Study protocol for an international, multicentre stepped-wedge cluster randomised trial to evaluate the impact of a digital antimicrobial stewardship smartphone application

Introduction With the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based antimicrobial stewardship interventions hold great promise as tools to promote appropriate antimicrobial drug prescribing. However, more research is needed to evaluate their optimal design and impact on quantity and quality of antimicrobial prescribing. Methods and analysis Use of smartphone-based digital stewardship applications (apps) with local guideline directed empirical antimicrobial use by physicians will be compared with antimicrobial prescription as per usual as primary outcome in three hospitals in the Netherlands, Sweden and Switzerland. Secondary outcomes will incl

How to design a study to evaluate therapeutic drug monitoring in infectious diseases?

Background: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM. Objectives: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM. Sources: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM. Content: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design. Implications: This is an overview of different aspects relevant for the conduct of a TDM study. We believe that this paper will help researchers and clinicians to design and conduct high-quality TDM studies

Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure

Background The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of ‘responsible’ antibiotic use. Objectives To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. Methods First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. Results A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. Conclusions A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use

Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure

Background This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. Methods A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. Results The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. Conclusions This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use

Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae : Treatment, Selection and International Spread

The prevalence of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases is increasing worldwide. Therapeutic options for infections with these bacteria are limited not only by the production of ESBLs and carbapenemases, which confer resistance to cephalosporins and carbapenems, but also by frequent co-resistance to other antibiotics. The overall aim of this thesis was to obtain a better understanding of multidrug-resistant E. coli and K. pneumoniae in relation to epidemiology, selection and susceptibility to antibiotic therapy. In a prospective study ESBL-producing E. coli was found to spread easily through international travel. Twenty-four of 100 Swedes travelling outside Northern Europe acquired ESBL-producing E. coli in the intestinal flora. The risk was highest for travelers visiting India and those suffering from gastroenteritis during travel. To minimize selection of ESBL-producing K. pneumoniae during a hospital outbreak with these bacteria, an educational antibiotic intervention was performed at Uppsala University Hospital in 2006. The primary aim of the intervention was to reduce the consumption of parenteral cephalosporins. An immediate and radical reduction of cephalosporins was demonstrated with interrupted time series analysis. The outbreak declined during 2007 and no increased resistance to replacement antibiotics was detected. The impact of ESBL production on the antibacterial activity of ertapenem was studied in time-kill experiments. It was shown that porin-deficient subpopulations with reduced susceptibility to ertapenem frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Further, the antibacterial effects of antibiotic combinations against four strains of K. pneumoniae producing carbapenemases of the metallo-beta-lactamase type were studied in time-kill experiments. Double and triple combinations of aztreonam, fosfomycin, meropenem, rifampin and colistin at clinically relevant static concentrations were effective despite that the bacteria were frequently resistant to the individual drugs. These results indicate that there is a largely unexplored potential of antibiotic combination therapy for multidrug-resistant K. pneumoniae

Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae : Treatment, Selection and International Spread

The prevalence of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases is increasing worldwide. Therapeutic options for infections with these bacteria are limited not only by the production of ESBLs and carbapenemases, which confer resistance to cephalosporins and carbapenems, but also by frequent co-resistance to other antibiotics. The overall aim of this thesis was to obtain a better understanding of multidrug-resistant E. coli and K. pneumoniae in relation to epidemiology, selection and susceptibility to antibiotic therapy. In a prospective study ESBL-producing E. coli was found to spread easily through international travel. Twenty-four of 100 Swedes travelling outside Northern Europe acquired ESBL-producing E. coli in the intestinal flora. The risk was highest for travelers visiting India and those suffering from gastroenteritis during travel. To minimize selection of ESBL-producing K. pneumoniae during a hospital outbreak with these bacteria, an educational antibiotic intervention was performed at Uppsala University Hospital in 2006. The primary aim of the intervention was to reduce the consumption of parenteral cephalosporins. An immediate and radical reduction of cephalosporins was demonstrated with interrupted time series analysis. The outbreak declined during 2007 and no increased resistance to replacement antibiotics was detected. The impact of ESBL production on the antibacterial activity of ertapenem was studied in time-kill experiments. It was shown that porin-deficient subpopulations with reduced susceptibility to ertapenem frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Further, the antibacterial effects of antibiotic combinations against four strains of K. pneumoniae producing carbapenemases of the metallo-beta-lactamase type were studied in time-kill experiments. Double and triple combinations of aztreonam, fosfomycin, meropenem, rifampin and colistin at clinically relevant static concentrations were effective despite that the bacteria were frequently resistant to the individual drugs. These results indicate that there is a largely unexplored potential of antibiotic combination therapy for multidrug-resistant K. pneumoniae

Introducing the C-reactive protein point-of-care test : A conversation analytic study of primary care consultations for respiratory tract infection

The C-reactive protein point-of-care test (CRP-POCT) can help distinguish between viral and bacterial infection and has been promoted as a strategy to improve antimicrobial stewardship. The test is widely used in Sweden. National guidelines advocate conservative use in primary care consultations with patients presenting with symptoms of respiratory tract infection (RTI). Previous research suggests low adherence to guidelines. We provide new insights into the communication surrounding the CRP-POCT by documenting how the decision to administer the test is interactionally motivated and organized in Swedish primary care. The data consists of video-recordings of RTI-consultations. A CRP-POCT was performed in nearly two thirds of the consultations and our study is focused on a subset where the test is ordered by a medical doctor. We find that doctors order the test during the transition from or after physical examination, a practice that aligns with national guidelines. Guidelines indicate that pathological findings from physical examination are warrants for ordering the test but we only found one example where this was communicated to the patient. A more prevalent pattern was that doctors ordered the CRP-POCT even though the outcome of the physical examination was assessed as normal. Our analyses of these show that doctors can provide the rationale for ordering the test in subtle ways and that failure to provide a rationale is treated as a noticeable absence. We also find that the CRP-POCT can be used to reconcile the contrast between the normal physical examination and the patient's problem presentation. Doctors can also order the test in ways that position the CRP-POCT as criterial for antibiotic prescription. Consultations where the patients described the symptoms as particularly severe and/or persistent were more likely to engender elaborate accounts than consultations where patients presented their symptoms as less problematic.Uppsala Antibiotic Cente

Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men

Objectives: This study aimed to retrospectively assess the clinical outcome with nitrofurantoin and pivmecillinam for lower urinary tract infections (UTI) in men. Patients treated with trimethoprim were also included for comparison. Methods: All prescriptions of the study antibiotics to adult men in Uppsala County, Sweden, during 2012 were extracted. Data on patient characteristics, therapy, clinical outcome and microbiological results were obtained from the electronic medical records. The relative impact of antibiotic therapy, patient factors and pathogens on clinical outcome was assessed with univariate logistic regression using a 95% confidence interval (CI). Results: 832 prescriptions were identified, and 171 patients treated with nitrofurantoin (n = 69), pivmecillinam (n = 57) and trimethoprim (n = 45) met the inclusion criteria. Treatment failure occurred in one patient treated with nitrofurantoin and in four patients treated with pivmecillinam. New prescriptions of UTI antibiotics and relapse within 3 months after completion of therapy were more frequent with nitrofurantoin (34% and 15%) and pivmecillinam (30% and 17%) than trimethoprim (22 and 7%). However, these differences were not statistically significant and substantial heterogeneity was noted between the treatment groups. Urinary tract catheterization was associated with a higher risk for new antibiotic prescriptions (OR 2.34, 95% CI 1.14–4.80; P = 0.022) and prostate cancer was associated with a higher incidence of relapse (OR 3.01, 95% CI 1.09–8.29; P = 0.042). Conclusions: The clinical outcome with nitrofurantoin and pivmecillinam was acceptable in comparison with the results of previous studies. These antibiotics are suitable for empirical treatment of lower UTI in men considering their high activity against Escherichia coli and limited impact on the intestinal microbiota

Foreign Travel Is a Major Risk Factor for Colonization with Escherichia coli Producing CTX-M-Type Extended-Spectrum β-Lactamases: a Prospective Study with Swedish Volunteers ▿

Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing Escherichia coli before travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing Escherichia coli after the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%; n = 7). Gastroenteritis during the trip was an additional risk factor (P = 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances