General practitioners' antibiotic prescribing practices in Malta : understanding drivers to inform the implementation of a social marketing behaviour change intervention

Background: Antibiotic resistance is a leading global public health problem and complex challenge. Although a multitude of factors affect its development, antibiotic use is a key driver. In fact, in Europe, a positive correlation between antibiotic use and resistance has been shown. The largest volumes of antibiotics are prescribed in the community setting and respiratory tract infections (RTIs) remain the most common diagnoses despite often being self-limiting. Malta has one of the highest antibiotic consumption rates in Europe with the top two reasons being sore throat and the flu. Since most antibiotics are obtained through a medical prescription, this suggests that antibiotics are overprescribed by doctors, and general practitioners (GPs) in particular are a suitable target group for interventions to improve antibiotic prescribing. However, prescribing decisions are often complex and influenced by numerous interrelated factors. Therefore changing prescribing behaviour first necessitates an in-depth understanding of antibiotic prescribing practices and factors that impact this behaviour. To date, large knowledge gaps remain in Malta which makes the implementation of evidence-based interventions targeting prescribers challenging. Aim: The aim of this thesis, which forms part of a larger intervention project, was to explore GPs’ views on antibiotic use and resistance in Malta, and to gain a better understanding of their antibiotic prescribing patterns for RTIs including the factors that influence their prescribing behaviour. Methods: Data were derived from two pre-intervention studies; one qualitative [Papers I & II] and one quantitative [Papers III & IV]. For the qualitative study, individual face-to-face interviews were held in 2014 with a quota sample of 20 GPs. Interviews were audio recorded and transcribed verbatim. Data were analysed iteratively using manifest and latent content analysis [Paper I] and phenomenography [Paper II]. The quantitative study was a repeated cross-sectional surveillance study for which 30 GPs and 3 GP trainees collected monthly data for all patients with an acute respiratory tract complaint during predetermined one week periods between May 2015 and April 2016. Descriptive statistics were used to examine patient, consultation and clinical characteristics, and to describe GPs’ prescribing patterns [Paper III]. In Paper IV, the association between GP-, practice- and consultationlevel factors, patient sociodemographic factors and patient health status factors, and antibiotic prescription (yes/no) was investigated using generalised estimating equations to estimate population-averaged effects. Key findings: GPs’ provided an antibiotic prescription to 45.7% of cases, the majority of which (99.6%) were broad-spectrum. Almost all (84.3%) were for immediate use, whilst 15.7% were delayed prescriptions. Through qualitative interviews five qualitatively different ways by which GPs perceived delayed antibiotic prescribing were described: (i) to maintain a good GP-patient relationship, retain patients and avoid doctor-shopping, (ii) to reach a compromise and provide treatment just in case, (iii) to provide the patient comfort and reassurance, (iv) to empower and educate patients, and limit antibiotic use, and (v) to retain GP responsibility by employing a wait-and-see approach. Surveillance data also revealed that GPs’ antibiotic prescribing is associated with a number of GP-, patient-, clinical- and consultation- level factors. This was largely corroborated by qualitative evidence that showed that antibiotic prescribing is impacted not only by intrinsic GP factors but several other factors, including but not limited to, diagnostic uncertainty, patient demand, interaction with drug reps, availability of guidelines and community resistance data, and access to diagnostic testing. Conclusions: GPs’ antibiotic prescribing for RTIs in Malta is high. The abundant use of broad-spectrum antibiotics is of particular concern and indicates that antibiotics are not being used appropriately. A number of factors were found to impact GPs’ antibiotic prescribing behaviour. In order to improve this behaviour, targeted and coordinated implementation activities must address barriers identified at all levels of the system and provide GPs with the necessary tools to alleviate diagnostic uncertainty

Определение сроков годности экстракционных лекарственных средств корневищ с корнями синюхи голубой

РАСТЕНИЙ ЭКСТРАКТЫСИНЮХА ГОЛУБА

Impact of a social marketing intervention on general practitioners’ antibiotic prescribing practices for acute respiratory tract complaints in Malta

Introduction: Antibiotics are commonly prescribed in primary care for acute respiratory tract complaints (aRTCs), often inappropriately. Social marketing interventions could improve prescribing in such settings. We evaluate the impact of a social marketing intervention on general practitioners’ (GPs’) antibiotic prescribing for aRTCs in Malta.Methods: Changes in GPs’ antibiotic prescribing were monitored over two surveillance periods between 2015 and 2018. Primary outcome: change in antibiotic prescription for aRTCs. Secondary outcomes: change in antibiotic prescription: (i) for immediate use, (ii) for delayed antibiotic prescription, (iii) by diagnosis, and (iv) by antibiotic class. Data were analysed using clustered analysis and interrupted time series analysis (ITSA).Results: Of 33 participating GPs, 18 successfully completed the study. Although clustered analyses showed a significant 3% decrease in overall antibiotic prescription (p = 0.024), ITSA showed no significant change overall (p = 0.264). Antibiotic prescription decreased significantly for the common cold (p < 0.001), otitis media (p = 0.044), and sinusitis (p = 0.004), but increased for pharyngitis (p = 0.015).Conclusions: The intervention resulted in modest improvements in GPs’ antibiotic prescribing. A more top-down approach will likely be required for future initiatives to be successful in this setting, focusing on diagnostic and prescribing support like rapid diagnostic testing, prescribing guidelines, and standardised delayed antibiotic prescriptions.peer-reviewe

Identification of conformational epitopes for human IgG on Chemotaxis inhibitory protein of Staphylococcus aureus

<p>Abstract</p> <p>Background</p> <p>The Chemotaxis inhibitory protein of <it>Staphylococcus aureus </it>(CHIPS) blocks the Complement fragment C5a receptor (C5aR) and formylated peptide receptor (FPR) and is thereby a potent inhibitor of neutrophil chemotaxis and activation of inflammatory responses. The majority of the healthy human population has antibodies against CHIPS that have been shown to interfere with its function <it>in vitro</it>. The aim of this study was to define potential epitopes for human antibodies on the CHIPS surface. We also initiate the process to identify a mutated CHIPS molecule that is not efficiently recognized by preformed anti-CHIPS antibodies and retains anti-inflammatory activity.</p> <p>Results</p> <p>In this paper, we panned peptide displaying phage libraries against a pool of CHIPS specific affinity-purified polyclonal human IgG. The selected peptides could be divided into two groups of sequences. The first group was the most dominant with 36 of the 48 sequenced clones represented. Binding to human affinity-purified IgG was verified by ELISA for a selection of peptide sequences in phage format. For further analysis, one peptide was chemically synthesized and antibodies affinity-purified on this peptide were found to bind the CHIPS molecule as studied by ELISA and Surface Plasmon Resonance. Furthermore, seven potential conformational epitopes responsible for antibody recognition were identified by mapping phage selected peptide sequences on the CHIPS surface as defined in the NMR structure of the recombinant CHIPS_31–121protein. Mapped epitopes were verified by <it>in vitro </it>mutational analysis of the CHIPS molecule. Single mutations introduced in the proposed antibody epitopes were shown to decrease antibody binding to CHIPS. The biological function in terms of C5aR signaling was studied by flow cytometry. A few mutations were shown to affect this biological function as well as the antibody binding.</p> <p>Conclusion</p> <p>Conformational epitopes recognized by human antibodies have been mapped on the CHIPS surface and amino acid residues involved in both antibody and C5aR interaction could be defined. This information has implications for the development of an effective anti-inflammatory agent based on a functional CHIPS molecule with low interaction with human IgG.</p

General practitioners’, pharmacists’ and parents’ views on antibiotic use and resistance in Malta : an exploratory qualitative study

Background: Antibiotic resistance (ABR) remains a global health threat that requires urgent action. Antibiotic use is a key driver of ABR and is particularly problematic in the outpatient setting. General practitioners (GPs), the public, and pharmacists therefore play an important role in safeguarding antibiotics. In this study, we aimed to gain a better understanding of the antibiotic prescribing-use-dispensation dynamic in Malta from the perspective of GPs, pharmacists, and parents; Methods: we conducted 8 focus groups with 8 GPs, 24 pharmacists, and 18 parents between 2014 and 2016. Data were analysed using inductive and deductive content analysis; Results: Awareness on antibiotic overuse and ABR was generally high among interviewees although antibiotic use was thought to be improving. Despite this, some believed that antibiotic demand, non-compliance, and over-the-counter dispensing are still a problem. Nevertheless, interviewees believed that the public is more accepting of alternative strategies, such as delayed antibiotic prescription. Both GPs and pharmacists were enthusiastic about their roles as patient educators in raising knowledge and awareness in this context; Conclusions: While antibiotic use and misuse, and knowledge and awareness, were perceived to have improved in Malta, our study suggests that even though stakeholders indicated willingness to drive change, there is still much room for improvement.peer-reviewe

Maltese antibiotic stewardship programme in the community (MASPIC) : protocol of a prospective quasiexperimental social marketing intervention

Introduction: Antibiotic misuse is a key driver of antibiotic resistance. In 2015/2016, Maltese respondents reported the highest proportions of antibiotic consumption in Europe. Since antibiotics are prescription-only medicines in Malta, research on effective strategies targeting general practitioners’ (GPs) knowledge and behaviour is needed. Multifaceted behaviour change (BC) interventions are likely to be effective. Social marketing (SM) can provide the tools to promote sustained BC; however, its utilisation in Europe is limited. This paper aims to describe the design and methods of a multifaceted SM intervention aimed at changing Maltese GPs’ antibiotic prescribing behaviour for patients with acute respiratory tract infections (aRTIs).Methods and analysis: This 4-year quasiexperimental intervention study will be carried out in Malta and includes three phases: preintervention, intervention and postintervention. The preintervention phase intends to gain insight into the practices and attitudes of GPs, pharmacists and parents through interviews, focus group discussions and antibiotic prescribing surveillance. A 6-month intervention targeting GPs will be implemented following assessment of their prescribing intention and readiness for BC. The intervention will likely comprise: prescribing guidelines, patient educational materials, delayed antibiotic prescriptions and GP education. Outcomes will be evaluated in the postintervention phase through questionnaires based on the theory of planned behaviour and stages-of-change theory, as well as postintervention surveillance. The primary outcome will be the antibiotic prescribing rate for all patients with aRTIs. Secondary outcomes will include the proportion of diagnosis-specific antibiotic prescription and symptomatic relief medication prescribed, and the change in GPs stage-of-change and their intention to prescribe antibiotics.peer-reviewe

Antibiotic prescribing for respiratory tract complaints in Malta : a 1 year repeated cross-sectional surveillance study

Objectives: To determine the 1 year antibiotic prescribing patterns by GPs for acute respiratory tract complaints (aRTCs) in Malta. Methods: In this repeated cross-sectional surveillance study, GPs collected data for patients seen for aRTCs during a designated 1 week period each month, between May 2015 and April 2016. GPs received three text reminders during surveillance weeks and were contacted by phone at most four times during the year. GPs also received 3 monthly individual- and aggregate-level feedback reports on their antibiotic prescribing patterns. Descriptive statistics were used to examine patient, consultation and clinical characteristics, and to describe GPs’ prescribing patterns. Results: Participating GPs (n = 33) registered 4641 patients with an aRTC, of whom 2122 (45.7%) received an antibiotic prescription. The majority (99.6%) of antibiotics prescribed were broad-spectrum and the most commonly prescribed antibiotics were macrolides (35.5%), followed by penicillins with a β-lactamase inhibitor (33.2%) and second-generation cephalosporins (14.2%). Specifically, co-amoxiclav (33.2%), clarithromycin (19.6%), azithromycin (15.1%) and cefuroxime axetil (10.9%) represented 78.8% of all antibiotics prescribed. Patients with tonsillar exudate (99.1%), purulent sputum (84%), otorrhoea (78%), tender cervical nodes (74.4%) and fever (73.1%) received most antibiotics. The diagnoses that received the highest proportion of antibiotic treatment were tonsillitis (96.3%), otitis media (92.5%) and bronchitis (87.5%). Wide variation in the choice of antibiotic class by diagnosis was observed. Conclusions: GP antibiotic prescribing in Malta is high. The abundant use of broad-spectrum antibiotics, particularly macrolides, is of particular concern and indicates that antibiotics are being used inappropriately. Efforts must be made to improve GP awareness of appropriate antibiotic prescribing.peer-reviewe

Factors associated with antibiotic prescribing in patients with acute respiratory tract complaints in Malta : a 1-year repeated cross-sectional surveillance study

Objective: To identify factors that influence general practitioners’ (GPs’) oral antibiotic prescribing for acute respiratory tract complaints (aRTCs) in Malta. Design: Repeated, cross-sectional surveillance. Setting: Maltese general practice; both public health centres and private GP clinics. Participants: 30 GPs registered on the Malta Medical Council’s Specialist Register and 3 GP trainees registered data of 4831 patients of all ages suffering from any aRTC. Data were collected monthly between May 2015 and April 2016 during predetermined 1-week periods. Outcome measures: The outcome of interest was antibiotic prescription (yes/no), defined as an oral antibiotic prescription issued for an aRTC during an in-person consultation, irrespective of the number of antibiotics given. The association between GP, practice and consultation-level factors, patient sociodemographic factors and patient health status factors, and antibiotic prescription was investigated. Results: The antibiotic prescription rate was 45.0%. Independent factors positively associated with antibiotic prescribing included female GP sex (OR 2.3, 95% CI 1.22 to 4.26), GP age with GPs ≥60 being the most likely (OR 34.7, 95% CI 14.14 to 84.98), patient age with patients ≥65 being the most likely (OR 2.3, 95% CI 1.71 to 3.18), number of signs and/or symptoms with patients having ≥4 being the most likely (OR 9.6, 95% CI 5.78 to 15.99), fever (OR 2.6, 95% CI 2.08 to 3.26), productive cough (OR 1.3, 95% CI 1.03 to 1.61), otalgia (OR 1.3, 95% CI 1.01 to 1.76), tender cervical nodes (OR 2.2, 95% CI 1.57 to 3.05), regular clients (OR 1.3, 95% CI 1.05 to 1.66), antibiotic requests (OR 4.8, 95% CI 2.52 to 8.99) and smoking (OR 1.4, 95% CI 1.13 to 1.71). Conversely, patients with non-productive cough (OR 0.3, 95% CI 0.26 to 0.41), sore throat (OR 0.6, 95% CI 0.53 to 0.78), rhinorrhoea (OR 0.3, 95% CI 0.23 to 0.36) or dyspnoea (OR 0.6, 95% CI 0.41 to 0.83) were less likely to receive an antibiotic prescription. Conclusion: Antibiotic prescribing for aRTCs was high and influenced by a number of factors. Potentially inappropriate prescribing in primary care can be addressed through multifaceted interventions addressing modifiable factors associated with prescription.peer-reviewe

Perlecan Maintains microvessel integrity in vivo and modulates their formation in vitro

Perlecan is a heparan sulfate proteoglycan assembled into the vascular basement membranes (BMs) during vasculogenesis. In the present study we have investigated vessel formation in mice, teratomas and embryoid bodies (EBs) in the absence of perlecan. We found that perlecan was dispensable for blood vessel formation and maturation until embryonic day (E) 12.5. At later stages of development 40% of mutant embryos showed dilated microvessels in brain and skin, which ruptured and led to severe bleedings. Surprisingly, teratomas derived from perlecan-null ES cells showed efficient contribution of perlecan-deficient endothelial cells to an apparently normal tumor vasculature. However, in perlecan-deficient EBs the area occupied by an endothelial network and the number of vessel branches were significantly diminished. Addition of FGF-2 but not VEGF165 rescued the in vitro deficiency of the mutant ES cells. Furthermore, in the absence of perlecan in the EB matrix lower levels of FGFs are bound, stored and available for cell surface presentation. Altogether these findings suggest that perlecan supports the maintenance of brain and skin subendothelial BMs and promotes vasculo- and angiogenesis by modulating FGF-2 function

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation