Biology subjects

Ammerman, N. C.

Publications and source records attributed to Ammerman, N. C..

8 recordsLinked to original sources

bioRxiv2026

One-Dose Efficacy of Long-Acting Sorfequiline in a Mouse Model of Tuberculosis Preventive Therapy

Rationale: Tuberculosis preventive therapy (TPT) is essential for global tuberculosis control, yet estimated coverage remains well below global targets. Current World Health Organization (WHO)-recommended regimens require 1-9 months of treatment and are associated with suboptimal completion rates. Long-acting injectable (LAI) formulations offer the potential to improve TPT uptake and completion, with ideal products providing "one-and-done" options via a single administration. Sorfequiline, a second-generation diarylquinoline with superior potency over bedaquiline and lower QT prolongation risk, is a promising candidate for LAI TPT.

microbiology↗

bioRxiv2024

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.

pharmacology and toxicology↗

bioRxiv2023

Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We utilized a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally-determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that has utility beyond latent tuberculosis infection.

microbiology↗

bioRxiv2020

Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

microbiology↗

bioRxiv2019

Treatment-shortening effect of a novel regimen combining high-dose rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis

High-dose rifapentine and clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

microbiology↗

bioRxiv2019

Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection

The potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

microbiology↗

bioRxiv2018

In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams against Mycobacterium abscessus complex clinical isolates

Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to MABCs intrinsic resistance to most antibiotics, including {beta}-lactams. MABC organisms express a broad-spectrum {beta}-lactamase that is resistant to traditional {beta}-lactam-based {beta}-lactamase inhibitors but inhibited by a newer non-{beta}-lactam-based {beta}-lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC to some {beta}-lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-{beta}-lactam-based {beta}-lactamase inhibitors, relebactam and vaborbactam, would also increase susceptibility of MABC to {beta}-lactams. The objective of the present study was to evaluate the in vitro activity of various marketed {beta}-lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both {beta}-lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem/vaborbactam combination is now marketed and an imipenem/relebactam combination is currently in phase III trials, these fixed combinations may become the {beta}-lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual {beta}-lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a {beta}-lactamase inhibitor, deserving of further evaluation in combination with these carbapenem/{beta}-lactamase inhibitor products.

microbiology↗

bioRxiv2018

Progressive Mycobacterium abscessus lung infection in C3HeB/FeJ mice associated with corticosteroid administration

Mycobacterium abscessus (Mab) is a rapidly-growing nontuberculous mycobacterium that is a growing health concern among both immunocompetent and immunocompromised patient populations. It most commonly causes skin and soft tissue or pulmonary infection. As an emerging health issue there is much that still needs to be understood about the infection and its progression to disease. In the context of pulmonary infection, an in vivo system of Mab infection that permits investigation of host-microbe interactions that result in Mab infection and the transition to pathogenesis, and also the evaluation of treatments, is an essential tool that is currently lacking. Here, we describe a system of pulmonary Mab infection in the C3HeB/FeJ mouse strain under corticosteroid immunosuppressive therapy that progresses to pathology.

microbiology↗