Boutonneuse Fever Treatment & Management
- Author: Jason F Okulicz, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD more...
The course of boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), can be shortened with appropriate treatment (ie, antibiotics). The illness sometimes takes a malignant form—for instance, in people who are elderly and especially in those who are immunocompromised. In a study of 142 patients hospitalized with BF, 5% of patients presented with malignant BF.
Tetracyclines, along with chloramphenicol and quinolones, may be considered first-line antibiotics for BF. After 2-4 days of first-line therapy, the fever decreases and the rash usually disappears. Patients already in good health are usually discharged after 7-8 days of treatment. Single-dose azithromycin can be used for prophylaxis of BF.
Because the differential diagnosis for BF includes many rare diseases, consultations with a dermatologist and an infectious disease specialist should be considered.
Patients with the benign form of BF are usually treated with antibiotics for 7 days; those with the malignant form of BF are usually treated with antibiotics for 2 weeks.
The preferred drug is doxycycline (100 mg PO q12hr). Other effective treatments include the following:
Ciprofloxacin (200 mg IV q12hr or 750 mg PO q12hr)
Levofloxacin (500 mg PO once daily)
Chloramphenicol (50-60 mg/kg/day PO in 4 divided doses)
Macrolides such as azithromycin (500 mg PO once daily) and clarithromycin (500 mg PO q12h) - These have been shown to be efficacious in children  and can be used as alternatives to doxycycline in adults, including pregnant women. A small randomized trial in children and adults showed a similar time to resolution of fever and other symptoms among those treated with clarithromycin versus doxycycline (or doxycycline plus josamycin in children). 
For children with malignant BF, tetracyclines (especially doxycycline) should be considered first; these are the most effective drugs for this potentially life-threatening disease. A single short (≤1 week) course of doxycycline should not result in cosmetically significant staining of teeth. In malignant BF, there is a narrow window of time during which effective antibiotic therapy delivered in an extremely efficient way can substantially reduce the risk of an unfavorable outcome.
In pregnant women, erythromycin should be administered; however, it is not as effective as the tetracyclines are.
In an analysis of risk factors for malignant BF, researchers noted that fluoroquinolones may have a deleterious effect.
Josamycin, a newer macrolide antibiotic, seems to be effective against malignant BF (when available). Some have suggested that it may be the drug of choice for malignant BF in pregnant women.[28, 29, 30]
Rifampin, though designated by the US Food and Drug Administration (FDA) as a category C drug in pregnancy and tuberculosis, has also been used extensively in this setting and appears to be safe.
To prevent infection by rickettsiae, precautions should be taken to avoid exposure to ticks, in particular by refraining from close contact with ticks’ animal vectors (eg, dogs, goats, and sheep) when in endemic areas.
Protective clothing should be worn, preferably impregnated with permethrin or another pyrethroid. Topical repellents can be used on any exposed skin; however, these agents have a short duration of effect (~1-2 hours per application), and frequent application is therefore recommended. During travel, daily self-checks and removal of any ticks found should be performed.
At present, there is no vaccine for BF.
Popivanova NI, Murdjeva MA, Baltadzhiev IG, Haydushka IA. Dynamics in serum cytokine responses during acute and convalescent stages of Mediterranean spotted fever. Folia Med (Plovdiv). 2011 Apr-Jun. 53(2):36-43. [Medline].
Valbuena G, Walker DH. Expression of CX3CL1 (fractalkine) in mice with endothelial-target rickettsial infection of the spotted-fever group. Virchows Arch. 2005 Jan. 446(1):21-7. [Medline].
Rydkina E, Sahni A, Baggs RB, Silverman DJ, Sahni SK. Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins. Infect Immun. 2006 Sep. 74(9):5067-74. [Medline]. [Full Text].
de Sousa R, Ismail N, Nobrega SD, França A, Amaro M, Anes M, et al. Intralesional expression of mRNA of interferon- gamma , tumor necrosis factor- alpha , interleukin-10, nitric oxide synthase, indoleamine-2,3-dioxygenase, and RANTES is a major immune effector in Mediterranean spotted fever rickettsiosis. J Infect Dis. 2007 Sep 1. 196(5):770-81. [Medline].
Damås JK, Davì G, Jensenius M, Santilli F, Otterdal K, Ueland T, et al. Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever. J Infect. 2009 Jan. 58(1):68-75. [Medline].
Brouqui P, Parola P, Fournier PE, Raoult D. Spotted fever rickettsioses in southern and eastern Europe. FEMS Immunol Med Microbiol. 2007 Feb. 49(1):2-12. [Medline].
Palau LA, Pankey GA. Mediterranean Spotted Fever in Travelers from the United States. J Travel Med. 1997 Dec 1. 4(4):179-182. [Medline].
Jufresa J, Alegre J, Suriñach JM, Aleman C, Recio J, Juste C, et al. [Study of 86 cases of Mediterranean boutonneuse fever hospitalized at a university hospital]. An Med Interna. 1997 Jul. 14(7):328-31. [Medline].
Segura-Porta F, Diestre-Ortin G, Ortuño-Romero A, Sanfeliu-Sala I, Font-Creus B, Muñoz-Espin T, et al. Prevalence of antibodies to spotted fever group rickettsiae in human beings and dogs from and endemic area of mediterranean spotted fever in Catalonia, Spain. Eur J Epidemiol. 1998 Jun. 14(4):395-8. [Medline].
de Sousa R, Nóbrega SD, Bacellar F, Torgal J. Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 hospitalized patients. Ann N Y Acad Sci. 2003 Jun. 990:285-94. [Medline].
Cascio A, Iaria C. Epidemiology and clinical features of Mediterranean spotted fever in Italy. Parassitologia. 2006 Jun. 48(1-2):131-3. [Medline].
Mert A, Ozaras R, Tabak F, Bilir M, Ozturk R. Mediterranean spotted fever: a review of fifteen cases. J Dermatol. 2006 Feb. 33(2):103-7. [Medline].
Tijsse-Klasen E, Jameson LJ, Fonville M, Leach S, Sprong H, Medlock JM. First detection of spotted fever group rickettsiae in Ixodes ricinus and Dermacentor reticulatus ticks in the UK. Epidemiol Infect. 2011 Apr. 139(4):524-9. [Medline].
Popivanova N, Hristova D, Hadjipetrova E. Guillain-Barré polyneuropathy associated with mediterranean spotted fever: case report. Clin Infect Dis. 1998 Dec. 27(6):1549. [Medline].
Aliaga L, Sánchez-Blázquez P, Rodríguez-Granger J, Sampedro A, Orozco M, Pastor J. Mediterranean spotted fever with encephalitis. J Med Microbiol. 2009 Apr. 58:521-5. [Medline].
Ezpeleta D, Muñoz-Blanco JL, Tabernero C, Giménez-Roldán S. [Neurological complications of Mediterranean boutonneuse fever. Presentation of a case of acute encephalomeningomyelitis and review of the literature]. Neurologia. 1999 Jan. 14(1):38-42. [Medline].
Leone S, De Marco M, Ghirga P, Nicastri E, Lazzari R, Narciso P. Retinopathy in Rickettsia conorii infection: case report in an immunocompetent host. Infection. 2008 Aug. 36(4):384-6. [Medline].
Tsiachris D, Deutsch M, Vassilopoulos D, Zafiropoulou R, Archimandritis AJ. Sensorineural hearing loss complicating severe rickettsial diseases: report of two cases. J Infect. 2008 Jan. 56(1):74-6. [Medline].
Demeester R, Claus M, Hildebrand M, Vlieghe E, Bottieau E. Diversity of life-threatening complications due to Mediterranean spotted fever in returning travelers. J Travel Med. 2010 Mar-Apr. 17(2):100-4. [Medline].
Broadhurst LE, Kelly DJ, Chan CT, Smoak BL, Brundage JF, McClain JB, et al. Laboratory evaluation of a dot-blot enzyme immunoassay for serologic confirmation of illness due to Rickettsia conorii. Am J Trop Med Hyg. 1998 Jun. 58(6):786-9. [Medline].
Ergas D, Sthoeger ZM, Keysary A, Strenger C, Leitner M, Zimhony O. Early diagnosis of severe Mediterranean spotted fever cases by nested-PCR detecting spotted fever Rickettsiae 17-kD common antigen gene. Scand J Infect Dis. 2008. 40(11-12):965-7. [Medline].
Giulieri S, Jaton K, Cometta A, Trellu LT, Greub G. Development of a duplex real-time PCR for the detection of Rickettsia spp. and typhus group rickettsia in clinical samples. FEMS Immunol Med Microbiol. 2012 Feb. 64(1):92-7. [Medline].
Dzelalija B, Petrovec M, Avsic-Zupanc T, Strugar J, Milic TA. Randomized trial of azithromycin in the prophylaxis of Mediterranean spotted fever. Acta Med Croatica. 2002. 56(2):45-7. [Medline].
Anton E, Muñoz T, Travería FJ, Navarro G, Font B, Sanfeliu I, et al. Randomized Trial of Clarithromycin for Mediterranean Spotted Fever. Antimicrob Agents Chemother. 2015 Dec 28. 60 (3):1642-5. [Medline].
Botelho-Nevers E, Rovery C, Richet H, Raoult D. Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect. J Antimicrob Chemother. 2011 Aug. 66(8):1821-30. [Medline].
Antón E, Font B, Muñoz T, Sanfeliu I, Segura F. Clinical and laboratory characteristics of 144 patients with mediterranean spotted fever. Eur J Clin Microbiol Infect Dis. 2003 Feb. 22(2):126-8. [Medline].
Bentov Y, Sheiner E, Kenigsberg S, Mazor M. Mediterranean spotted fever during pregnancy: case presentation and literature review. Eur J Obstet Gynecol Reprod Biol. 2003 Apr 25. 107(2):214-6. [Medline].
Cohen J, Lasri Y, Landau Z. Mediterranean spotted fever in pregnancy. Scand J Infect Dis. 1999. 31(2):202-3. [Medline].