Dipsticks and point-of-care Microscopy to reduce antibiotic use in women with an uncomplicated Urinary Tract Infection (MicUTI): protocol of a randomised controlled pilot trial in primary care.

INTRODUCTION: Uncomplicated urinary tract infections (uUTIs) in women are common infections encountered in primary care. Evidence suggests that rapid point-of-care tests (POCTs) to detect bacteria and erythrocytes in urine at presentation may help primary care clinicians to identify women with uUTIs in whom antibiotics can be withheld without influencing clinical outcomes. This pilot study aims to provide preliminary evidence on whether a POCT informed management of uUTI in women can safely reduce antibiotic use. METHODS AND ANALYSIS: This is an open-label two-arm parallel cluster-randomised controlled pilot trial. 20 general practices affiliated with the Bavarian Practice-Based Research Network (BayFoNet) in Germany were randomly assigned to deliver patient management based on POCTs or to provide usual care. POCTs consist of phase-contrast microscopy to detect bacteria and urinary dipsticks to detect erythrocytes in urine samples. In both arms, urine samples will be obtained at presentation for POCTs (intervention arm only) and microbiological analysis. Women will be followed-up for 28 days from enrolment using self-reported symptom diaries, telephone follow-up and a review of the electronic medical record. Primary outcomes are feasibility of patient enrolment and retention rates per site, which will be summarised by means and SDs, with corresponding confidence and prediction intervals. Secondary outcomes include antibiotic use for UTI at day 28, time to symptom resolution, symptom burden, number of recurrent and upper UTIs and re-consultations and diagnostic accuracy of POCTs versus urine culture as the reference standard. These outcomes will be explored at cluster-levels and individual-levels using descriptive statistics, two-sample hypothesis tests and mixed effects models or generalised estimation equations. ETHICS AND DISSEMINATION: The University of Würzburg institutional review board approved MicUTI on 16 December 2022 (protocol n. 109/22-sc). Study findings will be disseminated through peer-reviewed publications, conferences, reports addressed to clinicians and the local citizen's forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05667207.

Antimicrobial effects of clindamycin-loaded platelet-rich fibrin (PRF).

OBJECTIVES: Recent research has demonstrated that platelet-rich fibrin (PRF) is an appropriate carrier for ampicillin/sulbactam. The aim of the study was to investigate whether PRF is also a suitable bio-carrier for clindamycin (CLI). METHODS: PRF membranes were produced from 36 patients receiving intravenous therapy with CLI (e.g. due to the diagnosis of an osteonecrosis of the jaw or infections). Concentrations of CLI in PRF membranes were measured with liquid chromatography-tandem mass spectrometry, and the antimicrobial effects were investigated in vitro in agar diffusion tests with fresh PRF and PRF stored for 24 h. Storage was performed in an incubator at 36 °C to simulate the in-vivo situation. RESULTS: The mean concentration of CLI in plasma was 1.0 ± 0.3 µg/100 mg plasma; in resulting PRF membranes 0.7 ± 0.4 µg/100 mg PRF. Agar diffusion tests were performed with Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus mitis, Porphyromonas gingivalis, and Fusobacterium nucleatum. Mean inhibition zones, in mm, for fresh PRF were 17.3, 12.2, 18.8, 17.1, 25.8 and 18.1, 12.7, 19.2, 17.3, and 26.3 for stored PRF, respectively. CONCLUSION: The results demonstrate that PRF is a suitable bio-carrier for CLI when administered systemically to patients. The concentration in PRF generated from patients after infusion of 600 mg CLI dose suffices to target clinically relevant bacteria. CLINICAL RELEVANCE: Using PRF as a carrier for local antibiotic application can prevent infections in oral and maxillofacial surgery. Within the study limitations, the findings could expand the scope of PRF application by adding CLI as a new antibiotic to the spectrum of PRF therapy.

Investigation of clindamycin concentrations in human plasma and jawbone tissue in patients with osteonecrosis of the jaw: A prospective trial.

The aim of this study was to investigate the jawbone concentration of clindamycin (CLI) in patients with an osteonecrosis of the jaw (ONJ). Patients with medication-related ONJ (MRONJ) and osteoradionecrosis (ORN) with an antibiotic treatment with CLI were included. Plasma, vital and necrotic bone samples were collected. Plasma and jawbone samples were analyzed by liquid chromatography-tandem mass spectrometry. Patients with MRONJ exhibited a mean plasma CLI concentration of 9.6 µg/mL (SD ± 3.6 µg/mL) and mean concentrations of 2.3 µg/g CLI (SD ± 1.4 µg/g) and 2.1 µg/g CLI (SD ± 2.4 µg/g) in vital and necrotic bone samples, without statistical significance (p = 0.79). In patients with ORN, mean concentration in plasma was 12.0 µg/mL (SD ± 2.6 µg/mL), in vital bone 2.1 µg/g (SD ± 1.5 µg/g), and in necrotic bone 1.7 µg/g (SD ± 1.2 µg/g). Vital and necrotic bone concentrations did not differ significantly (p = 0.88). The results demonstrate that CLI concentrations are considerably lower than in plasma, but sufficient for most bacteria present in ONJ. Within the limitations of the study, it seems that CLI is a relevant alternative to other antibiotics in the treatment of ONJ because it reaches adequate concentrations in jawbone.

The Increase in Invasive Bacterial Infections With Respiratory Transmission in Germany, 2022/2023.

BACKGROUND: In late 2022, health care institutions in Germany reported an unusual number of severe, invasive bacterial infections in association with a high incidence of viral respiratory infections. METHODS: We analyzed routine data on invasive infections due to Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes (2017-2023) from a voluntary, laboratory-based surveillance system involving continuously participating facilities providing diagnostic routine data that cover approximately one-third of the German population. RESULTS: In the first quarter (Q1) of 2023, the number of invasive S. pyogenes isolates rose by 142% (n = 837 vs. mean Q1/2017-2019 = 346, 95% CI [258; 434]), while the number of H. influenzae isolates rose by 90% (n = 209 in Q1/2023 vs. mean Q1/2017-2019 = 110, 95% CI [79; 142]), compared to pre-pandemic seasonal peak values. The number of invasive S. pneumoniae isolates was high in two quarters (n = 1732 in Q4/2022 und Q1/2023). Adults aged 55 and older and children younger than 5 years were most affected by invasive H. influenzae, S. pneumoniae, and S. pyogenes infections. N. meningitidis was most commonly found in children under age 5. CONCLUSION: The reason for the marked rise in invasive bacterial infections may be an increased circulation of respiratory pathogens and elevated susceptibility in the population after relaxation of the measures taken to prevent COVID-19 infection. Coinfections with respiratory viruses may have reinforced this effect. We recommend continuous surveillance, preventive measures such as raising awareness about invasive bacterial diseases, and vaccination as recommended by the German Standing Committee on Vaccinations (STIKO).

Prevalence of piperacillin/tazobactam resistance in invasive Haemophilus influenzae in Germany.

Background: Haemophilus influenzae (Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes ß-lactam antibiotics. Since 2019 EUCAST breakpoints for piperacillin/tazobactam have been available. Little is known about the prevalence and mechanisms of piperacillin/tazobactam resistance in Hi. Objectives: To provide reliable prevalence data for piperacillin/tazobactam resistance in Hi in Germany, to evaluate different antibiotic susceptibility testing methods and to examine possible resistance mechanisms. Methods: According to EUCAST breakpoints, the MIC for piperacillin/tazobactam resistance is >0.25 mg/L. All invasive Hi in Germany from 2019 were examined by gradient agar diffusion (GAD) for piperacillin/tazobactam susceptibility. Piperacillin/tazobactam broth microdilution (BMD), piperacillin GAD on tazobactam-containing agar [piperacillin GAD on Mueller-Hinton agar with horse blood (MH-F)/tazobactam) and piperacillin/tazobactam agar dilution (AD) were used for confirmation. Phenotypic testing was complemented by ftsI sequencing. Results: Piperacillin/tazobactam GAD resulted in 2.9% (21/726) resistant Hi. BMD did not confirm piperacillin/tazobactam resistance. Two strains were found resistant by AD, of which one was also resistant using piperacillin GAD on MH-F/tazobactam. Overall, we found two strains with a piperacillin/tazobactam MIC >0.25 mg/L in at least two different tests (0.3%). Both were ß-lactamase-producing amoxicillin/clavulanate-resistant with PBP3 mutations characterized as group III-like+. Relevant PBP3 mutations occurred in six strains without phenotypic piperacillin/tazobactam resistance. These mutations suggest a reduced efficacy of ß-lactam antibiotics in these isolates. Conclusions: Piperacillin/tazobactam resistance prevalence in invasive Hi is low in Germany. Reduced susceptibility was correlated with PBP3 mutations, in particular with group III mutations.

Impact of aminopenicillin administration routes on antimicrobial effects of platelet-rich fibrin: An in-vitro investigation.

INTRODUCTION: The aim of the study was to investigate the impact of different aminopenicillin administration routes on the antimicrobial effects of platelet-rich fibrin (PRF). METHODS: We enrolled patients undergoing treatment with amoxicillin/clavulanic acid (AMC) orally or ampicillin/sulbactam (SAM) intravenously. AMC was applied in a single oral dose (875/125 mg), or in a double oral dose (1750/250 mg), and SAM in a dose of 2000/1000 mg. Blood was obtained one hour after the intake of AMC or 15 min after the infusion of SAM ended. Antimicrobial effects were investigated in agar diffusion tests with fresh PRF, PRF stored for 24, and PRF stored for 48 h. Agar diffusion tests were performed with Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Porphyromonas gingivalis. Inhibition zones (IZs) around a 6 mm PRF disc were measured after 24 h. RESULTS: IZs for fresh PRF and the single oral dose of AMC were 0.0, 4.7, 15.2, 2.3, and 0.9 mm (E. coli, S. aureus, S. pneumoniae, H. influenzae, and P. gingivalis, respectively). For the double oral dose, these values were 0.0, 11.4, 20.0, 8.1, and 7.4 mm. IZs for SAM were 11.9, 18.2, 24.7, 20.3, and 22.1 mm. Differences between parenteral and oral application as well as between different oral doses were significant (p<0.0001, one-way ANOVA). DISCUSSION: The results of our study demonstrate that oral administration is a suitable route to load PRF with these drugs. This could expand the scope of PRF application to prevent infections at the surgical site, especially in an outpatient setting in which drugs are normally applied orally.

Investigation of three common centrifugation protocols for platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam: a prospective trial.

OBJECTIVES: Different platelet-rich fibrin (PRF) protocols exist and are known to differ in resulting mechanical and bioactive properties. Centrifugation parameters may also influence drug release, in particular antibiotics, when using PRF as a bio-carrier. We thus evaluated three common protocols regarding effects on the bio-carrier properties. MATERIALS AND METHODS: In a prospective trial comprising 33 patients, we compared different protocols for PRF as a bio-carrier for ampicillin/sulbactam (SAM). Blood samples were taken shortly after a single dose of ampicillin/sulbactam (2 g/1 g) was administered to patients intravenously. PRF was obtained by centrifugation and three protocols were used: protocol A (1300 rpm, 8 min, RCF-max = 208 g), B (2300 rpm, 12 min, RCF-max = 652 g), and C (1500 rpm, 14 min, RCF-max = 276 g). The antibacterial activity of PRF was investigated against five oral species in vitro, based on agar diffusion methodology. RESULTS: The study demonstrates that a single dose of SAM is sufficient to reach high concentrations in PRF in all protocols (150 µg/ml), which is comparable to the plasma SAM concentration. Antibacterial activity was inferred from the diameter of inhibition zones seen in agar diffusion tests using PRF discs. Protocol B resulted in the largest inhibition zones. One-way ANOVA revealed statistically improved results for protocol B for some bacteria. CONCLUSIONS: The study provides valuable data on PRF antibiotic enrichment, notably SAM. A single dose of SAM is sufficient to reach clinically relevant concentrations in PRF. CLINICAL RELEVANCE: These findings potentially extend the application of PRF, for example in patients with osteonecrosis of the jaw or in oral surgery (e.g., stick bone).

Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium.

BACKGROUND: The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. METHODS: For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. FINDINGS: Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. INTERPRETATION: COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. FUNDING: Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization.

The relationship between mental health, sleep quality and the immunogenicity of COVID-19 vaccinations.

Sleep modulates the immune response, and sleep loss can reduce vaccine immunogenicity; vice versa, immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID-19 vaccinations and, conversely, of COVID-19 vaccinations on sleep quality. The prospective CoVacSer study monitored mental health, sleep quality and Anti-SARS-CoV-2-Spike IgG titres in a cohort of 1082 healthcare workers from 29 September 2021 to 19 December 2022. Questionnaires and blood samples were collected before, 14 days, and 3 months after the third COVID-19 vaccination, as well as in 154 participants before and 14 days after the fourth COVID-19 vaccination. Healthcare workers with psychiatric disorders had slightly lower Anti-SARS-CoV-2-Spike IgG levels before the third COVID-19 vaccination. However, this effect was mediated by higher median age and body mass index in this subgroup. Antibody titres following the third and fourth COVID-19 vaccinations ("booster vaccinations") were not significantly different between subgroups with and without psychiatric disorders. Sleep quality did not affect the humoral immunogenicity of the COVID-19 vaccinations. Moreover, the COVID-19 vaccinations did not impact self-reported sleep quality. Our data suggest that in a working population neither mental health nor sleep quality relevantly impact the immunogenicity of COVID-19 vaccinations, and that COVID-19 vaccinations do not cause a sustained deterioration of sleep, suggesting that they are not a precipitating factor for insomnia. The findings from this large-scale real-life cohort study will inform clinical practice regarding the recommendation of COVID-19 booster vaccinations for individuals with mental health and sleep problems.

Appropriate antibiotic use and antimicrobial resistance: knowledge, attitudes and behaviour of medical students and their needs and preferences for learning.

BACKGROUND: The impact of an appropriate use of antibiotics on the prevention of antimicrobial resistance (AMR) has been demonstrated. Surveys have shown, however, that medical students do not feel sufficiently trained to use antibiotics wisely. The aims of our study were (1) to describe what medical students currently know about appropriate antibiotic use, and (2) to identify students' learning preferences as a basis for developing student-centred teaching modules to convey the basics of AMR prevention. METHODS: We performed an online survey at Charité Universitätsmedizin Berlin and the Julius-Maximilians-University Würzburg on the knowledge, attitudes, and behaviour (KAB) of medical students concerning AMR, antibiotic treatment options, and their perceptions of AMR topics addressed in the medical curriculum. Participants were able to fill out an online questionnaire between December 2019 and February 2020. In addition, we conducted focus group discussions with lecturers and medical students in winter 2019/2020 to identify AMR-related learning needs and preferences. Data were analysed descriptively. RESULTS: Overall, 356 students (response rate 5.1%) participated in the KAB survey. Of these, 192 (54%) strongly agreed that the topic of AMR is relevant to students' clinical practice and 48% (171/355) stated that their future antibiotic prescription behaviour will have an influence on AMR development in their region. Participating students seemed to be interested in the topic of AMR and antibiotic therapy. But even of them, only 46% answered the question about the length of antibiotic use for community-acquired pneumonia correctly and 57% the question about the appropriate use of antibiotics in Staphylococcus aureus infections. Focus group discussions with students (n = 7) and lecturers (n = 9) identified a lack of competence in the responsible use of antibiotics and the prevention of AMR. Respondents stated that the teaching formats and AMR-related content should emphasize clinical applications, interaction with peers/clinicians, and repeated formative feedback from instructors. CONCLUSIONS: Our results show that even medical students who were interested in the AMR problem were not able to use antibiotics appropriately due to gaps in knowledge and a lack of clinical skills. Based on the insights gained in the learning preferences of students and their content priorities, improved student-centred teaching materials should be developed.

Uncoupling of platelet granule release and integrin activation suggests GPIIb/IIIa as a therapeutic target in COVID-19.

Thromboembolic events are frequent and life-threating complications of COVID-19 but are also observed in patients with sepsis. Disseminated thrombosis can occur despite anticoagulation, suggesting that platelets play a direct but incompletely understood role. Several studies demonstrated altered platelet function in COVID-19 with some controversial findings, while underlying disease-specific mechanisms remain ill defined. We performed a comprehensive cohort study with 111 patients, comprising 37 with COVID-19, 46 with sepsis, and 28 with infection, compared with control participants. Platelet phenotype and function were assessed under static and flow conditions, revealing unexpected disease-specific differences. From hospital admission onward, platelets in COVID-19 failed to activate the integrin glycoprotein IIb/IIa (GPIIb/IIIa) in response to multiple agonists. Dense granule release was markedly impaired due to virtually missing granules, also demonstrated by whole-mount electron microscopy. By contrast, α-granule marker CD62P exposure was only mildly affected, revealing a subpopulation of PAC-1-/CD62P+ platelets, independently confirmed by automated clustering. This uncoupling of α-granule release was not observed in patients with sepsis, despite a similar disease severity. We found overall unaltered thrombus formation in COVID-19 and sepsis samples under venous shear rates, which was dependent on the presence of tissue factor. Unexpectedly, under arterial shear rates, thrombus formation was virtually abrogated in sepsis, whereas we detected overall normal-sized and stable thrombi in blood from patients with COVID-19. These thrombi were susceptible to subthreshold levels of GPIIb/IIIa blockers, eptifibatide, or tirofiban that had only a minor effect in control participants' blood. We provide evidence that low-dose GPIIb/IIIa blockade could be a therapeutic approach in COVID-19.

Influencing factors of anti-SARS-CoV-2-spike-IgG antibody titers in healthcare workers: A cross-section study.

Against the background of the current COVID-19 infection dynamics with its rapid spread of SARS-CoV-2 variants of concern (VOC), the immunity and the vaccine prevention of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. This observational cross-section study assesses factors influencing the level of anti-SARS-CoV-2-spike IgG after SARS-CoV-2 infection or vaccination. One thousand seven hundred and fifty HCWs were recruited meeting the following inclusion criteria: age ≥18 years, PCR-confirmed SARS-CoV-2 infection convalescence and/or at least one dose of COVID-19 vaccination. anti-SARS-CoV-2-spike IgG titers were determined by SERION ELISA agile SARS-CoV-2 IgG. Mean anti-SARS-CoV-2-spike IgG levels increased significantly by number of COVID-19 vaccinations (92.2 BAU/ml for single, 140.9 BAU/ml for twice and 1144.3 BAU/ml for threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titers compared with convalescent only HCWs. Anti-SARS-CoV-2-spike IgG titers declined significantly with time after the second vaccination. Smoking and high age were associated with lower titers. Both recovered and vaccinated HCWs presented a predominantly good humoral immune response. Smoking and higher age limited the humoral SARS-CoV-2 immunity, adding to the risk of severe infections within this already health impaired collective.

Bone Concentration of Ampicillin/Sulbactam: A Pilot Study in Patients with Osteonecrosis of the Jaw.

Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as Streptococci and Staphylococci, which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of Escherichia coli towards beta-lactam antibiotics have been reported and should be considered.

Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam.

OBJECTIVES: Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders. The application of platelet-rich fibrin (PRF) after necrosectomy between bone and mucosa may constitute a promising approach to improve surgical results. An aspect that was not investigated until now is that PRF acts as a "bio-carrier" for antibiotics previously applied intravenously. MATERIALS AND METHODS: We investigated the antimicrobial properties of PRF in 24 patients presenting ONJ undergoing systemic antibiosis with ampicillin/sulbactam. We measured the concentration of ampicillin/sulbactam in plasma and PRF and performed agar diffusion tests. Ampicillin/sulbactam was applied intravenously to the patient 10 minutes for blood sampling for PRF. No further incorporation of patients' blood or PRF product with antibiotic drugs was obtained. Four healthy patients served as controls. RESULTS: Our results revealed that PRF is highly enriched with ampicillin/sulbactam that is released to the environment. The antibiotic concentration in PRF was comparable to the plasma concentration of ampicillin/sulbactam. The inhibition zone (IZ) of PRF was comparable to the standard ampicillin/sulbactam discs used in sensitivity testing. CONCLUSIONS: The results of our study demonstrated that PRF is a reliable bio-carrier for systemic applied antibiotics and exhibits a large antimicrobial effect. CLINICAL RELEVANCE: We describe a clinically useful feature of PRF as a bio-carrier for antibiotics. Especially when applied to poorly perfused tissues and bone such as in ONJ, the local release of antibiotics can reduce wound healing disorders like infections.

Diagnostic accuracy and feasibility of a rapid SARS-CoV-2 antigen test in general practice - a prospective multicenter validation and implementation study.

BACKGROUND: PCR testing is considered the gold standard for SARS-CoV-2 diagnosis but its results are earliest available hours to days after testing. Rapid antigen tests represent a diagnostic tool enabling testing at the point of care. Rapid antigen tests have mostly been validated by the manufacturer or in controlled laboratory settings only. External validation at the point of care, particularly in general practice where the test is frequently used, is needed. Furthermore, it is unclear how well point of care tests are accepted by the practice staff. METHODS: In this prospective multicenter validation study in primary care, general practitioners included adult individuals presenting with symptoms suggesting COVID-19. Each patient was tested by the general practitioner, first with a nasopharyngeal swab for the point of care test (Roche SARS-CoV-2 Rapid Antigen Test) and then with a second swab for PCR testing. Using the RT-PCR result as a reference, we calculated specificity, sensitivity, positive predictive value and negative predictive value, with their 95% confidence intervals. General practitioners and medical assistants completed a survey to assess feasibility and usefulness of the point of care tests. RESULTS: In 40 practices in Würzburg, Germany, 1518 patients were recruited between 12/2020 and 06/2021. The point of care test achieved a sensitivity of 78.3% and a specificity of 99.5% compared to RT-PCR. With a prevalence of 9.5%, the positive predictive value was 93.9% and the negative predictive value was 97.8%. General practitioners rated the point of care test as a helpful tool to support diagnostics in patients with signs and symptoms suggestive for infection, particularly in situations where decision on further care is needed at short notice. CONCLUSION: The point of care test used in this study showed a sensitivity below the manufacturer's specification (Sensitivity 96.25%) in the practice but high values for specificity and high positive predictive value and negative predictive value. Although widely accepted in the practice, measures for further patient management require a sensitive interpretation of the point of care test results.

Phylogenetic Structure and Comparative Genomics of Multi-National Invasive Haemophilus influenzae Serotype a Isolates.

Recent reports have indicated a rise of invasive disease caused by Haemophilus influenzae serotype a (Hia) in North America and some European countries. The whole-genome sequences for a total of 410 invasive Hia isolates were obtained from 12 countries spanning the years of 1998 to 2019 and underwent phylogenetic and comparative genomic analysis in order to characterize the major strains causing disease and the genetic variation present among factors contributing to virulence and antimicrobial resistance. Among 410 isolate sequences received, 408 passed our quality control and underwent genomic analysis. Phylogenetic analysis revealed that the Hia isolates formed four genetically distinct clades: clade 1 (n = 336), clade 2 (n = 13), clade 3 (n = 3) and clade 4 (n = 56). A low diversity subclade 1.1 was found in clade 1 and contained almost exclusively North American isolates. The predominant sequence types in the Hia collection were ST-56 (n = 125), ST-23 (n = 98) and ST-576 (n = 51), which belonged to clade 1, and ST-62 (n = 54), which belonged to clade 4. Clades 1 and 4 contained predominantly North American isolates, and clades 2 and 3 predominantly contained European isolates. Evidence of the presence of capsule duplication was detected in clade 1 and 2 isolates. Seven of the virulence genes involved in endotoxin biosynthesis were absent from all Hia isolates. In general, the presence of known factors contributing to ß-lactam antibiotic resistance was low among Hia isolates. Further tests for virulence and antibiotic susceptibility would be required to determine the impact of these variations among the isolates.

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.

BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. METHODS: In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. FINDINGS: 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded. INTERPRETATION: The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. FUNDING: Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).