Inactivating
in multidrug-resistant
with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors ...gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of
RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose.
Background
Antimicrobial stewardship (AMS) programs are effective tools for improving antibiotic prescription quality. Their implementation requires the regular surveillance of antibiotic consumption ...at the patient and institutional level. Our study captured and analyzed antibiotic consumption density (ACD) for hospitalized pediatric patients.
Method
We collected antibacterial drug consumption data for 2020 from hospital pharmacies at 113 pediatric departments of acute care hospitals in Germany. ACD was calculated as defined daily dose (DDD, WHO/ATC Index 2019) per 100 patient days (pd). In addition, we analyzed the trends in antibiotic use during 2013–2020.
Results
In 2020, median ACD across all participating hospitals was 26.7 DDD/100 pd, (range: 10.1–79.2 DDD/100 pd). It was higher at university vs. non-university hospitals (38.6 vs. 25.2 DDD/100 pd,
p
< 0.0001). The highest use densities were seen on oncology wards and intensive care units at university hospitals (67.3 vs. 38.4 DDD/100 pd). During 2013–2020, overall ACD declined (− 10%) and cephalosporin prescriptions also decreased (− 36%). In 2020, cephalosporins nevertheless remained the most commonly dispensed class of antibiotics. Interhospital variability in cephalosporin/penicillin ratio was substantial. Antibiotics belonging to WHO AWaRe “Watch” and “Reserve” categories, including broad-spectrum penicillins (+ 31%), linezolid (+ 121%), and glycopeptides (+ 43%), increased over time.
Conclusion
Significant heterogeneity in ACD and prescription of different antibiotic classes as well as high prescription rates for cephalosporins and an increased use of reserve antibiotics indicate improvable antibiotic prescribing quality. AMS programs should urgently prioritize these issues to reduce antimicrobial resistance.
The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only ...remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.
After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to ...important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance. Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure–activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial efflux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition. Recent studies of pump–substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the efflux mechanisms and, finally, may result in a clinically useful molecule.
Background
Pelargonium sidoides (P. sidoides), also known as Umckaloabo, is a herbal remedy thought to be effective in the treatment of acute respiratory infections (ARIs).
Objectives
To assess the ...efficacy and safety of P. sidoides for the treatment of ARIs in children and adults.
Search methods
In April 2013 we searched MEDLINE, Journals@Ovid, The Cochrane Library, Biosis Previews, Web of Science, CINAHL, CCMed, XToxline, Global Health, AMED, Derwent Drug File and Backfile, IPA, ISTPB + ISTP/ISSHP, EMBASE, Cambase, LILACS, PubMed component “Supplied by Publisher”, TRIPdatabase, the publisher databases: Deutsches Ärzteblatt, Thieme, Springer, ScienceDirect from Elsevier. We conducted a cited reference search (forward) in Web of Science of relevant papers for inclusion. In addition we searched the study registries ClinicalTrials.gov, Deutsches Register klinischer Studien DRKS (German Clinical Trials Register), International Clinical Trials Registry Platform (ICTRP) – WHO ICTRP, Current Controlled Trials and EU Clinical Trials Register.
Selection criteria
Double‐blind, randomized controlled trials (RCTs) examining the efficacy of P. sidoides preparations in ARIs compared to placebo or any other treatment. Complete resolution of all symptoms was defined as the primary outcome; in addition, we examined resolution of predefined key symptoms.
Data collection and analysis
At least two review authors (AT, JG, WK) independently extracted and quality scored the data. We performed separate analyses by age group and disease entity. Subanalysis considered type of preparation (liquid, tablets). We examined heterogeneity using the I2 statistic. We calculated pooled risk ratios (RR) using a fixed‐effect model if heterogeneity was absent (I2 < 5%; P > 0.1), or a random‐effects model in the presence of heterogeneity. If heterogeneity was substantial (I2 > 50%; P < 0.10), a pooled effect was not calculated.
Main results
Of 10 eligible studies eight were included in the analyses; two were of insufficient quality. Three trials (746 patients, low quality of evidence) of efficacy in acute bronchitis in adults showed effectiveness for most outcomes in the liquid preparation but not for tablets. Three other trials (819 children, low quality of evidence) showed similar results for acute bronchitis in children. For both meta‐analyses, we did not pool subtotals due to relevant heterogeneity induced by type of preparation.
One study in patients with sinusitis (n = 103 adults, very low quality of evidence) showed significant treatment effects (complete resolution at day 21; RR 0.43, 95% confidence interval (CI) 0.30 to 0.62). One study in the common cold demonstrated efficacy after 10 days, but not five days (very low quality of evidence). We rated the study quality as moderate for all studies (unvalidated outcome assessment, minor attrition problems, investigator‐initiated trials only). Based on the funnel plot there was suspicion of publication bias.
There were no valid data for the treatment of other acute respiratory tract infections. Adverse events were more common with P. sidoides, but none were serious.
Authors' conclusions
P. sidoides may be effective in alleviating symptoms of acute rhinosinusitis and the common cold in adults, but doubt exists. It may be effective in relieving symptoms in acute bronchitis in adults and children, and sinusitis in adults. The overall quality of the evidence was considered low for main outcomes in acute bronchitis in children and adults, and very low for acute sinusitis and the common cold. Reliable data on treatment for other ARIs were not identified.
BackgroundThe exact epidemiology of tick-borne encephalitis virus (TBEV) infections is unknown because many TBEV infections have an influenza-like or asymptomatic course. Surveillance data are based ...on patients with any (predominantly neurological) symptoms that prompted diagnostic testing. Infection- and vaccine-induced antibodies against TBEV can be distinguished using an NS1 IgG ELISA.AimIn a seroprevalence study we aimed to investigate TBEV antibody prevalence, incidences, manifestation indices and potential protection rates in a highly endemic district in south-western Germany.MethodsWe analysed 2,220 samples from healthy blood donors collected between May and September 2021. The reported number of TBEV infections was provided on a sub-district level by the local public health authorities. Blood samples were first screened using a TBEV IgG ELISA. In a second step, all positive samples were further analysed with a recently established NS1 IgG ELISA. The presence of specific antibodies against TBEV (excluding cross-reacting antibodies against other flaviviruses) was confirmed by testing screening-positive samples with a microneutralisation assay.ResultsOf 2,220 included samples, 1,257 (57%) tested positive by TBEV IgG ELISA and 125 tested positive for infection-induced TBEV NS1 antibodies, resulting in a TBEV NS1 IgG seroprevalence at 5.6% in our population. The yearly incidence based on the NS1 ELISA findings resulted in 283 cases per 100,000 inhabitants.ConclusionUsing the TBEV NS1 IgG assay, we confirmed a manifestation index of ca 2% and a high incidence of predominantly silent TBEV infections (> 250/100,000/year), which exceeds the incidence of notified cases (4.7/100,000/year) considerably.
Ecology and epidemiology of
Echinococcus multilocularis
and human alveolar echinococcosis (AE) are changing in Central Europe. Our data from a regional referral center for AE in southwest Germany ...suggest rising regional incidence for AE (annual incidence per 100,000 population 2004–2011: 0.12; 2012–2019: 0.20) and emerging urban AE (of 7 cases of AE in Freiburg city dwellers none was diagnosed before 2012) calling for an intensification of
E. multilocularis
and AE surveillance and of AE prevention measures.
Tickborne relapsing fever caused by Borrelia species is rarely reported in travelers returning from Africa. We report a case of a 71-year-old woman who sought treatment at University Medical Center ...in Freiburg, Germany, in 2015 with recurrent fever after traveling to southern Africa. We detected spirochetes in Giemsa-stained blood smears. Treatment with doxycycline for suspected tickborne relapsing fever was successful. Sequence analyses of several loci (16S rRNA, flagellin, uvrA) showed high similarity to the recently described Candidatus Borrelia kalaharica, which was found in a traveler returning from the same region earlier that year. We provide additional information regarding the genetic relationship of Candidatus B. kalaharica. Sequence information for an additional 6 housekeeping genes enables improved comparability to other borrelial species that cause relapsing fever. Our report underlines the importance and possible emergence of the only recently delineated pathogen in southern Africa.
In response to a high number of incoming asylum seekers and refugees (AS&R) in Germany, initial reception centres were established to provide immediate shelter, food and health support. This study ...evaluates the satisfaction with and use of the health care available at the Freiburg initial reception centre (FIRC) where an integrated health care facility (ICF) was set up in 2015.
We assessed use and satisfaction with health services available to resident AS&R within and outside the FIRC in a cross-sectional design. Data were collected in 2017 using a questionnaire with both open and closed ended items.
The majority of 102 included participants were young (mean age 24.2; 95%CI 22.9-25.5, range 18-43) males (93%), from Sub-Saharan Africa (92%). High use frequencies were reported from returning patients of the ICF; with 56% fortnightly use and 19% daily use reported. The summary of satisfaction scores indicated that 84% (CI95 76-89%) of respondents were satisfied with the ICF. Multivariate analysis showed female gender and non-English speaking as risk factors for low satisfaction. Outside the FIRC, the satisfaction scores indicated that 60% of participants (95%CI 50-69%) were satisfied with the health care received.
Our study shows that AS&R residing in the FIRC are generally satisfied with the services at the ICF, though strategies to enhance care for females and non-English speakers should be implemented. Satisfaction with health care outside of the FIRC was not as high, indicating the need to improve quality of care and linkage to regular health care services.
Objectives
To evaluate the antimicrobial and synergistic (hypothetically due to the inhibition of efflux pumps) effects of selective serotonin reuptake inhibitors (SSRIs) in Escherichia coli strains ...overproducing various resistance-nodulation-division (RND) efflux pumps.
Methods
MICs of various SSRIs and of clinically relevant antibiotics in the presence and absence of sertraline were determined for E. coli strains overproducing the RND efflux pumps AcrAB, AcrEF, MdtEF and MexAB. The effect of sertraline on Nile red efflux was evaluated in a real-time efflux assay. Expression of marA and acrB was monitored using quantitative RT-PCR.
Results
In MIC assays there was limited synergy of sertraline with tetracycline, oxacillin, linezolid and clarithromycin, depending on the individual pump overexpressed and on whether rich or minimal medium was used. Sertraline, as the most potent SSRI with regard to bacterial growth inhibition, led to rapid dose-dependent Nile red efflux inhibition, and was also found to increase the expression of marA and acrB.
Conclusions
A possible explanation for the discrepancy between the MIC and real-time efflux assays was that sertraline is a weak inducer of marA and acrB, thereby reducing its initial antibacterial and sensitizing effects over time. The results indicate that sertraline may be useful as a model efflux pump inhibitor for in vitro short-term experiments in E. coli, but is unlikely to be clinically useful as a co-drug against Gram-negative bacteria.
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