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Efficacy and safety of individualised versus standard 10-day antibiotic treatment in children with febrile urinary tract infection (INDI-UTI): a pragmatic, open-label, multicentre, randomised, controlled, non-inferiority trial in Denmark
Authors: Sethi, Naqash Javaid et al.
Abstract
Background: The optimal antibiotic duration for febrile urinary tract infection (UTI) in children remains uncertain. We aimed to assess whether individualised treatment was non-inferior to standard 10-day treatment in terms of recurrent UTI and superior in reducing overall antibiotic exposure.
Methods: INDI-UTI was a pragmatic, open-label, multicentre, randomised, controlled, non-inferiority trial conducted at eight Danish hospitals. Children aged 3 months to 12 years who were febrile (≥38°C), within 24 h of treatment start, and with significant growth of uropathogenic bacteria were randomly assigned (1:1) using a web-based module with randomly permuted blocks to individualised or standard 10-day treatment. Main exclusion criteria included known urinary tract abnormalities, complicated medical history, bacteraemia, and elevated serum creatinine. The individualised group stopped treatment 3 days after adequate clinical improvement (ie, absence of fever, flank pain, and dysuria), with a minimum treatment duration of 4 days. The primary outcomes were recurrent UTI within 28 days after treatment cessation (non-inferiority margin 7·5 percentage points) and total antibiotic days within 28 days of treatment initiation (superiority assessment). No sample size calculation was performed for the assessment of total antibiotic days. Safety was assessed in all included patients. Main analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05301023.
Findings: Between March 28, 2022, and March 3, 2024, 694 patients were assessed for eligibility and 408 patients were randomly assigned to individualised (n=205; median antibiotic duration 5·3 days [IQR 4·8 to 6·5]) or standard 10-day treatment (n=203; 10·0 days [10·0 to 10·0]). Median age was 1·5 years (IQR 0·7 to 5·4), and there were 326 (80%) female and 82 (20%) male participants. Recurrent UTI within 28 days occurred in 23 (11%) of 205 patients in the individualised group and 12 (6%) of 203 patients in the standard 10-day group (difference 5·3 percentage points, one-sided 97·5% CI –∞ to 11·1, pnon_inferiority=0·24). Total antibiotic days within 28 days were 6·0 (IQR 5·3 to 7·5) in the individualised group and 10·0 (10·0 to 10·0) in the standard 10-day group (median difference –4·0 days [97·5% CI –4·5 to –3·7], p<0·0001). The incidence rate of antibiotic-related adverse events within 28 days was 6·8 per 100 patient-days in the individualised group and 11·1 per 100 patient-days in the standard 10-day group (rate ratio 0·61 [95% CI 0·47 to 0·80], p=0·0003). Serious adverse events occurred in 17 (8%) of 205 patients in the individualised group and 15 (7%) of 203 patients in the standard 10-day group (difference 0·9 percentage points [95% CI –4·6 to 6·5], p=0·79).
Interpretation: Children with febrile UTI assigned to individualised treatment duration had an increased risk of recurrent UTI (by 5·3 percentage points) but reduced antibiotic use and fewer adverse event days within 28 days compared with those assigned to standard 10-day treatment. These findings highlight the potential of individualised treatment strategies to reduce antibiotic exposure and associated harms in most children with febrile UTI, supporting antimicrobial stewardship goals. Further research is needed to identify those requiring 10-day treatment to avoid compromising care for most children with febrile UTI who respond well to shorter durations.
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Rates of infection with other pathogens after a positive COVID-19 test versus a negative test in US veterans (November, 2021, to December, 2023): a retrospective cohort study
Authors: Cai, Miao et al
Abstract
Background: SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system, including the immune system. However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens.
Methods: We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023. We first did a discovery approach to map the associations between those with a positive COVID-19 test versus a negative test and laboratory-based outcomes of infectious illnesses. We then compared rates of a prespecified set of infectious disease outcomes between those with and without a positive COVID-19 test. To evaluate the specificity of the findings to COVID-19, we compared the rates of a prespecified set of infectious disease outcomes in a spatiotemporally aligned cohort of people admitted to hospital for COVID-19 (n=12 450) versus those admitted for seasonal influenza (n=3293). Outcomes were ascertained 30 days after the date of the first test until the end of follow-up (365 days after the first test plus 30 days, death, or July 18, 2024, whichever came first). An inverse probability weighting approach was used to balance demographic and health characteristics across cohorts. Log-binomial regression models were used to estimate risk ratios (RRs) and 95% CIs.
Findings: In the 12 months of follow-up, compared with participants who had a negative test for COVID-19, people with COVID-19 who did not require admission to hospital during the acute phase of infection had increased test positivity rates for bacterial infections (in blood, urine, and respiratory cultures) and viral diseases (including Epstein–Barr virus, herpes simplex virus reactivation, and respiratory viral infections). People who were positive for COVID-19 and admitted to hospital also had increased rates of bacterial infections in blood, respiratory, and urine biospecimens, and viral infections in blood and respiratory biospecimens. Analyses of prespecified outcomes showed that, compared with the test-negative control group, participants with a positive COVID-19 test who were not admitted to hospital had significantly increased rates of outpatient diagnosis of infectious illnesses (RR 1·17 [95% CI 1·15–1·19]), including bacterial, fungal, and viral infections; outpatient respiratory infections (1·46 [1·43–1·50]); and admission to hospital for infectious illnesses (1·41 [1·37–1·45]), including for sepsis and respiratory infections; the rates of prespecified outcomes were generally higher among those who were admitted to hospital for COVID-19 during the acute phase. Compared with people admitted to hospital for seasonal influenza, those admitted for COVID-19 had higher rates of admission to hospital for infectious illnesses (1·24 [1·10–1·40]), admission to hospital for sepsis (RR 1·35 [1·11–1·63]), and in-hospital use of antimicrobials (1·23 [1·10–1·37]).
Interpretation: Our results suggest that a positive test for COVID-19 (vs a negative test) was associated with increased rates of diagnosis of various infections in the 12 months following an acute SARS-CoV-2 infection. The putative long-term effects of COVID-19 on the immune system and the propensity for infection with other pathogens should be further evaluated in future studies.
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“What am I?” Microbiology of Culture-Positive, BioFire® Blood Culture Identification 2 Panel-Negative Bloodstream Infections
Authors: Joseph Berger
Abstract
Background: The BioFire® blood culture identification 2 panel (BCID2) detects 33 of the most common bloodstream infection (BSI) pathogens, yet it can fail to detect the causal agent of sepsis in up to 13% of cases, mostly due to infections caused by off-panel target microorganisms. A better understanding of the microbiology of culture-positive, BCID2-negative BSI is needed.
Methods: Single-center, retrospective study of microbiology and outcomes in 275 cases of BCID2-negative BSI between 2022 and 2024.
Results: A total of 257 adult patients with 275 cases of culture-positive, BCID2-negative BSI were analyzed. Viable organisms were identified in 95.2% of the cases. False negative results (i.e., in-BCID2 panel target microorganism) occurred at 3.3% and corresponded mostly to Candida spp. (67%). Although microorganisms considered of low clinical significance accounted for more than a third of the cases, off-BCID2 panel, clinically relevant microorganisms identified by culture included Bacteroides spp. (other than B. fragilis; 12%), Clostridium spp. (5.8%), Candida spp. (4.4%), Achromobacter xylosoxidans, Pasteurella multocida, Trichosporon asahii, Fusarium spp., Rhodococcus equi, Capnocytophaga spp., and Burkholderia cepacia, among others. Only 116 (42%) were on appropriate antibiotic therapy at the time of BCID2 result. 30-day mortality was 24% in the entire cohort, but as high as 33%, 44%, and 42% for Bacteroides spp., Clostridium spp. and Candida BSI, respectively.
Conclusions: These results highlight the limitations of the BCID2 panel (e.g., need for inclusion of pan-Bacteroides and Clostridium spp., and optimization of sensitivity for Candida spp.); and provide useful insights on the most common causes of BCID2-negative BSI.
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Prevalence, genomic features, and antibiotic sensitivities of Neisseria meningitidis isolates from patients with invasive meningococcal disease and healthy carriers in Zhejiang Province, 2015-2023
Authors: Torre-Cisneros
Abstract
Objective: A comprehensive understanding of invasive meningococcal disease (IMD) and healthy carriers is critical to monitor, control, and prevent the disease. This study investigated the epidemiology of IMD cases and carriage, and compared population-specific genetic variations and antimicrobial susceptibility of Neisseria meningitidis (N. meningitidis) strains isolated from patients with IMD and carriers.
Methods: Surveillance data from 2015 to 2023 on patients with epidemic meningitis and healthy carriers in Zhejiang Province, China. We successfully collected 21 isolates from healthy individuals and 16 isolates from meningitis patients during this period. Serogroups of a total of 37 N. meningitidis isolates were determined by polymerase chain reaction (PCR) and slide agglutination, as well as whole genome sequencing to assess various genes, single nucleotide polymorphisms (SNPs), and core-pan genome differences. The antibiotic susceptibility of 37 isolates to 12 antibiotics was evaluated using the E-Test on Mueller-Hinton agar supplemented with 5% sheep blood.
Results: The annual incidence of IMD and carriage rates remained relatively low from 2015-2023. IMD cases were primarily observed in infants under 12 months-of-age. Healthy carriers were predominantly 5-9 and 30-59 years-of-age. Population gene analysis revealed no significant difference in genes between the two groups. Strains of patient and carrier groups were both highly resistant to quinolones and sulfonamides.
Conclusions: The findings enhance the understanding of N. meningitidis carriage in the context of prevalent invasive meningococcal strains. The findings will facilitate the development and updating of the immunization program of meningitis vaccine, and are critical in understanding the spread and drug use strategies of N. meningitidis.
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Immunogenicity and safety of an Escherichia coli-produced bivalent human papillomavirus vaccine (Cecolin) in girls aged 9–14 years in Ghana and Bangladesh: a randomised, controlled, open-label, non-inferiority, phase 3 trial
Authors: Agbenyega, Tsiri et al
Abstract
Background: Human papillomavirus (HPV) vaccines have been available for nearly 20 years. However, the overall coverage of girls aged 15 years and younger is low, especially in low-resource settings, where the burden of cervical cancer is highest. Increasing access and facilitating implementation of HPV vaccination will contribute to cervical cancer elimination efforts. To generate data in different dosing regimens and in low-resource settings, we aimed to evaluate the safety and immunogenicity of various schedules of an Escherichia coli-expressed bivalent HPV vaccine (2vHPV) compared with a widely used quadrivalent vaccine.
Methods: This randomised, controlled, open-label, non-inferiority, phase 3 trial enrolled healthy girls aged 9–14 years from single sites in Ghana and Bangladesh. Participants were randomly assigned via interactive web response system technology equally into five study groups, stratified by site: two doses of 2vHPV, the first at baseline and the second 6, 12, or 24 months later; a quadrivalent HPV vaccine (4vHPV) at baseline followed 24 months later by 2vHPV; or two doses of 4vHPV given 6 months apart (referent). We tested for antigen-specific (HPV-16 and HPV-18) binding antibodies by ELISA at baseline and before and 1 month after the second dose. The primary objective was to show immunological non-inferiority of the 2vHPV vaccine schedules to the referent 1 month after the second dose in the per-protocol population, with a non-inferiority margin of 0·5 for the lower bound of the 98·3% CI for the geometric mean concentration (GMC) ratio. Adverse events and serious adverse events were evaluated as secondary endpoints in the total vaccinated population. The study is registered at ClinicalTrials.gov (NCT04508309) and is completed.
Findings: Between March 15 and Nov 18, 2021, 1025 girls were enrolled and received 2vHPV at baseline and 6 months (n=205), 12 months (n=206), or 24 months (n=204); 4vHPV at baseline and 6 months (n=205); or 4vHPV at baseline and 2vHPV at 24 months (n=205). 96–99% of participants across groups were included in the per-protocol analysis. 1 month after the second dose, 2vHPV non-inferiority was shown, with GMC ratios between 1·1 and 2·4 (lower bound of the 98·3% CI of the GMC ratio between 0·9 and 1·9) for HPV-16, and between 1·3 and 1·7 (1·0 and 1·4) for HPV-18. As an exploratory objective, we assessed 2vHPV immunogenicity after one dose, finding that it was similar to that of 4vHPV up to 24 months, with GMC ratios at 24 months of 1·1 (95% CI 0·9–1·4) for HPV-16 and 1·4 (1·1–1·7) for HPV-18. The frequency of adverse events was similar across study groups, with no related unsolicited events reported. Serious adverse events were rare and none were determined to be related to vaccination.
Interpretation: Non-inferior immune responses for extended two-dose regimens of 2vHPV support dosing flexibility. For up to 24 months, one dose of 2vHPV elicited immunogenicity that was similar to one dose of 4vHPV, for which single-dose efficacy has been shown, supporting a single-dose use of 2vHPV.
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Management of Carbapenem Resistant Gram-Negative Infections.
Authors: Krishna V
Abstract
Due to increasing carbapenem usage, resistance to gram negative bacteria is steadily going up in India. Resistance is often enzyme-mediated and transmissible horizontally by plasmids. Use of invasive lines, procedures, prior antibiotic exposure, recent hospitalization, ICU stay, colonization and severity of illness are important risk factors for infections with these bacteria. Before starting therapy, it is important to distinguish colonization from true infection. Early targeted therapy using rapid diagnostic methods is important to ensure optimal outcomes. A growing body of literature recommends the use of novel beta lactam-beta lactamase inhibitors over polymyxins in the management of these infections. Treatment strategies for carbapenem resistant Enterobacterales differs from non-Enterobacterales and is discussed in detail in this review. Infection control and antimicrobial stewardship are crucial preventive measures to curb the emergence of further resistance.
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Epidemiology and Clinical Impact of Vancomycin-Resistant Enterococcus at King Abdulaziz University Hospital (2015-2022): Prevalence, Risk Factors, and Mortality.
DOI: 10.2147/ijgm.s508262
Authors: Mokhtar JA et al
Abstract
Background: Enterococcus faecalis and Enterococcus faecium are part of the human microbiota but pose significant risks in clinical settings due to increasing antimicrobial resistance. Vancomycin-resistant enterococci (VRE) are a growing concern, linked to high morbidity and mortality in hospitalized patients.
Aim: This study is the first comprehensive investigation of VRE prevalence and associated risk factors at King Abdulaziz University Hospital (KAUH) from 2015 to 2022.
Methods: Clinical samples were collected, and VRE isolates were identified using VRE Card GeneXpert, BioFire PCR, and the VITEK 2 system. Descriptive statistical analysis with Stata version 17 summarized patient characteristics, including demographics, comorbidities, hospital exposure, and laboratory findings. Categorical variables were reported as frequencies/percentages, while continuous variables were expressed as mean ± SD or median [IQR].
Results: Among 254 adult patients with VRE infections, the median age was 61 years. The most common comorbidities were diabetes, hypertension, and kidney disease. VRE infections peaked in 2021, with urine cultures being the most frequent source. Most patients had prior antibiotic exposure, particularly to vancomycin and carbapenems. Enterococcus faecium was the predominant species, with the VanA phenotype being most common. Alarmingly, 61.8% of VRE-infected patients died during the study period.
Conclusion: These findings underscore the critical need for enhanced infection control measures and antimicrobial stewardship to combat VRE and improve patient outcomes.
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Gallium nitrate inhibits multidrug-resistant Acinetobacter baumannii isolated from bloodstream infection by disrupting multiple iron-dependent metabolic processes.
Authors: Yao Z et al
Abstract
Background: Acinetobacter baumannii is a major pathogen in hospitals, causing a notable rise in bloodstream infections among inpatients. Its growing resistance to multiple drugs limits treatment options. This study aims to examine the antibacterial effects of gallium nitrate [Ga(NO3)3] against A. baumannii and elucidate the underlying molecular mechanism.
Methods: 40 strains of A. baumannii with different antimicrobials susceptibility patterns were isolated from bloodstream infections. The in vitro antibacterial activity of Ga(NO3)3 was analyzed by micro-dilution method and time-kill assay. The influence of ferric chloride/hemin on the antibacterial efficacy of Ga(NO3)3 was investigated. Transcriptome sequencing was performed to elucidate the antibacterial mechanism of Ga(NO3)3. A mouse infection model was conducted to assess its in vivo performance.
Results: Ga(NO3)3 exhibited a potent antibacterial effect in RPMI 1640 medium containing 10% human serum, with MICs ranging from 0.06 μg/mL to 0.125 μg/mL. The antibacterial activity of Ga(NO3)3 was found to be dose- and time- dependent. However, the antibacterial effect of Ga(NO3)3 was partially compromised in the presence of exogenous ferric chloride/hemin. Transcriptomics analysis revealed that Ga(NO3)3 exerted its antibacterial effect by up-regulating the expression of genes associated with siderophore biosynthesis and transport, while simultaneously disrupting multiple iron-dependent metabolic processes. Ga(NO3)3 treatment significantly reduced bacterial load in vivo using a neutropenic mouse thigh infection model.
Conclusion: This study sheds light on the antibacterial mechanisms of Ga(NO3)3 against A. baumannii, suggesting its potential as a promising antibacterial drug for treating bloodstream infections caused by multidrug-resistant A. baumannii.s.