meningococcal AC/Haemophilus influenzae B type vaccine (Hi Becam / HibACon)

Synergistic biofilm formation by the coexistence of nontypeable Haemophilus influenzae and Moraxella catarrhalis reduces amoxicillin efficacy.

Umar Nafisa Khamis NK, Ueda Ryo R, Shiga Tatsuya T, Fujishiro Taku T et al.

Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis are recognized as the key pathogens that cause respiratory tract infections, and both are capable of forming biofilms. Although interspecies biofilm formation has been described, the impact of co-culture conditions on antimicrobial responsiveness remains incompletely defined. In this study, we examined biofilm formation by co-culturing NTHi and M. catarrhalis and evaluated their antimicrobial responsiveness to amoxicillin and alternative clinically relevant antibiotics, including sequential exposure following initial amoxicillin treatment, in an in vitro model. Biofilm formation was quantitatively evaluated using the crystal violet staining method with a 96-well pin replicator. Twenty clinical isolates of M. catarrhalis were first cultured for 24 h to assess their biofilm-forming capacities, which varied considerably among strains, with some producing robust biofilms. To further examine interspecies interactions, M. catarrhalis and NTHi were co-cultured at different CFU ratios, revealing that increasing the proportion of M. catarrhalis in the inoculum enhanced overall biofilm production compared with either species alone. Additionally, exposure to selected antibiotics showed that respiratory quinolones were associated with greater reductions in biofilm biomass and viable bacteria within co-culture-derived biofilms compared with amoxicillin, both during direct treatment and following prior amoxicillin exposure, under the experimental conditions tested. Co-culture of NTHi and M. catarrhalis was shown to significantly enhance biofilm formation compared with either culture species alone. In particular, a higher proportion of M. catarrhalis was associated with increased biofilm production. These findings suggest that polymicrobial coexistence may contribute to reduced antimicrobial responsiveness through enhanced biofilm formation.

Insights into amoxicillin pharmacokinetics using physiology-based pharmacokinetic modelling.

Darlow Christopher A CA, Dubey Vineet V, Reza Nada N, Hope William W

Amoxicillin is the most commonly used antibiotic globally. However, there is a relatively poor understanding of its pharmacokinetics, pharmacodynamics, and clinical pharmacology. We constructed a physiology-based pharmacokinetic (PBPK) model of amoxicillin to gain deeper insights into the adequacy of amoxicillin regimens for the treatment of infections relevant to global health. We constructed an amoxicillin PBPK model in PK-Sim using known ADME and physicochemical parameters, in vitro characterized transporter kinetics of amoxicillin with OAT3, and time-concentration data from the published literature. Unknown parameters were fitted using a subset of available clinical pharmacokinetic data for training, before final validation with a holdout data set. Population simulations were performed using the final model for a range of amoxicillin regimens and contexts. The final amoxicillin PBPK model was high performing by fold-error metrics for both plasma and urinary concentrations. Simulations demonstrated all regimens achieved the 40%T>minimum inhibitory concentration (MIC) target for Streptococcus pneumoniae up to 1 mg/L and all except p.o. 500 mg amoxicillin q8h for the wild-type Haemophilus influenzae MIC distribution. The simulations also demonstrated high urinary amoxicillin exposures and evaluated the effects of inadequate active ingredient content, missed doses, and probenecid co-administration. This PBPK model gives the following insights into amoxicillin pharmacokinetics: i) the adequacy of amoxicillin for infections caused by S. pneumoniae and H. influenzae; ii) the impact of non-compliance and loss of active ingredients on antimicrobial coverage; iii) the effect of probenecid co-administration to improve coverage; and iv) the characterization of high urinary amoxicillin exposure with consequences for use in urinary tract infections.

Assessment of Bacterial Pathogens in Young Children with Acute Otitis Media: A Prospective Cohort Study in Western Pennsylvania, 2019-2023.

Martin Judith M JM, Hoberman Alejandro A, Lee Matthew C MC, Yahner Kristin A KA et al.

Since the introduction of pediatric pneumococcal conjugate vaccines (PCV) were introduced in the US in 2000, acute respiratory illnesses, including acute otitis media (AOM) due to Streptococcus pneumoniae (Spn) have declined. Pathogens associated with AOM have changed over time. Children aged 6 through 35 months diagnosed with either AOM (Cohort 1- AOM with tympanocentesis & Cohort 2 - AOM without tympanocentesis) or upper respiratory infection (URI) without AOM (Cohort 3) were concurrently enrolled in Pittsburgh, PA. Nasal specimens were collected for all children. Middle ear fluid (MEF) specimens were obtained by tympanocentesis for children in Cohort 1. MEF and nasal specimens were tested for Spn, Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat). Serotypes (Spn) and susceptibility (Spn and Hflu) were determined. From October 2019 through August 2023, 451 children were enrolled (Cohort 1: n=57; Cohort 2: n=262; Cohort 3: n=132). For bacterial testing of MEF, 45/57 (79%) had a single pathogen detected. Pathogens detected, alone or in combination in the MEF were Hflu 32/57 (56%), Mcat 13/57 (23%) and Spn 12/57 (21%). Of participants with bacterial pathogens detected in the MEF, there was only modest concordance with the pathogens detected in the nose. Spn serotypes observed in MEF were 3, 11A, 15B, and 19A. Among nasal specimens from children with AOM (n=319), Spn, Hflu and Mcat were detected in 46%, 43%, and 70%, respectively. The majority (134/194; 69%) of Spn isolates from the nasal specimens were penicillin- susceptible; frequently observed serotypes were 3,15B, 15C, 23B/B1, 23A, and 35B. Almost 40% (63/162) of children colonized with Hflu had a β-lactamase producing isolate. Hflu was most frequently identified in MEF although sample size was small. In nasal specimens, antibiotic-resistant Hflu were common, while the majority of Spn were penicillin-susceptible. Continued surveillance could provide valuable data to guide vaccine development and therapeutic decision-making.

Immunogenicity of Hepatitis B Vaccine in Pediatric Systemic Lupus Erythematosus Patients: ERRATUM.

Madaeng Thanawat T, Soponkanaporn Sirisucha S, Tangnararatchakit Kanchana K, Apiwattanakul Nopporn N et al.