.
      Outcomes of early switching from intravenous to oral antibiotics on medical wards.
      .

      Statistical analysis

      We aimed to include 50 patients per group and year. The sample size estimation was based on Swiss DAT data from patients with community-acquired pneumonia (
      • Blum CA
      • Nigro N
      • Briel M
      • Schuetz P
      • Ullmer E
      • Suter-Widmer I
      • et al.
      Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial.
      ) and to detect a difference in the mean DAT of 2 days compared with the recommended DAT in guidelines (power = 90%, α= 0.05, SD = 5.4 days). Although the target sample size was not achieved for endocarditis (<50 patients per year treated at our center), we elected not to expand the time frame for inclusion to maintain comparability between the disease groups. Data were entered in an electronic case report form using EpiData Version 4.4.3.1 (Association EpiData®). Data were analyzed using IBM SPSS Statistics® version 25 and Microsoft Office 365 Excel®. Categorical variables were compared using the chi-square test and the Fisher's exact test, where appropriate. The metric variables were compared with the Mann-Whitney U-test and the Kruskal-Wallis-test, where appropriate. The results with a P-value below 0.05 were considered statistically significant. Multivariable stepwise logistic regression models that included potentially confounding variables with a univariate P-value <0.1 were performed to analyze associations between patient variables and adherence to guidelines and are presented as odds ratios with their 95% confidence interval.

      Results

      Patient characteristics

      A total of 243 patients were included in the analysis: 100 patients with diverticulitis, 100 with complicated UTI, and 43 with endocarditis (Supplement Figure S1). The median age was 63 years (interquartile range [IQR]: 46-74) and 53.1% of the patients were female (Table 2). The baseline characteristics within each group did not demonstrate significant differences between 2017 and 2018 (data not shown). Female patients with complicated UTI were younger (median age 54 years [IQR 30-76] vs 69 years [IQR 57-83], P = 0.015] and had less comorbidities (median Charlson comorbidity index of 3 [IQR 0-6] vs 6 [IQR 2.5-9], P = 0.001) than male patients. Patients with diverticulitis and endocarditis were frequently treated in a surgical ward (85% and 56%), whereas patients with complicated UTI were mainly admitted to a medical ward (68%). Complicated diverticulitis was observed in 38% of the patients (38/100). The majority of patients with endocarditis had native valve endocarditis (39/43 [90.7%]). Complications (e.g., abscess) were observed in 29/43 patients with endocarditis (67.4%), of whom 44.7% (n = 17/29) had metastatic spread of the infection.
      Table 2Overall baseline characteristics.
      Infectious disease
      VariableOverall (N = 243)Diverticulitis (N = 100)Complicated urinary tract infection (N = 100)Endocarditis (N = 43)
      Sex: female, N (%)129 (53.1)48 (48.0)68 (68.0)13 (30.2)
      Age in years, median (IQR)63 (46-74)65 (51-74)62 (38-78)62 (50-72)
      Length of stay in days, median (IQR)6 (4-11)4 (3-6)6 (4-9)20 (14-29)
      Admission to medical ward, N (%)100 (41.2)15 (15)68 (68)17 (39.5)
      Admission to surgical ward, N (%)139 (57.2)85 (85)30 (30)24 (55.8)
      Intensive care unit admission, N (%)44 (18.1)3 (3.0)7 (7.0)34 (79.1)
      Penicillin allergy, N (%)31 (12.8)15 (15.0)10 (10.0)6 (14.0)
      Charlson comorbidity index, median (IQR)3 (1-6)2 (1-5)4 (0-7)3 (1-6)
      Immunosuppression, N (%)32 (13.2)12 (12.0)15 (15.0)5 (11.6)
      Procalcitonin measurement on day 0, N (%)61 (25.1)9 (9.0)37 (37.0)15 (34.9)
      Identification of a pathogen, N (%)140 (57.6)13 (13.0)86 (86.0)41 (95.3)
      BC collection, N (%)178 (73.3)45 (45.0)90 (90.0)43 (100)
      Positive BC result of collected BC, N (%)82 (46.1)5 (11.1)40 (44.4)37 (86.0)
      Urine culture collection, N (%)104 (42.8)2 (2.0)94 (94.0)8 (18.6)
      Positive urine culture result of collected urine cultures, N (%)87 (83.7)0 (0)82 (87.2)5 (62.5)
      Infectious diseases consultation, N (%)65 (26.7)5 (5.0)17 (17.0)43 (100)
      Abbreviations: BC, blood culture; N, number.
      Blood culture (BC) positivity rate ranged from 86% in endocarditis to 44% in complicated UTI and 11% in diverticulitis (Table 2). The most frequently detected pathogen in BC was S. aureus in endocarditis and Escherichia coli in complicated UTI. ID specialists were involved in 100% of the endocarditis patients and in 5/100 (5%) patients with diverticulitis.

      Duration of antibiotic treatment

      The median DAT was 11 days (IQR 10-13) in diverticulitis, 14 days (IQR 10-15) in complicated UTI, and 43 days (IQR 31-59) in endocarditis (Table 3). In diverticulitis, the median DAT was significantly shorter in 2017 (10 days [IQR 9-13]) than in 2018 (12 days [IQR 10-14], P-value = 0.022) and was associated with the disease severity (uncomplicated diverticulitis: median 10 days [IQR 8-13] vs median 13 days [IQR 11-14] in complicated diverticulitis, P <0.001).
      Table 3DAT and assessment of its appropriateness according to local and international guidelines.
      Disease
      VariableDiverticulitis (N = 100)Complicated urinary tract infection (N = 100)Endocarditis (N = 43)
      DAT (days), median (IQR)11 (10-13)14 (10-15)43 (31-59)
      DAT according to international guidelines
      missing data to 100%: no guidelines applicable.
       Yes, N (%)18 (18)40 (40)37 (86)
       Too long, N (%)79 (79)46 (46)4 (9)
       Too short, N (%)3 (3)12 (12)1 (2)
      DAT according to local guidelinesa
       Yes, N (%)11 (11)39 (39)36 (84)
       Too long, N (%)87 (87)43 (43)4 (9)
       Too short, N (%)2 (2)15 (15)1 (2)
      Time to switch to oral antibiotics (days), median (IQR)3 (3-5)5 (4-6)33 (28-46)
      switch to oral treatment in case of metastatic infection requiring prolonged treatment.
      Discharge without antibiotics, N (%)12 (12)14 (14)6 (14)
      Length of stay (days), median (IQR)4 (3-6)6 (4-9)20 (14-29)
      In-hospital mortality, N (%)0 (0)2 (2)1 (2)
      30-day readmission, N (%)6 (6)12 (12)5 (12)
      Abbreviations: DAT, duration of antibiotic treatment; N, number.
      a missing data to 100%: no guidelines applicable.
      b switch to oral treatment in case of metastatic infection requiring prolonged treatment.
      In patients with complicated UTI, the median DAT was similar in 2017 and 2018 (14 vs 11.5 days, P = 0.558) and decreased if ciprofloxacin was administered (11 days [IQR 9-14] vs 14 days [IQR 11-15], P = 0.002]). A positive BC result was not associated with a change in the median DAT (14 vs 12 days, P = 0.244). DAT was shorter in female patients than male patients (median 11 days [IQR 10-15] vs median 14 days [IQR 12-16], P = 0.008). Of note, the median DAT in female patients treated with ciprofloxacin was 11 days (IQR 9-14). The median DAT in patients with endocarditis was 43 days (IQR 31-59).
      A switch to oral antibiotic treatment was performed after a median of 3 and 5 days in diverticulitis and complicated UTI, respectively. In patients with endocarditis, a switch to oral treatment was performed in patients requiring prolonged antibiotic treatment due to metastatic spread of the disease (Table 3). The minority of patients were discharged without antibiotic treatment: 12/100 (12%) in diverticulitis, 14/100 (14%) in complicated UTI, and 6/43 (14%) in endocarditis.

      Adherence to guidelines

      Overall, guideline adherence differed significantly between patients treated for endocarditis compared with the group of patients with diverticulitis and complicated UTI (adherence to international guidelines were 86% vs 25%, respectively, P <0.0001) (Table 3). In diverticulitis, the DAT exceeded the recommended length in 80% of patients. In the surgical departments, 77/87 (90.6%) patients were treated longer than recommended, with a median DAT of 12 days (IQR 10-14) compared with 9 days (IQR 7.5-10) in the medical departments (P < 0.0001). The DAT in patients with complicated UTI was in accordance with local and international guidelines in 39% and 40% of patients, respectively (Figure 1). Between 2017 and 2018, the percentage of complicated patients with UTI treated shorter than recommended in local and international guidelines increased from 8% to 22% and from 6% to 18%, respectively. In endocarditis, adherence to local and international guidelines was high (84% [n = 36/43] and 86% [n = 37/43]), respectively (Figure 1).
      Figure 1
      Figure 1Compliance of antibiotic treatment duration according to local guidelines.
      Abbreviations: NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; UTI, urinary tract infection.
      No local guideline was available for the antibiotic treatment duration of Tropheryma whipplei endocarditis and complicated UTIs involving foreign bodies (e.g., double-J stents).

      Parameters associated with guideline adherence in patients with diverticulitis or complicated urinary tract infection

      Because patients with endocarditis differed distinctly from patients with diverticulitis or complicated UTI, such as regarding the severity of disease, total DAT, stay in the intensive care unit, and ID consultation, we decided to pool the complicated UTI and diverticulitis population to identify parameters associated with guideline adherence and excess treatment duration (Table 4). After adjustment, treatment in a medical department, ID consultation, and the detection of a pathogen in any microbiological sample were independently associated with higher odds of adherence to local guidelines. When focusing on treatment adherence according to international guidelines, only the detection of any pathogen in microbiological samples was identified as independent parameter associated with guideline adherence (data not shown).
      Table 4Parameters associated with adherence to local and international guidelines in a pooled patient population suffering from complicated urinary tract infection and diverticulitis.
      VariableUnivariable odds ratio (95% CI)P-valueMultivariable odds ratio (95% CI)P-value
      Accordance to local guidelines
      Age
      per 1 year increase.
      1.01 (0.99, 1.03)0.220
      Male sex1.00 (0.52, 1.92)1.000
      Antimicrobial allergy1.17 (0.48, 2.84)0.730
      Charlson comorbidity index
      per one point increment.
      1.14 (1.04, 1.23)0.005
      Chronic kidney disease3.14 (1.59, 6.20)0.001
      Immunosuppression2.84 (1.23, 6.58)0.015
      Department (medical vs surgical)3.88 (1.97, 7.64)<0.0012.53 (1.16, 5.09)0.019
      Intensive care unit admission4.98 (1.34, 18.43)0.016
      Identification of any pathogen6.17 (2.87, 13.29)<0.0013.94 (1.73, 8.98)0.001
      Multi-drug resistant gram-negative bacteria6.95 (2.00, 24.23)0.002
      Collection of blood culture3.87 (1.63, 9.19)0.002
      Positive blood culture result2.56 (1.26, 5.22)0.010
      Infectious diseases consultation4.42 (1.78, 11.01)0.0012.67 (1.00, 7.11)0.050
      a per 1 year increase.
      b per one point increment.
      Female sex, department, lack of BC collection, and pathogen identification were parameters associated with a longer than locally recommended DAT in the multivariable analysis (Supplemental Table S1), with similar results when applying international recommendations (data not shown).

      Discussion

      The current study assessed the adherence to local and international guidelines in patients with diverticulitis, complicated UTI, and endocarditis. Our findings showed that the treatment duration in diverticulitis and complicated UTI was in accordance with guidelines in only 15% and 40% of patients, respectively, but was much higher (84%) in endocarditis. These three disorders are characterized by very different treatment approaches. Patients with diverticulitis are primarily treated in surgical departments, where the main treatment focuses on surgical intervention rather than on antibiotic treatment (
      • Charani E
      • Tarrant C
      • Moorthy K
      • Sevdalis N
      • Brennan L
      • Holmes AH.
      Understanding antibiotic decision making in surgery-a qualitative analysis.
      ). In pyelonephritis, there are many high-quality trials available, showing that shorter treatment durations are effective and safe (
      • Drekonja DM
      • Trautner B
      • Amundson C
      • Kuskowski M
      • Johnson JR.
      Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ;
      • Eliakim-Raz N
      • Yahav D
      • Paul M
      • Leibovici L.
      Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Sandberg T
      • Skoog G
      • Hermansson AB
      • Kahlmeter G
      • Kuylenstierna N
      • Lannergård A
      • et al.
      Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ;
      • Yahav D
      • Franceschini E
      • Koppel F
      • Turjeman A
      • Babich T
      • Bitterman R
      • et al.
      Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial.
      ). In endocarditis, ID specialists are usually involved in the management of antibiotic treatment (
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • Fowler VG
      • Tleyjeh IM
      • Rybak MJ
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ;
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • Bongiorni MG
      • Casalta JP
      • Del Zotti F
      • et al.
      2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ).
      The adherence rates observed in diverticulitis were substantially lower than the results of a Dutch study, which assessed guideline adherence in intra-abdominal infections (15% vs 82%) (
      • Akhloufi H
      • Streefkerk RH
      • Melles DC
      • de Steenwinkel JE
      • Schurink CA
      • Verkooijen RP
      • et al.
      Point prevalence of appropriate antimicrobial therapy in a Dutch university hospital.
      ) and was similar to published data in pyelonephritis (
      • Chardavoyne PC
      • Kasmire KE.
      Appropriateness of antibiotic prescriptions for urinary tract infections.
      ;
      • Hecker MT
      • Fox CJ
      • Son AH
      • Cydulka RK
      • Siff JE
      • Emerman CL
      • et al.
      Effect of a stewardship intervention on adherence to uncomplicated cystitis and pyelonephritis guidelines in an emergency department setting.
      ). However, comparability between studies might be challenging due to the use of different guidelines. The rate of appropriate treatment would have increased up to 90% in our studied population if Dutch guidelines, recommending 7 to 14 days of antibiotic treatment in intra-abdominal infections, would have been applied. Of note, between 2017 and 2018, DAT shorter than recommended in local and international guidelines doubled for patients with complicated UTI. This observation might be related to the publication of several trials in this time, showing noninferiority of shorter antibiotic treatment in this patient population (
      • Drekonja DM
      • Trautner B
      • Amundson C
      • Kuskowski M
      • Johnson JR.
      Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ;
      • Eliakim-Raz N
      • Yahav D
      • Paul M
      • Leibovici L.
      Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Molina J
      • Montero-Mateos E
      • Praena-Segovia J
      • León-Jiménez E
      • Natera C
      • López-Cortés LE
      • et al.
      Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial.
      ;
      • Sandberg T
      • Skoog G
      • Hermansson AB
      • Kahlmeter G
      • Kuylenstierna N
      • Lannergård A
      • et al.
      Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.
      ;
      • Smith BJ
      • Heriot G
      • Buising K.
      Antibiotic treatment of common infections: more evidence to support shorter durations.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ;
      • Yahav D
      • Franceschini E
      • Koppel F
      • Turjeman A
      • Babich T
      • Bitterman R
      • et al.
      Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial.
      ). However, women with a negative BC result who were treated with ciprofloxacin were at risk to receive a prolonged course of antibiotic treatment; although, they were younger, had less comorbidities, and represent a group of patients in whom shorter treatment durations (5-7 days) are investigated most frequently (
      • Gupta K
      • Hooton TM
      • Naber KG
      • Wullt B
      • Colgan R
      • Miller LG
      • et al.
      International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
      ;
      • Johnson JR
      • Russo TA.
      Acute pyelonephritis in adults.
      ).
      In diverticulitis and complicated UTI, a majority of patients were treated for almost twice as long as recommended in the guidelines and investigated in randomized trials (
      • Daniels L
      • Ünlü Ç
      • de Korte N
      • van Dieren S
      • Stockmann HB
      • Vrouenraets BC
      • et al.
      Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis.
      ;
      • DeCesare L
      • Xu TQ
      • Saclarides C
      • Coughlin JM
      • Chivukula SV
      • Woodfin A
      • et al.
      Trends in antibiotic duration for complicated intra-abdominal infections: adaptation to current guidelines.
      ;
      • Drekonja DM
      • Trautner B
      • Amundson C
      • Kuskowski M
      • Johnson JR.
      Effect of 7 vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ;
      • Eliakim-Raz N
      • Yahav D
      • Paul M
      • Leibovici L.
      Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection– 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials.
      ;
      • Sandberg T
      • Skoog G
      • Hermansson AB
      • Kahlmeter G
      • Kuylenstierna N
      • Lannergård A
      • et al.
      Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.
      ;
      • Sawyer RG
      • Claridge JA
      • Nathens AB
      • Rotstein OD
      • Duane TM
      • Evans HL
      • et al.
      Trial of short-course antimicrobial therapy for intraabdominal infection.
      ;
      • Solomkin JS
      • Mazuski JE
      • Bradley JS
      • Rodvold KA
      • Goldstein EJ
      • Baron EJ
      • et al.
      Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.
      ;
      • Tansarli GS
      • Andreatos N
      • Pliakos EE
      • Mylonakis E.
      A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to enterobacteriaceae.
      ;
      • von Dach E
      • Albrich WC
      • Brunel AS
      • Prendki V
      • Cuvelier C
      • Flury D
      • et al.
      Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ;
      • Yahav D
      • Franceschini E
      • Koppel F
      • Turjeman A
      • Babich T
      • Bitterman R
      • et al.
      Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial.
      ;
      • Young-Fadok TM
      Diverticulitis.
      ). In patients with uncomplicated diverticulitis, previous studies have shown that antibiotic treatment can even be omitted (
      • Daniels L
      • Ünlü Ç
      • de Korte N
      • van Dieren S
      • Stockmann HB
      • Vrouenraets BC
      • et al.
      Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis.
      ;
      • Sawyer RG
      • Claridge JA
      • Nathens AB
      • Rotstein OD
      • Duane TM
      • Evans HL
      • et al.
      Trial of short-course antimicrobial therapy for intraabdominal infection.
      ), highlighting the need to reduce treatment duration to a minimum while at the same time being effective and safe. Interestingly, 83% of patients were discharged with oral antibiotic treatment for diverticulitis and complicated UTI. This is in line with results of a study by
      • Vaughn VM
      • Gandhi TN
      • Chopra V
      • Petty LA
      • Giesler DL
      • Malani AN
      • et al.
      Antibiotic overuse after hospital discharge: a multi-hospital cohort study.
      , reporting an overuse of antibiotic treatment after discharge in 38.7% of patients with UTI. Because our rate was twice as high, this should be targeted by future AMS intervention because it is known that up to 70% of antibiotic courses prescribed at discharge can be either improved by narrowing the spectrum, reduced in duration, or stopped (
      • Scarpato SJ
      • Timko DR
      • Cluzet VC
      • Dougherty JP
      • Nunez JJ
      • Fishman NO
      • et al.
      An evaluation of antibiotic prescribing practices upon hospital discharge.
      ;
      • Vaughn VM
      • Gandhi TN
      • Chopra V
      • Petty LA
      • Giesler DL
      • Malani AN
      • et al.
      Antibiotic overuse after hospital discharge: a multi-hospital cohort study.
      ;
      • Yogo N
      • Haas MK
      • Knepper BC
      • Burman WJ
      • Mehler PS
      • Jenkins TC.
      Antibiotic prescribing at the transition from hospitalization to discharge: a target for antibiotic stewardship.
      ).
      In the pooled analysis, treatment in medical departments was associated with a better adherence to guidelines. Surgeons may be less familiar with the concept of AMS and likely are focusing more on surgical interventions than on antibiotic prescriptions (
      • Charani E
      • Tarrant C
      • Moorthy K
      • Sevdalis N
      • Brennan L
      • Holmes AH.
      Understanding antibiotic decision making in surgery-a qualitative analysis.
      ). These results are in line with a study from England, which showed that patients in surgical wards were at risk to receive more frequent and longer antibiotic treatment courses compared with patients hospitalized in medical wards (
      • Charani E
      • de Barra E
      • Rawson TM
      • Gill D
      • Gilchrist M
      • Naylor NR
      • et al.
      Antibiotic prescribing in general medical and surgical specialties: a prospective cohort study.
      ). Although only borderline statistically significant, there was a trend toward better adherence to guidelines in the pooled analysis when ID specialists were involved in treatment decisions. Accordingly, in patients with endocarditis, where the involvement of an ID specialist is standard of care and recommended (
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • Fowler VG
      • Tleyjeh IM
      • Rybak MJ
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      ;
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • Bongiorni MG
      • Casalta JP
      • Del Zotti F
      • et al.
      2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ), adherence rate increased to >80% in line with adherence rates of a published Spanish study (
      • Escolà-Vergé L
      • Cuervo G
      • de Alarcón A
      • Sousa D
      • Barca LV
      • Fernández-Hidalgo N
      • et al.
      Impact of the COVID-19 pandemic on the diagnosis, management and prognosis of infective endocarditis.
      ). A positive association between ID consultations and guideline adherence has been reported (
      • Byl B
      • Clevenbergh P
      • Jacobs F
      • Struelens MJ
      • Zech F
      • Kentos A
      • et al.
      Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia.
      ;
      • Gürtler N
      • Erba A
      • Giehl C
      • Tschudin-Sutter S
      • Bassetti S
      • Osthoff M.
      Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
      ;
      • Livorsi DJ
      • Nair R
      • Lund BC
      • Alexander B
      • Beck BF
      • Goto M
      • et al.
      Antibiotic stewardship implementation and antibiotic use at hospitals with and without on-site infectious disease specialists.
      ).
      Furthermore, the detection of a relevant pathogen in any microbiological sample was associated with a better adherence to guidelines, especially in patients with complicated UTI. The determination of the causative pathogen might be an important principle to enable optimal antibiotic treatment, as we observed the highest adherence to guidelines in endocarditis with the highest positivity rate, followed by complicated UTI and diverticulitis with the lowest positivity rate in the latter case.
      Our results show that despite the availability of local and international treatment guidelines, adherence to them was low in diverticulitis and only moderate in complicated UTI. Our study highlights that the sole implementation and availability of guidelines might not be sufficient to improve antibiotic prescription practices. The implementation of AMS programs may help to overcome this issue and increase adherence to guidelines to shorten DAT. Interventions to improve guideline adherence may include educational efforts to improve knowledge, audit, and feedback or the implementation of an electronic prescribing support system (
      • Di Bella S
      • Beović B
      • Fabbiani M
      • Valentini M
      • Luzzati R.
      Antimicrobial stewardship: from bedside to theory. Thirteen examples of old and more recent strategies from everyday clinical practice.
      ). Antibiotic overuse after discharge was identified as one important target to focus on.
      Our study has several limitations, including the single-center design, which limits generalizability. Another limitation is its retrospective design and the reliance on medical record review.

      Conclusion

      The adherence to local and international guidelines regarding DAT was low in diverticulitis, moderate in complicated UTI, and excellent in endocarditis. Consequently, a majority of patients received a prolonged course of antibiotic treatment. Pathogen identification was associated with improved adherence to guidelines. The implementation of AMS programs, involvement of ID specialists, and educational efforts may help to improve adherence to guidelines and to reduce unnecessary antibiotic prescriptions, especially after discharge.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethics approval and consent to participate

      The study protocol was approved by the ethics committee of northwest and central Switzerland (EKNZ 2019-00185) with a waiver for informed consent

      Author contributions

      NF and MO had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NF and MO designed the study. NF collected the data. FN, MO, SD, and MW analyzed the data. NF and SD prepared a first manuscript draft. All authors contributed substantially to the writing of the manuscript and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

      Declaration of Competing Interest

      The authors have no competing interests to declare.

      Appendix. Supplementary materials

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