Severe Infections Research Articles

Factors associated with the development, severity, and resolution of post COVID-19 condition in adults living in Canada, January 2020 to August 2022.

We aimed to characterize the burden of post COVID-19 condition (PCC) among adults in Canada and identify factors associated with its occurrence, severity, and resolution. We used self-report data from a population-based cross-sectional probability survey of adults in Canada conducted between April and August 2022. Incidence and prevalence of PCC were estimated using confirmed infections, as well as confirmed and suspected combined. Multivariable modeling using confirmed cases identified associated factors. As of August 2022, 17.2% (95% CI 15.7, 18.8) of adults with confirmed infections and 16.7% (95% CI 15.5, 18.0) of adults with confirmed or suspected infections experienced PCC, translating to 3.3% (95% CI 3.0, 3.6) and 4.4% (95% CI 4.1, 4.8) of all adults, respectively. Age less than 65years (aORs of 1.75 to 2.14), more pre-existing comorbidities (aORs of 1.75 to 3.57), and a more severe initial infection (aORs of 3.52 to 9.69) were all associated with higher odds of PCC, while male sex at birth (aOR = 0.54, 95% CI 0.41, 0.70), identifying as Black (aOR = 0.23, 95% CI 0.11, 0.51), and being infected after 2020 (aORs of 0.24 to 0.55) were associated with lower odds. Those residing in a rural area (aOR = 2.31, 95% CI 1.35, 3.93), or reporting a disability (aOR = 2.87, 95% CI 1.14, 7.25), pre-existing chronic lung condition (aOR = 5.47, 95% CI 1.85, 16.12) or back problem (aOR = 2.34, 95% CI 1.26, 4.36), or PCC headache (aOR = 2.47, 95% CI 1.60, 3.83) or weakness (aOR = 2.27, 95% CI 1.41, 3.68) had higher odds of greater limitations in daily activities, while males had lower odds (aOR = 0.54, 95% CI 0.34, 0.85). Two or more pre-existing chronic conditions (aHRs from 0.33 to 0.38), or PCC symptoms relating to the heart (aHR = 0.25, 95% CI 0.07, 0.90), brain fog (aHR = 0.44, 95% CI 0.23, 0.86), or stress/anxiety (aHR = 0.48, 95% CI 0.24, 0.96) were associated with a decreased rate of symptom resolution. Over the first two and a halfyears of the pandemic, a substantial proportion of infected adults in Canada reported PCC. Females and people with comorbidities were disproportionately impacted.

γδ T Cells Mediate Protection against Neutrophil-associated Lung Inflammation in Pulmonary Melioidosis.

Pulmonary melioidosis is a severe tropical infection caused by Burkholderia pseudomallei and is associated with high mortality, despite early antibiotic treatment. γδ T cells have been increasingly implicated as drivers of the host neutrophil response during bacterial pneumonia, but their role in pulmonary melioidosis is unknown. Here, we report that in patients with melioidosis, a lower peripheral blood γδ T-cell concentration is associated with higher mortality, even when adjusting for severity of illness. γδ T cells were also enriched in the lung and protected against mortality in a mouse model of pulmonary melioidosis. γδ T-cell deficiency in infected mice induced an early recruitment of neutrophils to the lung, independent of bacterial burden. Subsequently, γδ T-cell deficiency resulted in increased neutrophil-associated inflammation in the lung as well as impaired bacterial clearance. In addition, γδ T cells influenced neutrophil function and subset diversity in the lung after infection. Our results indicate that γδ T cells serve a novel protective role in the lung during severe bacterial pneumonia by regulating excessive neutrophil-associated inflammation.

Construction and validation of a mouse model for studying severe human adenovirus infections

Human adenoviruses (HAdVs) are highly contagious pathogens with various genotypes implicated in acute respiratory disease (ARD) and linked to mortality, especially in immunosuppressed patients, young children, and military recruits. Currently, no vaccines or specific drugs are approved for clinical use. The hosts of adenoviruses are strictly species-specific, which strongly limits the development of vaccines and drugs against HAdVs. In this study, immunocompetent BALB/c mice were challenged with different doses of human adenovirus type 5 (HAdV-5) via tail intravenous injection (i.v.). All mice challenged with a high dose of HAdV-5 (3.2×1010 TCID50/kg) died within 3 to 5 days, while those receiving a low dose of HAdV-5 (8×109 or 4×109 TCID50/kg) survived. Interestingly, among the mice receiving a medium dose of HAdV-5 (1.6×1010 TCID50/kg), 60% (n = 3/5) of male mice died, while all female mice survived. This suggests that male mice may be more susceptible to HAdV-5 infection than female mice, consistent with clinical findings in children. HAdV-5 DNA was mainly distributed in the liver, followed by the spleen and lungs. Pathological changes were observed in the lungs, liver, and spleen, with severity increasing in correlation with the virus challenge dosage. Transcriptome and qPCR analyses of the liver indicated that the down-regulated expression of the H2-Aa, H2-Ea-ps, CD74, and H2-Eb1 genes in male mice, as well as the AHR gene in female mice, may contribute to the observed higher mortality rates in male mice. Therefore, this effective, feasible, and cost-efficient mouse model could serve as a candidate for evaluating HAdV vaccines and anti-adenovirus therapeutics.

Intrapartum antibiotic exposure and infectious diseases in childhood – a population-based cohort study

Intrapartum antibiotics are used to prevent group B streptococcus disease in newborn infants. We hypothesised that intrapartum antibiotic exposure is associated with the occurrence of childhood infectious diseases because it influences the development of the gut microbiome. The cohort for this population-based study comprised vaginally delivered children born in Northern Finland in 2007-2018. We used structured electronic medical records linked to comprehensive national registers. Primary outcome was the number of infectious disease episodes leading to an emergency room visit, outpatient hospital visit, or hospitalisation from birth until five years of age. Analyses were performed on 9733 children (48.8% girls) exposed to intrapartum antibiotics and on 35,842 unexposed children (49.9% girls). Exposure to intrapartum antibiotics was associated with increased risk of any infectious disease episode at the ages 7-28 days (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.10-1.54) and 1-2 years (aIRR 1.10, 95% CI 1.02-1.18). The occurrence of urinary tract infections was associated with the exposure to intrapartum antibiotics whereas the occurrence of severe infections caused by pathogens susceptible to penicillin was reversely associated with the exposure to intrapartum antibiotics. Maternal intrapartum antibiotics were associated with the occurrence of infectious diseases in the offspring. The observed associations appeared to depend on bacterial pathogens and their antimicrobial susceptibility to penicillin. Pediatric Research Foundation, Alma och K.A. Snellman Foundation, Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Medical Foundation, Academy of Finland, Finland.

Maintenance immunosuppressive therapy in liver transplantation: results from CESIT study, an Italian retrospective cohort study

ObjectivesTo investigate the use of maintenance immunosuppressive treatments following liver transplantation and to compare their risk–benefit profiles in clinical practice.DesignRetrospective multicentrer cohort study.SettingFour Italian regions (Lombardy, Veneto, Lazio, Sardinia).MethodsData were...

Mucus-Penetrable Biomimetic Nanoantibiotics for Pathogen-Induced Pneumonia Treatment.

Bacterial pneumonia has garnered significant attention in the realm of infectious diseases owing to a surge in the incidence of severe infections coupled with the growing scarcity of efficacious therapeutic modalities. Antibiotic treatment is still an irreplaceable method for bacterial pneumonia because of its strong bactericidal activity and good clinical efficacy. However, the mucus layer forming after a bacterial infection in the lungs has been considered as the "Achilles' heels" facing the clinical application of such treatment. Herein, traceable biomimetic nanoantibiotics (BioNanoCFPs) were developed by loading indacenodithieno[3,2-b]thiophene (ITIC) and cefoperazone (CFP) in nanoplatforms coated with natural killer (NK) cell membranes. The BioNanoCFP exhibited excellent demonstrated mucus-penetrating abilities, facilitating their arrival at the infection site. The presence of Toll-like receptors in the NK cell membrane rendered the BioNanoCFP with the capability to recognize pathogen-associated molecular patterns within bacteria, allowing precise targeting of bacterial colonization sites and achieving substantial therapeutic efficacy. Overall, our findings demonstrate the viability and desirability of using NK cell membrane-mediated drug delivery as a promising strategy for precision treatment.

Cilgavimab and tixagevimab as pre-exposure prophylaxis in vaccine non-responder kidney transplant recipients during a period of prevalent SARS-CoV-2 BA.2 and BA.4/5 variants—a prospective cohort study (RESCUE-TX)

The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation. We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral invitro neutralization tests of patient sera. Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. Invitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR=0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR=0.37, 95% CI 0.17-0.79). This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5. This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585).

Prospective Attitudes Towards Respiratory Syncytial Virus (RSV) Vaccine in Pregnant Women in Greece

Respiratory Syncytial Virus (RSV) is a common respiratory pathogen with high morbidity and mortality, especially in children under two years of age. Severe RSV infection poses a significant threat to healthcare systems, making vaccination an utmost need. In August 2023, the U.S. FDA approved an RSV maternal vaccine to prevent lower respiratory tract disease (LRTD) in infants throughout their first six months of life. This cross-sectional survey was designed to evaluate pregnant women’s willingness to receive the vaccine during pregnancy. An anonymous survey was administered from April 2023 to December 2023 to pregnant women aged above 16 years old attending gynecology wards of randomly selected public and private hospitals in Crete. The primary outcome was the intention to receive the vaccine. Univariable and multivariable analyses were carried out to identify factors associated with the intention to get vaccinated. Questionnaires were distributed to a sample of 335 pregnant females who agreed to participate in this study. The intention to get vaccinated against RSV was positively associated with educational level, the presence of school-age children, RSV infection awareness, intention to get routine pregnancy vaccines according to the National Immunization Program (NIP), and previous vaccination against COVID-19. The majority of pregnant females were not familiar with the term RSV and the upcoming vaccine. An educational campaign regarding RSV infection and its vaccine is required to improve women’s perceptions and to support healthcare workers in promoting it upon its availability in Greece.

Hypersomnia secondary to severe acute respiratory syndrome coronavirus-2 infection

Excessive daytime sleepiness (EDS), with or without an excessive need for sleep, is a primary reason for patients seeking consultation at the sleep unit. EDS is observed in ~5% of the general population. Common causes of EDS include obstructive sleep apnea, sleep deprivation, effects of medication, psychiatric disease (especially depression), and circadian rhythm disorders. Coronavirus disease 2019 (COVID-19) infection is a rare cause of EDS. We present a case of mild COVID-19 infection as an unusual cause of hypersomnolence.

Leptin signaling maintains autonomic stability during severe influenza infection in mice.

Leptin signaling maintains autonomic stability during severe influenza infection in mice.

PARP15 is a Susceptibility Locus for Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome).

Vascular leakage is a deadly complication of severe infections, ranging from bacterial sepsis to malaria. Worldwide, septicemia is among the top 10 causes of lethality because of the shock and multiorgan dysfunction that arise from the host vascular response. In the monoclonal gammopathy-associated capillary leak syndrome (MG-CLS), even otherwise mundane infections induce recurrent septic-like episodes of profound microvascular hyperpermeability and shock. There are no defined genetic risk factors for MG-CLS or effective treatments for acute crises. We characterized predicted loss-of-function mutations in PARP15 (poly[ADP-ribose] polymerase 15), a protein of unknown function that is absent in mice, in patients with MG-CLS. We analyzed barrier function in PARP15-deficient vascular endothelial cells and vascular leakage in mice engineered to express WT or loss-of-function variant human PARP15. We discovered several loss-of-function PARP15 variants associated with MG-CLS. These mutations severely reduced PARP15 enzymatic function. The presence of the most frequently detected variant (G628R) correlated with clinical markers of severe vascular leakage. In human microvascular endothelial cells, PARP15 suppressed cytokine-induced barrier disruption by ADP-ribosylating the scaffold protein JIP3 (c-Jun N-terminal kinase-interacting protein 3) and inhibiting p38 MAP kinase activation. Mice expressing enzymatically inactive human PARP15(G628R) were significantly more prone to inflammation-associated vascular leakage than mice expressing WT PARP15 in a p38-dependent fashion. PARP15 represents a previously unrecognized genetic susceptibility factor for MG-CLS. PARP15-mediated ADP ribosylation is an essential and genetically determined mechanism of the human vascular response to inflammation.

Streptococcus anginosus orchestrates antibacterial potential of NETs facilitating survival of accompanying pathogens

Streptococcus anginosus is considered an emerging opportunistic pathogen causing life-threatening infections, including abscesses and empyema. Noticeably, clinical data revealed that S. anginosus also constitutes an important component of polymicrobial infections. Here, we showed for the first time that S. anginosus inactivates the antibacterial potential of neutrophil extracellular traps (NETs). The process is determined by a cell wall-anchored nuclease referred to as SanA, which high expression dominates in clinical strains isolated from severe infections. Nuclease activity protects S. anginosus against the antibacterial activity of NETs, supporting at the same time the survival of coexisting highly pathogenic species of Enterobacteriales. Obtained data suggest that SanA nuclease should be recognized as a critical S. anginosus virulence factor determining severe monospecies purulent infections but also shielding other pathogens promoting the development of polymicrobial infections.

Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome

BackgroundNetherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency.MethodsVaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls.ResultsNone of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls.ConclusionsVaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.

HPV Vaccines

Human papillomavirus (HPV) is a double-stranded DNA virus and a source of infection that primarily affects the skin and mucous membranes. It can be transmitted through sexual contact and contaminated surfaces. There are over 200 genotypes of HPV, approximately 40 of which infect the anogenital region. High-risk HPV types, such as HPV-16 and HPV-18, can lead to the development of various cancers, particularly cervical cancer. Factors that increase the risk of transmission include having multiple sexual partners, early initiation of sexual activity, and having an uncircumcised male partner. Low socioeconomic status, poor nutrition, immunosuppression, and co-infections with HIV, genital herpes, or chlamydia can result in persistent and severe HPV infection. Three types of vaccines have been developed against HPV: bivalent, quadrivalent, and nonavalent vaccines. The bivalent vaccine provides protection against HPV-16 and HPV-18; the quadrivalent vaccine is effective against HPV-16, HPV-18, as well as HPV-6 and HPV-11. The nonavalent vaccine offers the broadest protection, covering nine different types of HPV. All vaccines are approved for males and females aged 9 and older. Vaccination before the onset of sexual activity significantly increases protection against cervical cancer.

Isoniazid Prophylaxis Based on Tuberculosis Risk Factors in Living Kidney Transplantation Recipients: A Retrospective Cohort Study

BackgroundTuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection (LTBI). However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain. MethodsThis study included all living-donor kidney transplant recipients (KTRs) between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with isoniazid (R-INH), the risk group without isoniazid (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed. ResultsA total of 1348 patients were divided into R-INH (n=108), R-NINH (n=371), and NR (n=869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (HR, 0.55, 95% CI, 0.07-4.21, P = 0.564), whereas it was significantly higher in R-NINH (HR, 5.04, 95% CI, 2.64-9.62, P < 0.001). The median time from transplantation to TB was 19 months (IQR: 6-39), and 18 patients (38.3%) were diagnosed within one year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%). ConclusionsA 6-month INH regimen based on TB risk factors is effective and well tolerated for preventing post-transplant TB in KTRs

Synthesis, Characterization and Biological Studies of Gemifloxacin Mesylate with Nickel(II) and Copper(II)

Gemifloxacin mesylate, a fourth-generation fluoroquinolone-type antibiotic, is widely used for community treatment of acquired pneumonia and severe bacterial infections. The Cu(II) and Ni(II) complexes of gemifloxacin mesylate were synthesized by refluxing an aqueous solution of the ligand with the required amount of metal(II) salts in a round bottom flask with 2:1 (L:M) ratio in an oil bath at 90 ºC with a continuous stirring for 4 h. The mixture was kept overnight to obtain a coloured solid complex. The synthesized metal(II) complexes were characterized by physico-chemical parameters and spectral analyses, including UV-Vis, FT-IR and 1H NMR. The structures of the complexes were further confirmed by elemental (CHNS) and TG-DTA analyses. The spectral findings revealed that metal-ligand interaction has successfully occurred where the ligand acted as a bidentate chelate in the synthesized metal(II) complexes. The IR studies showed that upon complexation the characteristic carboxylic stretching frequency at 1714 cm-1 disappeared and the pyridone stretching frequency shifted to a lower frequency region. The 1H NMR data of the complexes confirm the effective interaction between the metal and the ligand via 3-carboxyl group and 4-oxo groups. The thermal and elemental analyses data were also in agreement with the proposed interaction. The ligand as well as its metal(II) complexes showed significant activity against all the studied 11 bacterial strains and one of the fungal strains, Candida sp.

Large-scale genomic analysis of Elizabethkingia anophelis

The recent emergence of Elizabethkingia anophelis as a human pathogen is a major concern for global public health. This organism has the potential to cause severe infections and has inherent antimicrobial resistance. The potential for widespread outbreaks and rapid global spread highlights the critical importance of understanding the biology and transmission dynamics of this infectious agent. We performed a large-scale analysis of available 540 E. anophelis, including one novel strain isolated from raw milk and sequenced in this study. Pan-genome analysis revealed an open and diverse pan-genome in this species, characterized by the presence of many accessory genes. This suggests that the species has a high level of adaptability and can thrive in a variety of environments. Phylogenetic analysis has also revealed a complex population structure, with limited source-lineage correlation. We identified diverse antimicrobial resistance factors, including core-genome and accessory ones often associated with mobile genetic elements within specific lineages. Mobilome analysis revealed a dynamic landscape primarily composed of genetic islands, integrative and conjugative elements, prophage elements, and small portion of plasmids emphasizing a complex mechanism of horizontal gene transfer. Our study underscores the adaptability of E. anophelis, characterized by a diverse range of antimicrobial resistance genes, putative virulence factors, and genes enhancing fitness. This adaptability is also supported by the organism’s ability to acquire genetic material through horizontal gene transfer, primarily facilitated by mobile genetic elements such as integrative and conjugative elements (ICEs). The potential for rapid evolution of this emerging pathogen poses a significant challenge to public health efforts.

Large Clostridial Toxins: A Brief Review and Insights into Antigen Design for Veterinary Vaccine Development.

The group of large clostridial toxins (LCTs) includes toxins A (TcdA) and B (TcdB) from Clostridioides difficile, hemorrhagic and lethal toxins from Paeniclostridium sordellii, alpha toxin from Clostridium novyi (TcnA), and cytotoxin from Clostridium perfringens. These toxins are associated with severe pathologies in livestock, including gas gangrene (P. sordellii and C. novyi), infectious necrotic hepatitis (C. novyi), avian necrotic enteritis (C. perfringens), and enterocolitis (C. difficile). Immunoprophylaxis is crucial for controlling these diseases, but traditional vaccines face production challenges, such as labor-intensive processes, and often exhibit low immunogenicity. This has led to increased interest in recombinant vaccines. While TcdA and TcdB are well-studied for human immunization, other LCTs remain poorly characterized and require further investigation. Therefore, this study emphasizes the importance of understanding lesser-explored toxins and proposes using immunoinformatics to identify their immunodominant regions. By mapping these regions using silico tools and considering their homology with TcdA and TcdB, the study aims to guide future research in veterinary vaccinology. It also explores alternatives to overcome the limitations of conventional and recombinant vaccines, offering guidelines for developing more effective vaccination strategies against severe infections in animals.

Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice.

Antibacterial activity can be classified as either bactericidal or bacteriostatic, using methods such as the MBC/MIC ratio and time-kill curves. However, such categorization has proven challenging in clinical practice, as these definitions only apply under specific laboratory conditions, which may differ from clinical settings. Several factors, such as the specific bacteria or infectious medium, can affect the action of antibiotics, with many antibacterials exerting both activities. These definitions have also led to the belief that bactericidal antibacterials are superior to bacteriostatic, especially in more severe cases, such as endocarditis, neutropenia and bacteraemia. Additionally, current dogma dictates against the combination of bactericidal and bacteriostatic antibacterials in clinical practice, due to potential antagonism. This review aimed to assess the differences in antibacterial activity of bactericidal and bacteriostatic antibacterials based on in vitro and in vivo studies and examine their antagonistic or synergistic effects. Our findings show that specific bacteriostatic agents, such as linezolid and tigecycline, are clinically non-inferior to bactericidals in multiple infections, including pneumonia, intra-abdominal infections, and skin and soft tissue infections. Studies also support using several bacteriostatic agents as salvage therapies in severe infections, such as neutropenic fever and endocarditis. Additionally, not all combinations of bacteriostatic and bactericidal agents appear to be antagonistic, with many combinations, such as linezolid and rifampicin, already being used. The findings should be interpreted with caution, as most evidence is from observational studies and there is a need for randomized controlled trials to assess their effectiveness and combinations, especially within the context of rising antimicrobial resistance.

Evaluation of adenoviral vector Ad19a encoding RSV-F as novel vaccine against respiratory syncytial virus

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants and toddlers. Since natural infections do not induce persistent immunity, there is the need of vaccines providing long-term protection. Here, we evaluated a new adenoviral vector (rAd) vaccine based on the rare serotype rAd19a and compared the immunogenicity and efficacy to the highly immunogenic rAd5. Given as an intranasal boost in DNA primed mice, both vectors encoding the F protein provided efficient protection against a subsequent RSV infection. However, intramuscular immunization with rAd19a vectors provoked vaccine-enhanced disease after RSV infection compared to non-vaccinated animals. While mucosal IgA antibodies and tissue-resident memory T-cells in intranasally vaccinated mice rapidly control RSV replication, a strong anamnestic systemic T-cell response in absence of local immunity might be the reason for immune-mediated enhanced disease. Our study highlighted the potential benefits of developing effective mucosal against respiratory pathogens.