C. burnetii is an obligate intraleukocytic Gram-negative bacterium responsible for query fever (Q fever). The infection is mainly caused by direct contact with infected animals, although cases of human transmission have also been described. Q fever diagnosis is primally founded on serological examination and based on a different evolution, acute and chronic infection can be distinguished. In 50% of cases, the acute phase is asymptomatic, but when the acute phase is symptomatic, it is characterized by a febrile illness, myalgia, headache, chills, atypical hepatitis, and pneumonia [122,123]. Approximately 2–5% of C. burnetii infections can develop into the chronic phase, leading to endocarditis and vascular infection. The risk of developing chronic fever is higher in patients with pre-existing vascular disorders or valvulopathies [123,124]. C. burnetii is known to replicate in an intracellular phagolysosome with a pH range of 4–5. However, at this pH, antibiotics, like doxycycline (DXC), exert only a bacteriostatic activity. Therefore, a combination of DXC with a lysosomotropic agent, such as HCQ, was suggested. In fact, HCQ was shown to increase the phagolysosomal compartment’s pH by improving the bactericidal activity of doxycycline [125,126]. The first successful results concerning the treatment of Q fever endocarditis combined with DXC and HCQ date back to 1993 [127]. These results were later confirmed by a case report of a young infected girl, where the treatment with 200 mg/day of DXC and 600 mg/day of HCQ led to a reduction in serum C. burnetii antibodies within 48 h [128]. Furthermore, in a 1999 clinical study, the administration of 100 mg DXC twice daily plus 200 mg HCQ three times daily for at least 18 months led to a short duration of therapy and a reduction in recurrences compared to alternative treatments including DXC plus 200 mg ofloxacin three times daily [129]. Since this moment, all infected subjects have been treated with DXC plus HCQ, as demonstrated by several case reports where this regimen results in an improvement of C. burnetii-related disease [130,131,132,133,134,135,139,140]. Furthermore, in patients with valvulopathy and diagnosticated acute Q fever (serologic criteria of a phase II IgG titer ≥ 200 and a phase II IgM titer ≥ 50) the administration as prophylaxis of DCX plus HCQ for at least 12 months resulted to be efficient in preventing Q fever endocarditis. Contrarily, shorter regimes are associated with a failure of antibiotics prophylaxis [141]. When Q fever endocarditis occurs, the optimal treatment duration with DXC and HCQ seems to be 18 months for native valve patients and 24 months for subjects with prosthetic valves [142]. This duration should only be extended in the absence of favorable serological results. However, long-term treatment with DXC and HCQ is not without important complications, since both can cause photosensitivity [144], abnormal weight gain [145], severe erythroderma, and impaired visual field [142]. Besides, it can be said that while the acute phase of the infection can be treated with only 200 mg/day DXC, the chronic phase is more difficult to treat and therapy with 100 mg DXC twice daily with 200 mg HCQ three times daily for 18–24 months was recommended [146]. Serological titers are used to follow the disease and determine the duration of therapy.