New therapeutic approaches for treatment of tularaemia: a review

Abstract

Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones (e.g., ciprofloxacin), the tetracyclines (e.g., doxycycline), and the aminoglycosides (streptomycin and gentamicin). Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients' management and prognosis. These new strategies have been evaluated in vitro, in axenic media and cell culture systems and/or in animal models. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline), ketolides (telithromycin and cethromycin), and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin). The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors) on the course of F. tularensis infection was characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is likely that new therapeutic alternatives that are effective against this intracellular pathogen could be, at least partially, extrapolated to other human pathogens.

Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

“…Treatment of tularemia in humans is confined to few antibiotics, including aminoglycosides (particularly streptomycin and gentamicin) with known toxicities at therapeutic doses (7,35). Even with antibiotic treatment, high failure and/or relapse rates (up to 33%) have been reported (35).…”

“…Resistance of this pathogen to conventional antibi- otic therapy has not been reported (8); however, in the context of a biological weapon of terror, antibiotic-resistant strains could be created and pose a significant public health threat. Therefore, there is substantial interest from a public health management perspective in developing new antimicrobial strategies to control this bacterial pathogen (7).…”

“…Moreover, antibiotic treatment of tularemia is limited to aminoglycosides, fluoroquinolones (e.g., ciprofloxacin), and tetracyclines (7). At present, there is no naturally acquired resistance to these antibiotics in human/environmental isolates of F. tularensis (8).…”

“…Given these issues, the development of new antibacterial agents with novel mechanisms of action against F. tularensis has become a priority. Indeed, novel therapeutic approaches have been explored in recent years (7), including the use of newer antibiotics (e.g., tigecycline, ketolides, and fluoroquinolones), improving antibiotic delivery in vivo (e.g., liposome delivery), enhancement of the innate immune response by use of antimicrobial peptides, and combinatorial approaches with conventional antibiotics and immune adjuvants (7,13).…”

Functional Characterization of the DNA Gyrases in Fluoroquinolone-Resistant Mutants of Francisella novicida

“…A few antibiotic classes are effective for treating tularemia, including aminoglycosides, tetracyclines, and fluoroquinolones (FQs) (4). Microbiological and clinical data show that ciprofloxacin, and possibly other FQs, is the best alternative for oral therapy of tularemia in patients with clinical manifestations of mild to moderate severity, but failures and relapses are frequent (5,6).…”