Infection rates and tolerability of three different immunoglobulin administration modalities in patients with primary immunodeficiency diseases

Aim: This post hoc analysis evaluated the efficacy and overall tolerability of immunoglobulin (Ig) treatment modalities (intravenous Ig [iv.Ig], subcutaneous Ig [sc.Ig] and facilitated sc.Ig [fsc.Ig]). Materials & methods: A total of 30 participants with primary immunodeficiency diseases aged ≥2 years sequentially received iv.Ig, sc.Ig and fsc.Ig during consecutive clinical studies. Results: For iv.Ig, sc.Ig and fsc.Ig, rates of validated acute serious bacterial infections/participant-year (0, 0.09 and 0.04, respectively) and all infections/participant year (4.17, 3.68 and 2.42, respectively) were similarly low; rates of systemic and local causally related adverse events/participant-year were 5.60, 1.93 and 0.88, respectively and 0.13, 0.92 and 1.57, respectively. Conclusion: fsc.Ig provided similar efficacy to iv.Ig and sc.Ig. Clinical Trial registration: NCT00546871 , NCT00814320 , NCT01175213 (ClinicalTrials.gov)

43 The Prevalence of Serious Bacterial Infections in Infants less than 90 Days with and without Features of a Viral Infection: A Retrospective Cohort Study

Primary Subject area Emergency Medicine - Paediatric Background Prior studies suggest the prevalence of serious bacterial infections (SBI) (i.e., urinary tract infection [UTI], bacteremia, or meningitis) is lower in infants with a viral infection compared to those with fever without a source (FWS) (2-3% vs. 10-15%). Objectives To determine the difference in proportion of SBI in infants with and without clinical features of a viral infection. Design/Methods A retrospective cohort study was done on a consecutive sample of infants ≤ 90 days seen at a pediatric ED over a 5-year period ending August 30, 2019. Eligible subjects had rectal temperatures ≥ 38°C, and had ≥ 1 screening test for SBI (urine, blood and/or cerebrospinal fluid cultures). Excluded were infants who received antibiotics in the past 7 days, had congenital anomalies, required intensive care, or were preterm. We defined a clinical viral infection as > 1 clinical features of a respiratory viral infection (new-onset sneezing, cough, rhinorrhea, or shortness of breath). UTI was defined as per American Academy of Pediatrics guidelines. Results We screened 7021 charts and 885 (12%) were eligible. Of these, 498 (56%) had a clinical viral infection and 387 (44%) did not. Blood and urine cultures were collected from 860 (97%) infants and 308 (35%) had a lumbar puncture. Overall, 84 (10%) infants had an SBI: 76 (9%) UTI, 6 (0.7%) isolated bacteremia, and 2 (0.2%) meningitis. Among those with clinical viral infection, 23 (5%) had SBI, compared to 61 (16%) without viral infection (risk difference [RD] 11%, 95% CI [7%, 15%]). Both cases of meningitis occurred in infants ≤28 days and without any viral symptoms. A logistic regression was done to ascertain the effects of clinical viral infection, known risk factors for sepsis, age ≤ 28 days, or a temperature ≥ 39°C on the likelihood of SBI. Of the 4 predictors, only clinical viral infection and the presence of known risk factors for sepsis were significantly associated with SBI (odds ratio [OR] 0.3, 95% CI [0.17, 0.48] and 2.5, 95% CI [1.4, 4.5], respectively). Proportions of contaminated blood culture and urine culture were 5% (95% CI [4%, 7%]) and 14% (95% CI [12%, 17%]), respectively. Conclusion SBI prevalence in infants without features of a viral infection on assessment is triple that of infants with viral symptoms. Contaminant blood and urine cultures are folds higher than true pathological cultures. Future research is needed to identify infants at low risk of SBI without invasive testing.

Structures of full-length VanR from Streptomyces coelicolor in both the inactive and activated states

Vancomycin has historically been used as a last-resort treatment for serious bacterial infections. However, vancomycin resistance has become widespread in certain pathogens, presenting a serious threat to public health. Resistance to vancomycin is conferred by a suite of resistance genes, the expression of which is controlled by the VanR–VanS two-component system. VanR is the response regulator in this system; in the presence of vancomycin, VanR accepts a phosphoryl group from VanS, thereby activating VanR as a transcription factor and inducing expression of the resistance genes. This paper presents the X-ray crystal structures of full-length VanR from Streptomyces coelicolor in both the inactive and activated states at resolutions of 2.3 and 2.0 Å, respectively. Comparison of the two structures illustrates that phosphorylation of VanR is accompanied by a disorder-to-order transition of helix 4, which lies within the receiver domain of the protein. This transition generates an interface that promotes dimerization of the receiver domain; dimerization in solution was verified using analytical ultracentrifugation. The inactive conformation of the protein does not appear intrinsically unable to bind DNA; rather, it is proposed that in the activated form DNA binding is enhanced by an avidity effect contributed by the receiver-domain dimerization.

Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes.