Drug of Choice

               The conventional antibiotic regimen for spotted fever group rickettsiosis is a 7 to 14 day oral course of doxycycline 200 mg daily (Table 6). Tetracyclines are contraindicated in children less than 8 years old because of the possibility of tooth discoloration. They are also contraindicated during pregnancy. Tetracyclines may be toxic to the fetus, including bone toxicity and discoloration of deciduous teeth when given after the 16th week of gestation. Tetracyclines have also been reported to cause serious hepatotoxicity, often with pancreatitis, in pregnant women. These antibiotics may also induce gastric intolerance and photosensitization as general side effects. Short course therapy with doxycycline (100 mg twice daily for 1 to 2 days) has been reported to be effective for Rocky Mountain spotted fever and Mediterranean Spotted Fever. As compared to conventional antibiotic regimen, the short- course regimen presents the advantages of being well tolerated in almost all patients and cost effective. It may represent an effective and safe alternative in children less than 8 year sold, preventing the occurrence of tooth discoloration. The use of a tetracycline even for short duration remains more problematic in the pregnant woman and cannot be currently encouraged.

Monotherapy or Combination Therapy

               Antibiotic combinations have not been tested against rickettsiae in vitro. To date, no antibiotic combination has been shown to be superior in vivo to doxycycline alone. Combination therapy is not indicated in common clinical presentations of spotted fever group rickettsiosis. In severely ill patients, early administration of doxycycline before definite diagnosis is made is critical.

Special Situations

               In severely diseased patients, doxycycline should be administered first by the intravenous route at 200 mg daily, and a prolonged duration up to three days following apyrexia should be considered. There is no clinical indication that other drugs should be more effective than tetracycline, even in patients with neurological complications.

Alternative Therapy

               Randomized clinical trials comparing various antibiotic regimens for Mediterranean spotted fever are summarized in Table 5. These alternative therapies are summarized in Table 6. Chloramphenicol (administered for at least 1 week) has long been considered the main alternative for rickettsial infections. However, chloramphenicol presents the potential risk of aplastic anemia, acute hemolytic anemia in patients with the Mediterranean form of glucose-6-phosphate dehydrogenase (G6PD) deficiency, and is contraindicated in the pregnant woman. Moreover, recent in vitro and in vivo data indicate that chloramphenicol is much less effective than tetracyclines. Prognosis in children involved with of Rocky Mountain spotted fever is significantly worse when chloramphenicol rather than a tetracycline has been administered. Relapse was reported in an Israeli patient suffering Mediterranean Spotted Fever who died despite completion of the chloramphenicol therapy. Fluoroquinolones, including pefloxacin, ofloxacin, and ciprofloxacin have been shown to be effective for the treatment of Mediterranean Spotted Fever. A 10 to 15 day oral regimen of either 200 mg bid of ofloxacin, 400 mg bid pefloxacin, or 500 mg bid of ciprofloxacin has been recommended. Shorter duration of antibiotic therapy was used with ciprofloxacin. A 2 day regimen of 500 mg bid of ciprofloxacin was compared to a 2 day course of doxycycline 200mg daily. All patients treated with ciprofloxacin resolved. However, apyrexia was delayed in the short-term ciprofloxacin therapy group as compared to the doxycycline group. Fluoroquinolones administered for 7 to 10 days may be considered as a safe alternative to tetracyclines to treat spotted fevers. However, as for tetracyclines, fluoroquinolones are contraindicated in the child and the pregnant woman. Among the macrolides, erythromycin is not considered a safe alternative for Mediterranean Spotted Fever. Following in vitro studies, josamycin has been proposed as a possible alternative to tetracyclines. The usefulness of josamycin has been assessed in a randomized trial for antibiotic therapy of Mediterranean Spotted Fever, both in adults and children. Josamycin 1g tid orally (50 mg/kg of body weight bid in children) was as active as the single day therapy with doxycycline (200mg bid for adults, 5mg/ kg of body weight in children). The clinical efficacy of clarithromycin (15mg/kg/day orally for 7 days) as compared to chloramphenicol (50mg/kg/day orally for 7 days) was recently assessed in a randomized control trial in 51 children with Mediterranean spotted fever. Mean time to defervescence were respectively 36.7h with clarithromycin and 47.1h with chloramphenicol. Azithromycin (10mg/kg/day orally for 3days) has also been evaluated comparatively to doxycycline (5mg/kg/day orally for 5 days) in 30 children with Mediterranean spotted fever, and both regimens had equal efficacy. More recently, azithromycin and clarithromycin were comparatively evaluated in 97 children suffering from Mediterranean spotted fever, with comparable efficacy. The mean time (+/- SD) to defervescence was 46.2 +/- 36.4 h in the clarithromycin-treated group and 39.3 +/- 31.3 h in the azithromycin-treated group. Thus, josamycin (50mg/Kg/d in two divided doses, for 7 days) and the newer macrolide compounds azithromycin (10mg/Kg/d in 1 dose for 3-5 days) and clarithromycin (15mg/Kg/d in 2 divided doses for 7 days), which have superior in vitro activity against rickettsiae as compared to erythromycin, may represent a current safe alternative to tetracyclines in children less than 8 years old. Josamycin may also represent a safe alternative to tetracyclines in the pregnant woman, but clinical data are lacking. Recently, Cascio et al. reported a successful outcome in a 20-year old woman with in the 13th week of gestation who was treated with the combination of erythromycin and rifampin for Mediterranean spotted fever.

               Cotrimoxazole is not useful to treat rickettsioses, and potentially may worsen the outcome of the disease. In vitro, isolation of spotted fever group rickettsiae from ticks was obtained in cell culture systems despite adding cotrimoxazole in the culture medium. A regimen of rifampin (10mg/kg bid for 5 days) was compared to the one day doxycycline therapy schedule, in the region of Catalonia, in Spain. Outcome was favorable in both groups. However, delayed apyrexia was noticed in patients receiving rifampin. Moreover 4 patients become apyretic only after 5 days therapy which is comparable to usual time of spontaneous fever resolution. In one patient rifampin therapy was considered a failure and was changed for doxycycline. Failures in patients with Mediterranean Spotted Fever in Catalonia (Spain) after treatment with rifampin has been tentatively correlated with recent isolation of rickettsial strains with natural resistance to this antibiotic (R. massiliae) from Rhipicephalus ticks in this region. This rickettsiae have been found recently to be human pathogens. It may be hypothesized that the existence of rifampin-resistant rickettsiae in some areas may explain therapy failures when using this antibiotic, as well as contradictory reports from different areas on the effectiveness of rifampin to treat rickettsial diseases. More isolates are needed to resolve this hypothesis.

Table 5: Summary of randomized clinical trials of antibiotic therapy for Mediterranean Spotted Fever

NS: no statistically significant differences in time to disappearance of fever and symptoms

Table 6. Recommendations for antibiotic treatment of Spotted Fever Group Rickettsiosis other than

Rocky Mountain Spotted Fever (due to R. rickettsii), and rickettsialpox (due to R. akari) which are

presented in specific chapters.