Novel Adjunctive Therapies for the Treatment of Tuberculosis

Ordoñez, Alvaro A.; Maiga, Mamoudou; Gupta, Sujata; Weinstein, Edwin A.; Bishai, William R.; Jain, Sanjay

doi:10.2174/1566524013666131118112431

Cited by 23 publications

(17 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, in children, adjunctive corticosteroids have been shown to not only be beneficial in reducing mortality, but also in reducing neurologic sequelae (Girgis et al, 1991; Schoeman et al, 1997). However, corticosteroid use leads to a nonspecific modulation of the immune response with significant side effects that can limit its use (Ordonez et al, 2014). Therefore, there is an urgent need for the development and validation of novel host-directed therapies for CNS TB.…”

Section: Introductionmentioning

confidence: 99%

Microglia activation in a pediatric rabbit model of tuberculous meningitis

Tucker

Pokkali

Zhi

et al. 2016

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.

show abstract

Section: Introductionmentioning

confidence: 99%

Microglia activation in a pediatric rabbit model of tuberculous meningitis

Tucker

Pokkali

Zhi

et al. 2016

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…It is possible that by reducing proinflammatory-cytokine production, roflumilast increases the proportion of rapidly dividing bacilli and thereby enhances isoniazid killing. While roflumilast had marginal effects on cellularity at early time points, adjunctive therapy with isoniazid certainly suggests that roflumilast may improve lung pathology at later time points and murine survival with adjunctive therapies and shorten the time to sterilization during multidrug TB treatment in the mouse model, as has been shown with other HDT agents (2,4). Since a high proportion of new drug candidates in development fail to advance to clinical use (16), the fact that roflumilast is already FDA approved makes it an attractive candidate for further evaluation.…”

mentioning

confidence: 98%

“…While type 4 PDE-I (PDE4-I) therapies have been hampered by adverse-effect profiles, two have been approved by the Food and Drug Administration (FDA) since 2011 and others are in development (3). PDE4-Is have recently been studied as adjunctive therapies for TB (1,4). Although the synergism of the PDE4-I CC-3052 with isoniazid (INH) has been reported (5), our group found that, when used as part of a complete tuberculosis multidrug regimen, the PDE4-I rolipram was detrimental to bacterial clearance (6).…”

mentioning

confidence: 99%

Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis

Maiga

Ahidjo

Maiga

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cWith phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA-approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT). The treatment of tuberculosis (TB) still takes at least 6 months of multidrug therapy, and adjunctive host-directed therapies (HDTs) have the potential to shorten its duration and prevent drug resistance (1). We have previously shown that type 3 and 5 phosphodiesterase inhibitors (PDE-Is) (cilostazol and sildenafil, respectively) are beneficial in shortening TB first-line standard treatment (2). While type 4 PDE-I (PDE4-I) therapies have been hampered by adverse-effect profiles, two have been approved by the Food and Drug Administration (FDA) since 2011 and others are in development (3). PDE4-Is have recently been studied as adjunctive therapies for TB (1,4). Although the synergism of the PDE4-I CC-3052 with isoniazid (INH) has been reported (5), our group found that, when used as part of a complete tuberculosis multidrug regimen, the PDE4-I rolipram was detrimental to bacterial clearance (6). Since PDE4 has four subtypes (PDE4A to -D), with at least 25 splice variants (7), these contradictory observations may be due to action on different PDE isoforms and the different isoform tissue distributions (7). Additionally, off-target effects or effects on the pharmacokinetics of anti-TB drugs cannot be ruled out.At the start of this study, the only PDE4-I approved by the FDA was roflumilast (trade names, Daxas and Daliresp) (8). Roflumilast is indicated for the management of severe chronic obstructive pulmonary disease (COPD). This agent induces accumulation of host cyclic AMP (cAMP) in lung cells, blocks neutrophil recruitment, and reduces inflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), all of which delay the progression of lung pathology in COPD. To determine whether these anti-inflammatory, tissue-protective effects of roflumilast might also be useful in the management of TB, we assessed the effect of roflumilast as an adjunctive, host-directed therapy on (i) the survival of Mycobacterium tuberculosis-infected mice, (ii) lung cytokine levels during infection, and (iii) bacillary burden during monotherapy and combination therapy with isoniazid.Six-week-old female BALB/c mice were aerosol infected with a high dose of M. tuberculosis H37Rv (4.06 Ϯ 0.20 log 10 CFU). Daily oral gavage (5 days per week) of each group of 20 mice was started the day following infection with roflumilast at the anti-inflammatory dose of 5 mg/kg of body weight/day (9) or isoniazid at 25 mg/kg/day (10) or sham treatment (water). As expected, isoniazid significantly prolonged mouse survival time (P Ͻ 0....

show abstract

“…Host-directed therapies could potentially be used in synergy with optimised drug regimens to boost or protect the host tissues or cells. Therapies could include corticosteroids, TNF-α inhibitors, phosphodiesterase inhibitors and matrix-metalloproteinases (Ordonez et al, 2014), as well as infusion of autologous mesenchymal stromal cells (Skrahin et al, 2014). With recent advances in rapid molecular drug susceptibility testing (Xie et al, 2017) and judicious prescribing stewardship of the newly available drugs, including an all oral treatment regimen (WHO, 2018b) we anticipate a substantial impact on the treatment of MDR and XDR-TB as new recommendations emerge from ongoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%