James S. Mccarthy

Description:Infection with Neisseria gonorrhoeae, the causative agent of gonorrhea, causes significant morbidity worldwide and can have long-term impacts on reproductive health. The greatest global burden of gonorrhea occurs in low- and middle-income settings. Global public health significance is increasing due to rising antimicrobial resistance, which threatens future gonorrhea management. The oropharynx is an important asymptomatic reservoir for gonorrhea transmission and a high-risk site for development of antimicrobial resistance and treatment failure. Controlled human infection model (CHIM) studies using N gonorrhoeae may provide a means to accelerate the development of urgently needed therapeutics, vaccines, and other biomedical prevention strategies. A gonorrhea urethritis CHIM has been used since the 1980s with no reported serious adverse events. Here, we describe the rationale for an oropharyngeal gonorrhea CHIM, including analysis of potential ethical issues that should inform the development of this novel study design.

Description:Although benzylpenicillin (penicillin G) is listed by the World Health Organization as an Essential Medicine, dose optimization is a persistent challenge, especially for long-acting intramuscular formulations. Maintaining sustained antibiotic exposure at target concentrations is crucial for secondary chemoprophylaxis of rheumatic heart disease and treatment of syphilis. This study compared the pharmacokinetic profile of continuous low-dose benzylpenicillin infusions with a standard-dose bolus and evaluated which renal function marker (serum creatinine, cystatin C, or combined e-glomerular filtration rate [eGFR]) best predicted clearance. Healthy adult volunteers received a single 600 mg IV benzylpenicillin bolus followed by randomization to continuous infusions targeting steady-state concentrations of 3, 6, 9, 12, or 20 ng/mL. Plasma benzylpenicillin concentrations were measured by liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM by incorporating both bolus and infusion data, and various GFR estimations were evaluated as covariates for clearance. Data from 72 participants were analyzed, including 504 bolus and 389 continuous infusion samples. A two-compartment model improved fit when the ratio of central volume of distribution between bolus and low-dose infusion was incorporated, and clearance differences at steady state plasma concentration of 3 ng/mL were accounted for. Of the GFR estimations, cystatin C-based eGFR significantly enhanced model fit compared with creatinine-based equations. Benzylpenicillin pharmacokinetics at very low concentrations demonstrated both a higher volume of distribution and increased clearance. Cystatin C-based eGFR may more accurately predict benzylpenicillin clearance, enabling precision dosing for long-acting preparations used for treatment of syphilis and prevention of rheumatic fever.

Description:Critical knowledge gaps have impeded progress towards reducing the global burden of disease due to Mycobacterium ulcerans, the cause of the neglected tropical disease Buruli ulcer (BU). Development of a controlled human infection model of BU has been proposed as an experimental platform to explore host-pathogen interactions and evaluate tools for prevention, diagnosis, and treatment. We have previously introduced the use case for a new human model and identified M. ulcerans JKD8049 as a suitable challenge strain. Here, we present a provisional protocol for an initial study, for transparent peer review during the earliest stages of protocol development. Following simultaneous scientific peer review and community/stakeholder consultation of this provisional protocol, we aim to present a refined protocol for institutional review board (IRB) evaluation.

Description:Background: The in-vivo plasma concentration of penicillin needed to prevent Streptococcus pyogenes pharyngitis, recurrent acute rheumatic fever, and progressive rheumatic heart disease is not known. We used a human challenge model to assess the minimum penicillin concentration required to prevent streptococcal pharyngitis. Methods: In CHIPS, a randomised, double-blind, placebo-controlled, human challenge trial, healthy adult volunteers were randomly assigned by a computer-generated random sequence to target steady-state penicillin plasma concentrations (placebo, 3, 6, 9, 12, or 20 ng/mL). The study was a single-centre trial held in Perth, WA, Australia. Participants had to be healthy adults, aged 18-40 years, at low risk of complicated S pyogenes disease, and without high type-specific IgG antibodies against the emm75 S pyogenes challenge strain. Participants and staff involved in clinical care remained masked to treatment allocation for the duration of the study. Individualised 5-day continuous intravenous infusions of penicillin were commenced 12 h before direct pharyngeal application of the emm75 challenge strain. The primary endpoint was clinical pharyngitis. This trial is registered on the Australian New Zealand Clinical Trials Registry, ACTRN12621000751875, and is completed. Results: Between Aug 23, 2022, and July 31, 2023, 60 participants were randomly assigned (35 [58%] were female and 25 [42%] were male), with 57 included in the analysis. The clinical pharyngitis endpoint was met in eight (57%) of 14 in the placebo group, four (44%) of nine in the 3 ng/mL target steady-state penicillin plasma concentration group, four (44%) of nine in the 6 ng/mL group, none of eight in the 9 ng/mL group, none of eight in the 12 ng/mL group, and none of nine in the 20 ng/mL group. No severe or serious adverse events occurred. Using Bayesian concentration-response modelling, the minimum steady-state plasma concentration of penicillin for which 90% of participants would avoid clinical pharyngitis was 8·1 ng/mL (95% credible interval 6·1-10·9). Conclusions: When steady-state penicillin concentrations are greater than 9 ng/mL, few people will develop experimental emm75 S pyogenes pharyngitis. These data will inform efforts to improve long-acting penicillin preparations and dosage regimens to prevent recurrent rheumatic fever and rheumatic heart disease. Background: The National Health and Medical Research Council of Australia.

Description:Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of NF-ƙB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), and is increasingly recognised as a marker of poor prognosis in a number of diseases. Here we demonstrate that in Malaysian adults with falciparum and vivax malaria, OPG is increased, and its ligands TRAIL and RANKL decreased, in proportion to disease severity. In volunteers experimentally infected with P. falciparum and P. vivax, RANKL was suppressed, while TRAIL was unexpectedly increased, suggesting binding of OPG to RANKL prior to TRAIL. We also demonstrate that P. falciparum stimulates B cells to produce OPG in vitro, and that B cell OPG production is increased ex vivo in patients with falciparum, vivax and knowlesi malaria. Our findings provide further evidence of the importance of the OPG/RANKL/TRAIL pathway in pathogenesis of diseases involving systemic inflammation, and may have implications for adjunctive therapies. Further evaluation of the role of B cell production of OPG in host responses to malaria and other inflammatory diseases is warranted.