Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin, and Co-trimoxazole Using In Vitro and In Vivo Models of Q Fever

Abstract

Q fever, caused by the intracellular pathogen Coxiella burnetii , is traditionally treated using tetracycline antibiotics, such as doxycycline. Doxycycline is often poorly tolerated and antibiotic resistant strains have been isolated. In this study, we have evaluated a panel of antibiotics (doxycycline, ciprofloxacin, levofloxacin, and, co-trimoxazole) against C. burnetii using in vitro methods (determination of MIC using liquid and solid media; efficacy assessment in a THP cell infection model) and in vivo methods (wax moth larvae and mouse models of infection). In addition, the schedule for antibiotic treatment has been evaluated, with therapy initiated at 24 h pre or post challenge. Both doxycycline and levofloxacin limited overt clinical signs during treatment in the AJ mouse model of aerosol infection, but further studies are required to investigate the possibility of disease relapse or incomplete bacterial clearance after the antibiotics are stopped. Levofloxacin was well tolerated and therefore warrants further investigation as an alternative to the current recommended treatment with doxycycline.

Antibiotic persistence of intracellular Brucella abortus

“…For L. pneumophila which alike Brucella is associated to an ER-derived intracellular niche [93] the observed intracellular MIC is roughly 2 and 17 times the extracellular MIC for ciprofloxacin and rifampicin, respectively [94], whereas no difference is observed for doxycycline or chloramphenicol [94]. For C. burnetii, which survives in a highly acidified phagolysosome-like compartment [95,96], a similar effect was described for doxycycline and ciprofloxacin with a protective range spanning 2-5x MIC [97,98]. Similar results were obtained with ciprofloxacin and other quinolones against intracellular Listeria monocytogenes (localized in the cytosol, 3x MIC), Staphylococcus aureus (localized in the phagolysosome, 8x MIC), and uropathogenic E. coli (localized in acidified compartment, >3x MIC) compared to extracellular bacteria [99,100].…”

“…For instance, the protectiveness of Brucella´s ER-associated intracellular niche against chloramphenicol has already long been recognized [104], although this antibiotic readily kills intracellular H. influenzae and L. pneumophila [94,105]. Inversely, if Brucella's and Coxiella´s [98] intracellular niches seem to confer a substantial protection against doxycycline, the one of L. pneumophila ´s fails to do so [94]. That the low pH in Coxiella´s phagolysosomal niche is most likely one of the main factors conferring partial protection against different antibiotics is a well-recognized fact [106][107][108][109].…”

Antibiotic persistence of Brucella abortus in its protective intracellular niche

“…For L. pneumophila which alike Brucella is associated to an ER-derived intracellular niche [95] the observed intracellular MIC is roughly 2 and 17 times the extracellular MIC for ciprofloxacin and rifampicin, respectively [96], whereas no difference is observed for doxycycline or Chloramphenicol [96]. For C. burnetii , which survives in a highly acidified phagolysosome-like compartment [97, 98], a similar effect was described for doxycycline and ciprofloxacin with a protective range spanning 2-5× MIC [99, 100]. Similar results were obtained with ciprofloxacin and other quinolones against intracellular Listeria monocytogenes (localized in the cytosol, 3× MIC), Staphylococcus aureus (localized in the phagolysosome, 8x MIC), and uropathogenic E. coli (localized in acidified compartment, >3x MIC) compared to extracellular bacteria [101, 102].…”

“…For instance, the protectiveness of Brucella ’s ER-associated intracellular niche against chloramphenicol has already long been recognized [106], although this antibiotic readily kills intracellular H. influenzae and L. pneumophila [96, 107]. Inversely, if Brucella ’ s and Coxiell’s [100] intracellular niches seem to confer a substantial protection against doxycycline, the one of L. pneumophil’s fails to do so [96]. That the low pH in Coxiell’s phagolysosomal niche is most likely one of the main factors conferring partial protection against different antibiotics is a well-recognized fact [108–111].…”

“…For instance, the protectiveness of Brucella´s ER-associated intracellular niche against chloramphenicol has already long been recognized [106], although this antibiotic readily kills intracellular H. influenzae and L. pneumophila [96,107]. Inversely, if Brucella's and Coxiella´s [100] intracellular niches seem to confer a substantial protection against doxycycline, the one of L.…”