Comparison of three different regimens in the treatment of acute brucellosis: a multicenter multinational study

133

Brucellosis is a common zoonosis in many parts of the world; the best regimen for the treatment of brucellosis has not been clearly determined. We have carried out a multicenter, open, controlled trial in five general hospitals in Spain to compare the efficacy and safety of doxycycline and rifampin (DR) versus doxycycline and streptomycin (DS) for the treatment of human brucellosis. The study included 194 ambulatory or hospitalized patients with acute brucellosis, without endocarditis or neurobrucellosis. The diagnostic criterion was isolation of Brucella species from blood or other tissues (n ‫؍‬ 120) or a standard tube agglutination titer of 1/160 or more for anti-Brucella antibodies with compatible clinical findings (n ‫؍‬ 74). Patients were randomly assigned to receive either 100 mg of doxycycline twice daily plus rifampin, 900 mg/day, in a single morning dose for 45 days (DR group) or the same dose of doxycycline for 45 days plus streptomycin, 1 g/day, intramuscularly for 14 days (DS group). A lack of therapeutic efficacy developed in 8 of the 100 patients in the DR group (8%) and in 2 of the 94 patients in the DS group (2%) (P ‫؍‬ 0.10). Relapses occurred in 16 of the 100 patients in the DR group (16%) but in only 5 of the 94 patients in the DS group (5.3%) (P ‫؍‬ 0.02). When relapse was considered in combination with initial lack of efficacy, 26 patients in the DR group (24%) and 7 patients in the DS group (7.45%) failed to respond to therapy (P ‫؍‬ 0.0016). In general, therapy was well tolerated, and only four patients (4%) in the DR group and two (2%) in the DS group had episodes of adverse effects necessitating discontinuation of treatment (P > 0.2). We conclude that a doxycycline-and-rifampin regimen is less effective than the doxycycline-and-streptomycin regimen in patients with acute brucellosis.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. The GECMEI Group. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas

Solera

Zapata

Geijo

et al. 1995

133

“…Trials employing rifampin alone were discouraged because of the high relapse rates and the possibility of development of resistance (18,21). The combination of rifampin plus doxycycline, administered for 6 weeks, resulted in failure rates of 0 to 13% (1,5,7,16) and was recommended by the World Health Organization in 1986 in treatment of brucellosis (10).…”

Section: Discussionmentioning

confidence: 99%

Quinolones in treatment of human brucellosis: comparative trial of ofloxacin-rifampin versus doxycycline-rifampin

Akova

Uzun

Akalın

et al. 1993

112

Quinolones have been reported to be active against BruceUla species in vitro. In this prospective randomized study, the efficacy and safety of the combination of ofloxacin plus rifampin were compared with the efficacy and safety of doxycycline plus rifampin, both combinations administered for a 6-week period in treatment of brucellosis. Sixty-one patients were enrolled in the study, and 49 had blood or bone marrow cultures positive for BruceUla melitensis. Thirty patients received 200 mg of doxycycline plus 600 mg of rifampin once daily, and 31 patients were treated with 400 mg of ofloxacin plus 600 mg of rifampin once daily for 6 weeks. Nine patients in each group had complications of the disease. There was one therapeutic failure in the ofloxacin-rifampin treatment group, and one patient from each group relapsed (3.3% of those in the doxycycline-rifampin treatment group versus 3.2% of those in the ofloxacin-rifampin treatment group). Gastric discomfort was the major side effect observed in 13 patients (43.3%) who received doxycycline plus rifampin, whereas only 2 patients (6.5%) treated with ofloxacin plus rifampin complained of gastric irritation. These results suggest that the combination of ofloxacin plus rifampin administered for 6 weeks is as effective as doxycycline plus rifampin given for the same period, regardless of the presence of complications of the disease.Brucellosis is a major health problem worldwide, especially in developing countries. The best regimen for the treatment of acute brucellosis is not clearly determined (2). Brucella species are facultative intracellular parasites; therefore, complete eradication of the microorganism is difficult to achieve, and relapses are common.The fluoroquinolones have excellent bactericidal activity against a variety of bacteria. In addition, they penetrate well into leukocytes and macrophages, which makes them suitable agents in treatment of intracellular infections. Several studies have reported the in vitro activity of quinolones against Brucella species (6,12,13,15,22 employed in the regimens were also not included in the study.The diagnostic criteria were a standard tube agglutination titer of 1/160 or more for anti-Brucella antibodies in the presence of compatible clinical findings (fever, night sweats, arthralgia, hepatomegaly, splenomegaly, and lymphadenopathy) and isolation of a Brucella sp. from blood or bone marrow cultures.Sacroiliitis, spondylitis, peripheral arthritis, and orchitis were defined by appropriate findings on physical examination and relevant radiographic, radionuclide, and tomographic studies. Briefly, pain over the involved vertebral bodies or sacroiliac joints, accompanied by isotope accumulation in a radionuclide scan, was defined as sacroiliitis or spondylitis. Narrowing and/or irregularity of the sacroiliac articular spaces in plain X-ray films were considered to support the diagnosis of sacroiliitis.

“…More recently, doxycycline (DOX) and rifampin (RIF) have been proposed as better agents by the joint FAO/WHO Expert Committee on Brucellosis (9) and have largely replaced the STR-tetr-acycline regimen. Despite the extensive cumulative clinical experience of therapy trials for human brucellosis, only in the past 7 years have controlled clinical trials been performed to compare the efficacy of the proposed combinations (1,3,5,17,21).…”

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confidence: 99%

Therapy of experimental murine brucellosis with streptomycin alone and in combination with ciprofloxacin, doxycycline, and rifampin

Lang

Shasha

Rubinstein

1993

The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a BruceUla melitensis experimental infection in a mouse model. Animals were infected with 2 x 104 to 4 x I04 CFU of B. melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days. Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy. Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice. RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained. DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured. All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls. These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B. melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis. The results also appear to support the clinical superiority of combination drug therapy over monotherapy.