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Azithromycin vs. Doxycycline for Mediterranean Spotted Fever

1996; Lippincott Williams & Wilkins; Volume: 15; Issue: 11 Linguagem: Inglês

10.1097/00006454-199611000-00022

1532-0987

Tullio Meloni, Tullio Meloni,

Mosquito-borne diseases and control

Mediterranean spotted fever (MSF) is a tick-borne infection caused by Rickettsia conorii that was first described by Connor in 1910. R. conorii is an obligate intracellular parasite of mites, which inoculate the microorganisms directly into the dermis of mammals and birds during feeding. In the Mediterranean area the vector is the brown dog tick, Rhiphicephalus sanguineus, that constitutes a reservoir of infection. There has recently been a resurgence of this disease, especially in the Mediterranean countries such as Spain, Italy and Israel,1, 2 and an increasing incidence of this disease has been observed also in Sassari, northern Sardinia, since 1975. The seasonal epidemiologic pattern of MSF is determined by the biology of the tick, which results in a consistent seasonal peak occurring from late June to mid-October. The natural cycle of the tick-borne rickettsiae may include dogs, wild rodents and birds; humans are introduced into the cycle incidentally. The disease is generally transmitted from bites by ticks that are found on the ground or during contacts with pets and other animals parasitized by ticks. The infecting bite passes unnoticed in most cases, and the incubation period varies from 6 to 10 days. The clinical picture of the disease is characterized by the abrupt onset of fever ranging from 39°C to 40°C associated with severe headache, malaise, generalized arthromyalgias and maculopapular lesions involving the trunk, head, extremities and, typically, palms and soles. The primary lesion (tâche noire), a necrotic eschar that develops at the site of the tick bite in 30 to 90% of patients, is virtually pathognomonic of MSF. Other features of the disease, sporadically encountered in adult patients but rare in children, include pericarditis, myocarditis, pneumonitis, pleuritis, venous thrombosis, disseminated intravascular coagulation, encephalitis, nephritis with acute renal failure and conjunctivitis with intense photophobia. The diagnosis is usually extablished clinically; laboratory diagnosis involves serologic identification of serum antibodies by means of complement fixation, microagglutination, and indirect immunofluorescence techniques. These techniques have recently replaced the Weil-Felix reaction, which relies on the cross-reaction between OX19, OX2 and OXK Proteus species and rickettsial antigens and frequently yields false negative results. Standard treatment for MSF is the oral or parenteral administration of tetracyclines or chloramphenicol.4 During the past 10 years doxycycline hyclate has been used in our department as the drug of choice for treatment of this rickettsial disease. The use of chloramphenicol was avoided in our patients with MSF because of the possibility of severe adverse events, such as aplastic anemia5 and acute hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient subjects,6 in view of the extremely high prevalence of glucose-6-phosphate dehydrogenase deficiency in our district.7 In a paper published in 1986 Muñoz-Espin et al.9 reported the efficacy and safety of erythromycin for treatment of MSF, although they observed a longer defervescence time in their patients compared with those treated with tetracyclines. The aim of this study was to compare the efficacy and safety of azithromycin, a recently available azalide, and doxycycline hyclate for treatment of MSF. Materials and methods. The trial consisted of 30 children with MSF (18 male and 12 female), ranging in age from 2 to 11 years, who were admitted from June, 1993, to October, 1995, to the Department of Pediatrics of the University of Sassari, Italy. The diagnosis of Mediterranean spotted fever was based on the presence of the following signs and symptoms: high temperature; maculopapular exanthem; headache; generalized arthromyalgias; tâche noire; hepatosplenomegaly; and lymphadenopathy (Table 1). Duration of the disease before admission was 3 to 8 days (mean ± SD, 5.0 ± 1.5 days). A peripheral venous blood sample was drawn from all the patients before antibiotic therapy for complete blood cell count, erythrocyte sedimentation rate and C-reactive protein. IgG class anti-R. conorii serum antibody determination by indirect immunofluorescence (Rickettsia conorii-Spot IF, BioMèrieux, Paris, France) was performed on sera obtained from 28 of 30 patients before dismissal. Samples were considered positive only if fluorescence occurred at a 1:40 titer or greater. Fifteen patients were randomly assigned to receive doxycycline in a dosage of 5 mg/kg/day once daily for 5 consecutive days orally, and the remaining 15 patients received azithromycin in a dosage of 10 mg/kg/day once daily for 3 consecutive days. Figure 1. Randomization was made on the basis of the table of random numbers derived from Scientific Geigy Tables.9 Clinical response to antibiotic treatment was evaluated on the basis of the pattern of body temperature and the improvement of the clinical signs and symptoms of the disease. Treatment safety and tolerability were judged on the basis of the incidence and severity of drug-related adverse effects observed in the two groups. Student's t test was used to evaluate differences between the two groups. All patients enrolled in this study were clinically examined at 15-day intervals for 30 days after treatment in order to exclude relapses. Results. Blood cell count, performed on admission, showed frank leukopenia (leukocyte count <5000/mm3) in 4 children, which normalized after treatment. In 5 children the erythrocyte sedimentation rates were <20 mm/h and C-reactive protein values were 1:160. No statistically significant difference was observed with regard to the mean of the peak daily temperature between the two groups. With regard to the other symptoms a gradual resolution was observed in all patients after the second day of treatment, without a clinically appreciable difference between the two groups. Azithromycin and doxycycline were equally well-tolerated by our patients; none of the 30 treated children presented signs or symptoms attributable to the administration of the antibiotics. All patients attended follow-up examinations at 15-day intervals for 30 days after discontinuation of antibiotics. None showed clinical signs or symptoms consistent with a recurrence of MSF. Discussion. Azithromycin is the first of a new class of antibiotics, the azalides, that differ in structure from the macrolide erythromycin by the incorporation of a nitrogen atom in the lactone ring, with the formation of a 15-membered ring. Azithromycin shows bactericidal activity against several Gram-positive and Gram-negative microorganisms10 and also retains the characteristic macrolide spectrum of activity against intracellular microorganisms, such as Legionella and Chlamydia spp.10 The pharmacokinetic properties of azithromycin are characterized by a rapid and substantial movement of the drug from serum into intracellular compartments resulting in large tissue and white blood cell concentrations. Tissue concentrations of azithromycin persist for several days after administration for three consecutive days. Thus azithromycin is believed to be therapeutically effective for as long as standard antibiotics are administered for 10 days.10, 11 Several studies have demonstrated the clinical efficacy and safety of short courses of therapy with azithromycin in a variety of pediatric infections, such as streptococcal pharyngitis,12, 13 acute otitis media,14 and lower respiratory tract infections.15 Information regarding azithromycin treatment in rickettsial infections is limited. Schönwald et al.16 administered azithromycin to 6 adult patients with Coxiella burnetii pneumonia. Three of these patients received azithromycin 500 mg/day once daily for 3 days, whereas 3 other patients received the same drug in a dosage of 500 mg once a day on the first day and 250 mg once a day for the following 4 days. According to these authors azithromycin proved to be effective and safe in the treatment of these patients. In vitro experiments have recently shown that the macrolides josamycin,17 roxithromycin18 and clarithromycin19 are effective against Rickettsia rickettsii and R. conorii, but no data about the in vitro or in vivo activity of azithromycin against R. conorii or other spotted fever group Rickettsiae is currently available in literature. Our trial, conducted in children affected by MSF, indicates the therapeutic efficacy and safety of azithromycin in the treatment of a systemic infection caused by R. conorii. Comparison in the rate of defervescene and in the rate of resolution of other clinical signs and symptoms associated with MSF in the two groups of patients indicates that azithromycin and doxycycline are comparably effective. Gianfranco Meloni, M.D.; Tullio Meloni, M.D. Department of Pediatrics and Neonatology; University of Sassari; Sassari, ItalyFIG. 1: Mean of the peak daily temperature (±SD (bars)) in the two groups of patients with MSF treated with azithromycin and doxycycline.