On the other hand, T. whipplei is a Gram-positive bacterium responsible for Whipple’s disease. The natural niche of T. whipplei is the human intestine since, in the intestinal mucosa, the bacterium is taken by macrophages, where it replicates [147]. This bacterial infection is primally characterized by digestive tract disorders such as diarrhea (75% of cases), malabsorption, and weight loss (80–90% of cases). Joint disease may appear more than six years before the diagnosis and occur in more than 80% of patients [148]. Furthermore, neurological and cardiac disorders can also be frequently associated with Whipple’s disease. For years the standard treatment for T. whipplei has included a combination of trimethoprim and sulfamethoxazole; however, relapses were not uncommon [149,150]. Later, in vitro studies, demonstrated that trimethoprim was inactive on this bacterium [154], while sulfamethoxazole induced bacterial resistance, making the co-administration completely ineffective [154,156]. Based on the good results of treating C. burnetii infections, it was decided to test in vitro the association DCX/HCQ on T. whipplei, obtaining good results [154]. DCX/HCQ efficacy on T. whipplei diseases was demonstrated in a clinical trial dated 2014. This study showed that the administration of 200 mg/day DCX and 600 mg/day HCQ to 13 patients results in better outcomes (0/13 failures) even after 1 year of treatment, compared to standard antibiotics regimens [155]. To date, several case reports available in the literature supported a therapy consisting of a combination of HCQ (600 mg/day) and DCX (200 mg/day) for a lifetime or at least one year, followed by a maintenance dosage of DXC used alone [156,157,158]. In some cases, prophylaxis of intravenous ceftriaxone (2g/day) for the first two weeks followed by HCQ/DXC for at least 12–18 months has been recommended [72,159,160,161].