Efficacy of Vancomycin and Meropenem in Central Nervous System Infections in Children and Adults: Current Update

The current antimicrobial therapy of bacterial infections of the central nervous system (CNS) in adults and pediatric patients is faced with many pitfalls as the drugs have to reach necessary levels in serum and cross the blood-brain barrier. Furthermore, several studies report that different factors such as the structure of the antimicrobial agent, the severity of disease, or the degree of inflammation play a significant role. Despite the available attempts to establish pharmacokinetic (PK) modeling to improve the required dosing regimen for adults and pediatric patients, conclusive recommendations for the best therapeutic strategies are still lacking. For instance, bacterial meningitis, the most common CNS infections, and ventriculitis, a severe complication of meningitis, are still associated with 10% and 30% mortality, respectively. Several studies report on the use of vancomycin and meropenem to manage meningitis and ventriculitis; therefore, this review aims to shed light on the current knowledge about their use in adults and pediatric patients. Consequently, studies published from 2015 until mid-July 2021 are included, and data about the study population, levels of drugs in serum and cerebrospinal fluid (CSF), and measured PK data in serum and CSF are provided. The overall aim is to provide the readers a recent reference that summarizes the pitfalls and success of the current therapy and emphasizes the importance of performing more studies to improve the clinical outcome of the current therapeutical approach

Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp

Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, not all drug classes suit a patient’s condition or long-time use. For that, repurposing chronically used medications is more appealing. This review highlights the importance of repurposing anti-diabetic and anti-hypertensive drugs in the global fight against human malignancies. Extensive searches of all available evidence (up to 30 March 2023) on the anti-cancer activities of anti-diabetic and anti-hypertensive agents are obtained from multiple resources (PubMed, Google Scholar, ClinicalTrials.gov, Drug Bank database, ReDo database, and the National Institutes of Health). Interestingly, more than 92 clinical trials are evaluating the anti-cancer activity of 14 anti-diabetic and anti-hypertensive drugs against more than 15 cancer types. Moreover, some of these agents have reached Phase IV evaluations, suggesting promising official release as anti-cancer medications. This comprehensive review provides current updates on different anti-diabetic and anti-hypertensive classes possessing anti-cancer activities with the available evidence about their mechanism(s) and stage of development and evaluation. Hence, it serves researchers and clinicians interested in anti-cancer drug discovery and cancer management

Reliability of species detection in 16S microbiome analysis: Comparison of five widely used pipelines and recommendations for a more standardized approach

The use of NGS-based testing of the bacterial microbiota is often impeded by inconsistent or non-reproducible results, especially when applying different analysis pipelines and reference databases. We investigated five frequently used software packages by submitting the same monobacterial datasets to them, representing the V1-2 and the V3-4 regions of the 16S-rRNA gene of 26 well characterized strains, which were sequenced by the Ion Torrent™ GeneStudio S5 system. The results obtained were divergent and calculations of relative abundance did not yield the expected 100%. We investigated these inconsistencies and were able to attribute them to failures either of the pipelines themselves or of the reference databases they rely on. On the basis of these findings, we recommend certain standards which should help to render microbiome testing more consistent and reproducible, and thus useful in clinical practice

No evidence of an association of multiple sclerosis (MS) with Borna disease virus 1 (BoDV-1) infections in patients within an endemic region: a retrospective pilot study

Background Borna disease virus 1 (BoDV-1) causes rare human infections within endemic regions in southern and eastern Germany. The infections reported to date have been linked to severe courses of encephalitis with high mortality and mostly irreversible symptoms. Whether BoDV-1 could act as a trigger for other neurological conditions, is, however, incompletely understood. Objectives and methods In this study, we addressed the question of whether the presentation of a clinically isolated syndrome (CIS) or of multiple sclerosis (MS) might be associated with a milder course of BoDV-1 infections. Serum samples of 100 patients with CIS or MS diagnosed at a tertiary neurological care center within an endemic region in southern Germany and of 50 control patients suffering from headache were retrospectively tested for BoDV-1 infections. Results In none of the tested sera, confirmed positive results of anti-BoDV-1-IgG antibodies were retrieved. Our results support the conclusion that human BoDV-1 infections primarily lead to severe encephalitis with high mortality

Short-term effects of etifoxine on human gut microbiome in healthy men

BackgroundNeurosteroids have recently gained in interest as a treatment strategy for affective disorders. Etifoxine is known for its dual mode of action, one of which is to stimulate endogenous neurosteroid synthesis. The gut microbiome has been studied in affective disorders, but it has not been investigated in the context of human etifoxine or neurosteroid interventions.MethodsWe performed a crossover study with 36 healthy male volunteers who received etifoxine versus alprazolam and placebo in a balanced Williams design. Participants were randomized into six sequences and went through three 5-day treatments followed by wash-out phases of 9 days. Bacterial compositions in stool samples were determined by high-throughput 16S rRNA amplicon sequencing.ResultsGut microbiome analyses revealed no relevant effects between treatments with respect to alpha and beta diversity. Differential abundance analyses yielded etifoxine treatment as the only effect related to changes in microbial features with reductions of Faecalibacterium duncaniae, Roseburia hominis and Lactobacillus rogosae (i.e., Bacteroides galacturonicus).ConclusionHere we report on the first human investigation of the gut microbiome with short-term etifoxine intervention. Differences in diversity and compositional structure of the microbiome were more likely due to between- subject effects rather than medication. However, five-day treatment with etifoxine reduced the abundance of a few bacterial species. These species are currently seen as beneficial components of a healthy intestinal microbiome. This reduction in abundances may be related to elevated endogenous neurosteroids

Potential Saving of Antibiotics for Respiratory Infections in Several European Countries: Insights from Market Research Data

Antibiotics represent an essential pillar in the treatment of respiratory infections (RI). Overuse of antibiotics in avoidable cases and inappropriate application in bacterial infections facilitate treatment resistance, threatening their effectiveness and causing a significant healthcare challenge. We therefore assessed the savings potential for antibiotics in ambulant care of selected RI (bronchitis and cough, pharyngitis, rhinosinusitis) in several European countries based on market research data for the year 2019. Number of antibiotic packages sold in pharmacies varied, with highest values in Serbia and France, and lowest in Sweden and Switzerland. Selected RI contributed nearly half of overall ambulant antibiotic prescriptions, with around one fifth given for bronchitis and cough; the vast majority was estimated to be of viral origin with potentially avoidable antibiotic use. Antibiotic consumption for selected RI in eight European countries (Austria, Belgium, the Czech Republic, France, Germany, Poland, Slovakia, and Switzerland) amounted to nearly 100 million, with an overall savings potential between 66.2 and 83.7 million packages. The highest estimated volume of avoidable antibiotics was in France (44.7 million, 0.80 per capita), and lowest in Switzerland (1.4 million, 0.18 per capita). Due to substantial savings potential, prudent use of antibiotics and adequate application of alternatives should be promoted in daily practice

Ceftazidime and cefepime antagonize 5-fluorouracil’s effect in colon cancer cells

Background Drug-drug interaction (DDI), which can occur at the pharmacokinetics and/or the pharmacodynamics (PD) levels, can increase or decrease the therapeutic or adverse response of a drug itself or a combination of drugs. Cancer patients often receive, along their antineoplastic agents, antibiotics such as ß-lactams to treat or prevent infection. Despite the narrow therapeutic indices of antibiotics and antineoplastic agents, data about their potential interaction are insufficient. 5-fluorouracil (5-FU), widely used against colon cancer, is known for its toxicity and large intra- and inter- individual variability. Therefore, knowledge about its interaction with antibiotics is crucial. Methods In this study, we evaluated at the PD levels, against HCT-116 colon cancer cells, DDI between 5-FU and several ß-lactams (ampicillin, benzypenicillin, piperacillin, meropenem, flucloxacillin, ceftazidime (CFT), and cefepime (CFP)), widely used in intensive care units. All drugs were tested at clinically achieved concentrations. MTT assay was used to measure the metabolic activity of the cells. Cell cycle profile and apoptosis induction were monitored, in HCT-116 and DLD-1 cells, using propidium iodide staining and Caspase-3/7 activity assay. The uptake of CFT and CFP by the cells was measured using LC-MS/MS method. Results Our data indicate that despite their limited uptake by the cells, CFT and CFP (two cephalosporins) antagonized significantly 5-FU-induced S-phase arrest (DLD-1 cells) and apoptosis induction (HCT-116 cells). Remarkably, while CFP did not affect the proliferation of colon cancer cells, CFT inhibited, at clinically relevant concentrations, the proliferation of DLD-1 cells via apoptosis induction, as evidenced by an increase in caspase 3/7 activation. Unexpectedly, 5-FU also antagonized CFT’s induced cell death in DLD-1 cells. Conclusion This study shows that CFP and CFT have adverse effects on 5-FU’s action while CFT is a potent anticancer agent that inhibits DLD-1 cells by inducing apoptotic cell death. Further studies are needed to decipher the mechanism(s) responsible for CFT’s effects against colon cancer as well as the observed antagonism between CFT, CFP, and 5-FU with the ultimate aim of translating the findings to the clinical settings

Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of the viral receptor-binding domain with angiotensin-converting enzyme 2 (ACE2), while class 3 antibodies target a highly conserved epitope outside the ACE2 binding site. We aimed to investigate the plasticity of the spike protein by propagating wild-type SARS-CoV-2 in the presence of class 3 antibody S309. After 12 weeks, we obtained a viral strain that was completely resistant to inhibition by S309, due to successively evolving amino acid exchanges R346S and P337L located in the paratope of S309. The antibody lost affinity to receptor-binding domains carrying P337L or both amino acid exchanges, while ACE2 binding was not affected. The resistant strain replicated efficiently in human CaCo-2 cells and was more susceptible to inhibition of fusion than the original strain. Overall, SARS-CoV-2 escaped inhibition by class 3 antibody S309 through a slow, but targeted evolution enabling immune escape and altering cell entry. This immune-driven enhancement of infectivity and pathogenicity could play an important role in the future evolution of SARSCoV-2, which is under increasing immunological pressure from vaccination and previous infections

Bacterial contamination rates in extracorporeal photopheresis

BACKGROUND Extracorporeal photopheresis (ECP) is an immunosuppressive treatment that involves leukocyte apheresis, psoralen and UV light treatment, and subsequent reinfusion. Patients treated with ECP are usually immunosuppressed. Bacterial contamination therefore poses a much unwanted risk, but incidence data are lacking. PATIENTS AND METHODS We screened all 1922 consecutive ECP procedures scheduled within a roughly 3-year period for eligibility. Those with missing data on ECP method (inline or offline) or type of venous access (peripheral or central) were excluded. ECPs with complete aerobic and anaerobic microbial testing of baseline patient blood samples (n = 1637) and of ECP cell concentrates (n = 1814) were included in the analysis. RESULTS A test for microbial contamination was positive for 1.82% of the cell concentrates, with central venous access was the most significant risk factor for the contamination (odds ratio = 19). Patient blood samples were positive in 3.85% of cases, but no patients became septic. Staphylococcus spp. were most abundant, and products with bacterial contamination did not cause side effects after reinfusion. There were no significant differences in contamination rates between inline and offline ECP. CONCLUSION These findings stress the importance of sterile procedures and the benefits of using peripheral over central venous access for reducing the risk of bacterial contamination in ECP

Association between Reactogenicity and Immunogenicity after Vaccination with BNT162b2

It is not clear whether there is an association between adverse reactions and immune response after vaccination. Seven hundred and thirty-five vaccinees from our University Medical Center vaccination clinic provided information about sex, age and adverse reactions after first and second vaccination with BNT162b2. Adverse reactions were categorized into three groups: no or minor on the injection side, moderate (not further classified) and severe—defined as any symptom(s) resulting in sick leave. We chose 38 vaccinees with the most severe adverse reactions and compared their humoral and T-cell-mediated immune responses after second vaccination with those of 38 sex and age matched controls without or only minor injection-side related adverse reactions. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-receptor binding domain (RBD) IgG titers were detectable in all participants (median 5528; range 958–26,285). Men with severe adverse reactions had 1.5-fold higher median SARS-CoV-2 RBD IgG titers compared to men without adverse reactions (median 7406 versus 4793; p < 0.001). Similarly; neutralization activity was significantly higher in men with severe adverse reactions (half maximal inhibitory concentrations (IC50) median 769 versus 485; p < 0.001). Reactogenicity did not influence humoral immune response in women nor T-cell-mediated immune response in any sex. To conclude; adverse reactions after vaccination with BNT162b2 do influence humoral immune response yet only in men and are not a prerequisite for a robust antibody response