Comparison of doxycycline–streptomycin, doxycycline–rifampin, and ofloxacin–rifampin in the treatment of brucellosis: a randomized clinical trial

Open ArchivePublished:February 01, 2012DOI:https://doi.org/10.1016/j.ijid.2011.12.003

      Summary

      Background

      Traditional regimens for the treatment of brucellosis are associated with significant relapse rates. The aim of this study was to compare the efficacy of ofloxacin plus rifampin (OFX–RIF) versus doxycycline plus streptomycin (DOX–STR) and doxycycline plus rifampin (DOX–RIF) regimens in the treatment of brucellosis.

      Methods

      Two hundred and nineteen patients with brucellosis were enrolled in a randomized clinical trial; 28 cases were withdrawn because they did not attend the follow-up. Out of 191 patients with brucellosis, 64 received OFX–RIF, 62 received DOX–RIF, and 65 patients received DOX–STR regimens. All patients were assessed during the period of therapy in the second, fourth, and sixth weeks by clinical course and were also followed up clinically and serologically for 6 months after the cessation of therapy.

      Results

      The highest clinical response (95.4%) was observed in the DOX–STR group (p = 0.009). The results of multivariate analysis indicate that treatment with DOX–STR had the least therapeutic failures among the three groups (p = 0.033). Adverse reactions were seen in 16.8% of patients, but there was no significant difference among the three groups (p = 0.613). The lowest relapse rate (4.6%) was observed in the DOX–STR group (p = 0.109).

      Conclusions

      We conclude that the DOX–STR combination should remain the first-line regimen for the treatment of brucellosis in our region; we recommend DOX–RIF and OFX–RIF combinations as the second-line regimens.

      Keywords

      1. Introduction

      Brucellosis is a major zoonosis worldwide and represents a serious public health problem, especially for the countries in the Indian subcontinent, Arabian Peninsula, South Eastern Europe, and Mediterranean Basin.
      • Donev D.M.
      Brucellosis as priority public health challenge in south eastern European countries.
      The disease is endemic in Iran, with the highest incidence rates of up to 130 per 100 000 population reported from the western part of the country. Due to improved efforts in the active immunization of young animals in recent years, the incidence rate decreased to 45 per 100 000 in 2008 in Hamedan, western Iran.
      • Moradi A.
      • Norouzi N.A.
      • Talebi B.
      • Erfani H.
      • Karimi A.
      • Bathaei S.J.
      • et al.
      Evaluation of animal vaccination against brucellosis on human incidence rate in Hamedan Province 2002–2008.
      However, the disease is still prevalent among those in the economically active age groups, especially in the rural population.
      The goals of the treatment of brucellosis are to reduce symptoms, length of disease, and complications, and to prevent relapses. The use of appropriate antibiotic combinations is also required for the successful treatment of brucellosis.
      In addition to standard regimens for brucellosis, which include doxycycline plus streptomycin or rifampin, a combination of one of these drugs with ciprofloxacin has also been used in recent years.
      • Pappas G.
      • Akritidis N.
      • Bosilkovski M.
      • Tsianos E.
      Brucellosis.
      • Ersoy Y.
      • Sonmez E.
      • Tevfik M.R.
      • But A.D.
      Comparison of three different combination therapies in the treatment of human brucellosis.
      However, a number of small clinical trials with combination regimens containing quinolones have shown adequacy, but not superiority.
      • Pappas G.
      • Christou L.
      • Akritidis N.
      • Tsianos E.V.
      Quinolones for brucellosis: treating old diseases with new drugs.
      The equal efficacy and relapse rates of ofloxacin plus rifampin and doxycycline plus rifampin have been reported in a randomized clinical trial.
      • Karabay O.
      • Sencan I.
      • Kayas D.
      • Şahin I.
      Ofloxacin plus rifampicin versus doxycycline plus rifampicin in the treatment of brucellosis: a randomized clinical trial.
      In this study, we aimed to compare the efficacy, relapse rate, therapeutic failure rate, and adverse effects of ofloxacin plus rifampin (OFX–RIF) versus doxycycline plus streptomycin (DOX–STR) and doxycycline plus rifampin (DOX–RIF) regimens in the treatment of brucellosis.

      2. Materials and methods

      2.1 Study design

      A prospective randomized clinical trial with repeated measurements was carried out. From April 2008 to March 2010, 219 patients with brucellosis who were referred to Sina Hospital as outpatients or inpatients were enrolled in this study. Sina Hospital is the main referral center for infectious diseases in Hamedan Province in the west of Iran.
      Exclusion criteria were defined age under 17 years, endocarditis, neurobrucellosis, spondylitis, renal failure, hepatic failure, or a history of treatment for brucellosis in the last 6 months.

      2.2 Diagnosis of brucellosis

      Brucellosis was diagnosed based on clinical presentation compatible with brucellosis in the presence of significant titers of specific antibodies (standard tube agglutination ≥1/160, Coombs test ≥1/160, 2-mercaptoetanol (2-ME) ≥1-80, or Brucella IgG-ELISA >12) and/or a positive blood culture. ELISA for Brucella IgG was performed using a specific kit (IBL, Hamburg, Germany), and the antigens for other serologic tests were obtained from the Pasteur Institute, Iran.

      2.3 Randomization, treatment, and follow-up

      According to the results of previous studies, we considered the efficacy rate of the DOX–STR regimen to be 90–95% and for the DOX–RIF and OFX–RIF regimens to be 75–85%. Based on a confidence interval of 95% (α = 0.05) and a power calculation of 80% (β = 20%), the sample size required for each group was estimated to be 73 cases. In this study, 246 patients were assessed for eligibility and 27 cases were excluded because they did not meet the inclusion criteria or declined to participate. Therefore, on the basis of a random numbers table, 219 prepared questionnaires were divided into the three antimicrobial therapy groups and the patients were enrolled into the study in questionnaire number order. Twenty-eight patients did not attend the first follow-up examinations and so were excluded at the beginning of the study (Figure 1). Finally, 65 patients in the DOX–STR group received doxycycline 200 mg daily for 6 weeks plus streptomycin 1000 mg daily for the first 3 weeks; 62 patients in the DOX–RIF group were treated with doxycycline 200 mg daily plus rifampin 15 mg/kg daily for 6 weeks; and 64 patients in the OFX–RIF group received ofloxacin 800 mg daily plus rifampin 15 mg/kg daily for 6 weeks. The study was approved by the Research Committee of Hamedan University of Medical Sciences.
      Figure thumbnail gr1
      Figure 1Flow chart of patient recruitment and follow-up in this study.
      After obtaining informed consent, a detailed medical history was taken from each patient and a complete physical examination was performed. The information was recorded in the questionnaires.

      2.4 Definitions

      Primary outcomes were evaluated by measuring clinical response rates and therapeutic failure rates. Secondary outcomes were evaluated by measuring relapse rates and adverse reaction rates.
      Clinical response was defined as clinical improvement of primary signs (objective) and symptoms (subjective) of disease at the end of treatment recorded apart for each patient. Therapeutic failure was defined as the persistence of symptoms and signs at the end of 6 weeks of therapy. Relapse was defined as the reappearance of symptoms and signs accompanied by a 2-ME titer ≥1/80 during the follow-up period.

      2.5 Follow-up

      All patients were assessed in the second, fourth, and sixth weeks of therapy by clinical course. They were also followed-up clinically and serologically for 6 months after the cessation of therapy.

      2.6 Statistical analysis

      Data were analyzed using SPSS statistical package, version 15. The analysis of variance (ANOVA) test was used for quantitative variables, the Chi-square test for qualitative variables, and logistic regression for multivariate analysis. A sensitivity analysis was conducted to investigate the best and the worst case scenarios in this study to reduce the risk of bias. In the best case scenario, it was assumed that all patients excluded had a good response to treatment, and in the worst case scenario, it was assumed that all patients excluded did not respond to treatment, for all three treatment groups. Differences with a p-value of <0.05 were considered statistically significant.

      3. Results

      Of the 191 patients with brucellosis, 64 received OFX–RIF, 62 received DOX–RIF, and 65 received DOX–STR regimens. There were no significant differences in the demographic and clinical characteristics and laboratory findings among the three groups (Table 1). The most common symptoms and signs included arthralgia (74.3%), fatigue (73.8%), low back pain (68.1%), body ache (57.6%), sweating (49.2%), headache (46.6%), and anorexia (45.0%). Brucella melitensis was isolated from three of 12 patients for whom blood cultures were obtained.
      Table 1Demographic and clinical characteristics of 191 patients with brucellosis in the three therapy groups
      CharacteristicOfloxacin–rifampin (n = 64)Doxycycline–rifampin (n = 62)Doxycycline–streptomycin (n = 65)p-Value
      Age (years), mean ± SD40.5 ± 14.238.6 ± 17.339.9 ± 15.40.797
      Gender, female/male28/3628/3429/360.987
      Living, rural27 (42.2%)24 (38.7%)22 (33.8%)0.364
      Duration of symptoms (days), mean ± SD60.1 ± 10368.6 ± 150.946.6 ± 34.30.573
      Fever17 (26.6%)16 (25.8%)23 (35.4%)0.415
      Anorexia24 (37.5%)29 (46.8%)33 (50.8%)0.300
      Sweating36 (56.3%)23 (37.1%)35 (53.8%)0.065
      Weight loss14 (21.9%)14 (22.6%)19 (29.2%)0.564
      Headache31 (48.4%)29 (46.8%)29 (44.6%)0.218
      Low back pain43 (67.2%)40 (64.5%)47 (72.3%)0.631
      Arthralgia46 (71.9%)46 (74.2%)50 (76.9%)0.806
      Body ache38 (59.4%)34 (54.8%)38 (58.5%)0.862
      Fatigue45 (70.3%)43 (69.4%)53 (81.5%)0.218
      Splenomegaly10 (15.6%)5 (8.1%)10 (15.4%)0.352
      Arthritis7 (10.9%)16 (25.8%)10 (15.4%)0.077
      Orchitis (males)6/36 (16.7%)2/34 (5.9%)1/36 (2.8%)0.086
      SD, standard deviation.
      The primary and secondary outcomes of the disease in the three treatment groups are shown in Table 2. After 6 weeks of therapy, the highest clinical response was observed in the DOX–STR group (95.4%), in whom the symptoms including body ache, fatigue, sweating, and low back pain were significantly relieved. However, the sensitivity analysis for clinical response based on the worst and the best case scenarios showed that there were no significant differences among the three treatment groups (p = 0.095 and p = 0.064, respectively).
      Table 2Primary and secondary outcomes of brucellosis with the three therapy regimens
      CharacteristicOfloxacin–rifampin (n = 64)Doxycycline–rifampin (n = 62)Doxycycline–streptomycin (n = 65)p-Value
      Clinical response60 (93.8%)52 (83.9%)62 (95.4%)0.009
      Therapeutic failure4 (6.3%)10 (16.1%)3 (4.6%)0.036
      Adverse reactions12 (18.8%)8 (12.9%)12 (18.5%)0.613
      Relapse5 (7.8%)9 (15.3%)
      After the cessation of therapy, 59 patients underwent the 6-month follow-up.
      3 (4.6%)0.109
      a After the cessation of therapy, 59 patients underwent the 6-month follow-up.
      Therapeutic failure was observed in 8.9% of all patients. The DOX–RIF group showed the highest rate of failure (16.1%), and the lowest rate was observed in the DOX–STR group (4.6%). Logistic regression analysis was used to estimate differences among the three therapy groups based on selected characteristics; results are show in Table 3. The results of multivariate analysis indicate that treatment with DOX–STR had the least therapeutic failures among the three groups (p = 0.033). Adverse reactions were seen in 16.8% of patients, and there were no significant differences among the three groups (Table 4). Most of the adverse effects were classified as mild; therefore, these reactions were not severe enough to discontinue therapy. Of the 191 patients, 188 underwent 6 months of follow-up; three patients did not attend these follow-up examinations after the cessation of therapy. Relapse was observed in 9.0% of all patients. The lowest relapse rate was observed in the DOX–STR group (4.6%) and the highest in the DOX-RIF group (15.3%), although the difference was not significant.
      Table 3Multivariate analyses for different events in patients with brucellosis according to selected characteristics among the three therapy groups
      Eventp-ValueOR (95% CI)
      Clinical improvement
       Doxycycline–streptomycin
       Ofloxacin–rifampin0.9230.922 (0.178–4.788)
       Doxycycline–rifampin0.0350.233 (0.060–0.902)
       Age in years0.1670.978 (0.947–1.009)
       Male sex0.9300.954 (0.329–2.768)
      Therapeutic failure
       Doxycycline–streptomycin
       Ofloxacin–rifampin0.6191.482 (0.314–6.986)
       Doxycycline–rifampin0.0334.398 (1.128–17.144)
       Age in years0.0781.029 (0.997–1.063)
       Male sex0.9390.960 (0.341–2.700)
      Adverse reactions
       Doxycycline–streptomycin
       Ofloxacin–rifampin0.9800.988 (0.395–2.474)
       Doxycycline–rifampin0.3860.648 (0.242–1.730)
       Age in years0.1171.020 (0.995–1.046)
       Male sex0.9080.955 (0.435–2.095)
      Relapse
       Doxycycline–streptomycin
       Ofloxacin–rifampin0.3931.912 (0.433–8.452)
       Doxycycline–rifampin0.0673.598 (0.915–14.148)
       Age in years0.2380.980 (0.948–1.013)
       Male sex0.4520.085 (0.520–4.346)
      OR, odds ratio; CI, confidence interval.
      Table 4Frequency of adverse reactions among patients with brucellosis in the three therapy groups
      Some patients had more than one adverse effect. A total of 12 patients (18.8%) in the ofloxacin–rifampin group, eight patients (12.9%) in the doxycycline–rifampin group, and 12 patients (18.5%) in the doxycycline–streptomycin group had adverse reactions. No statistically significant differences among groups were found.
      Adverse reactionsOfloxacin–rifampin (n = 64)Doxycycline–rifampin (n = 62)Doxycycline–streptomycin (n = 65)
      Photosensitivity--2
      Epigastric pain632
      Nausea or vomiting121
      Diarrhea2--
      Heartburn1--
      Dizziness2-2
      Rash111
      Circumoral paresthesia115
      Urticaria11-
      Total15813
      a Some patients had more than one adverse effect. A total of 12 patients (18.8%) in the ofloxacin–rifampin group, eight patients (12.9%) in the doxycycline–rifampin group, and 12 patients (18.5%) in the doxycycline–streptomycin group had adverse reactions. No statistically significant differences among groups were found.

      4. Discussion

      In the present study, the highest clinical response rate and the lowest therapeutic failure rate were observed with the DOX–STR regimen, while the lowest clinical response rate and the highest therapeutic failure and relapse rates were seen in the DOX–RIF group. According to the results, the OFX–RIF regimen showed more efficacy than the DOX–RIF regimen. However, some clinical trials with combination regimens containing quinolones such as OFX–RIF have shown adequacy, but not superiority.
      • Pappas G.
      • Christou L.
      • Akritidis N.
      • Tsianos E.V.
      Quinolones for brucellosis: treating old diseases with new drugs.
      • Karabay O.
      • Sencan I.
      • Kayas D.
      • Şahin I.
      Ofloxacin plus rifampicin versus doxycycline plus rifampicin in the treatment of brucellosis: a randomized clinical trial.
      The superiority of the DOX–STR regimen has been reported in various studies, hence some authorities recommend the use of DOX–STR as the regimen of choice for the treatment of brucellosis.
      • Solera J.
      Treatment of human brucellosis.
      • Buzgan T.
      • Karahocagil M.K.
      • Irmak H.
      • Baran A.I.
      • Karsen H.
      • Evirgen O.
      • et al.
      Clinical manifestations and complications in 1028 cases of brucellosis: a retrospective evaluation and review of the literature.
      Nevertheless, there is no general agreement on the most appropriate regimen.
      In 1986, the World Health Organization proposed the two antibiotic combinations DOX–RIF and DOX–STR as standard therapeutic regimens for brucellosis.

      Joint FAO/WHO expert committee on brucellosis. World Health Organ Tech Rep Ser 1986;740:1–132.

      DOX–RIF was noted as the preferred choice due to the cheaper cost and the oral administration of the drugs. In the last two decades, several studies have indicated the equal efficacy of the two regimens; however, the DOX–STR regimen has been regarded as the therapy of choice for the treatment of osteoarticular complications of brucellosis.
      • Ariza J.
      • Bosilkovski M.
      • Cascio A.
      • Colmenero J.D.
      • Corbel M.J.
      • Falagas M.E.
      • et al.
      Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations.
      • Solera J.
      • Martinez-Alfaro E.
      • Espinosa A.
      • Castillejos M.L.
      • Geijo P.
      • Rodríguez-Zapata M.
      Multivariate model for predicting relapses in human brucellosis.
      Nevertheless, these regimens are still accompanied by 5–15% relapse rates.
      • Solera J.
      • Martinez-Alfaro E.
      • Espinosa A.
      • Castillejos M.L.
      • Geijo P.
      • Rodríguez-Zapata M.
      Multivariate model for predicting relapses in human brucellosis.
      • Ariza J.
      • Corredoira J.
      • Pallares R.
      • Viladrich P.F.
      • Rufi G.
      • Pujol M.
      • et al.
      Characteristics of and risk factors for relapse of brucellosis in humans.
      A long duration of therapy decreases the risk of relapse. However, the prolonged use of rifampin may increase the potential risk for the emergence of tuberculosis in endemic areas, such as our region, in which both brucellosis and tuberculosis are endemic.
      • Al-Hajjaj M.S.
      • Al-Kassimi F.A.
      • Al-Mobeireek A.F.
      • Alzeer A.H.
      Progressive rise of Mycobacterium tuberculosis resistance to rifampicin and streptomycin in Riyadh, Saudi Arabia.
      In a systemic review and meta-analysis of randomized controlled trials in 2008, the authors concluded that the DOX–RIF regimen is accompanied by more therapeutic failures than the DOX–STR regimen.
      • Skalsky K.
      • Yahav D.
      • Bishara J.
      • Pitlik S.
      • Leibovici L.
      • Paul M.
      Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials.
      They also concluded that the combination of a quinolone with rifampin is less effective than the DOX–RIF or DOX–STR combinations.
      Besides the superior efficacy of the DOX–STR regimen, our study also indicates the higher therapeutic failure and relapse rates of the OFX–RIF than the DOX–STR regimen. Moreover, in a recent clinical trial, we reported a high relapse rate of quinolone-containing regimens, including ciprofloxacin–rifampin and ciprofloxacin–doxycycline.
      • Keramat F.
      • Ranjbar M.
      • Mamani M.
      • Hashemi S.H.
      • Zeraati F.
      A comparative trial of three therapeutic regimens: ciprofloxacin–rifampin, ciprofloxacin–doxycycline and doxycycline–rifampin in the treatment of brucellosis.
      According to our results and those of other studies indicating the emergence of quinolone resistance, we recommend the use of fluoroquinolone-containing regimens only as alternative regimens and not as the first choice for the treatment of brucellosis.
      Of note is the prominence of B. melitensis in our region and many other endemic areas, which is the most virulent species and commonly results in complications with osteoarticular involvement.
      • Zowghi E.
      • Ebadi A.
      • Yarahmadi M.
      Isolation and identification of Brucella organisms in Iran.
      The consensus of most researchers that aminoglycoside-containing regimens such as DOX–STR are preferred for complicated brucellosis is in accordance with the brucellosis situation in our region, and may be explained by the reported superiority of DOX–STR in our results and those of other studies that have been conducted in our region and in other developing countries.
      • Hashemi S.H.
      • Keramat F.
      • Ranjbar M.
      • Mamani M.
      • Farzam A.
      • Jamal-Omidi S.
      Osteoarticular complications of brucellosis in Hamedan, an endemic area in the west of Iran.
      • Roushan M.R.
      • Baiani M.
      • Javanian M.
      • Kasaeian A.A.
      Brucellar epididymo-orchitis: review of 53 cases in Babol, northern Iran.
      • Al-Tawfiq J.A.
      Therapeutic options for human brucellosis.
      Our study had some limitations. The study was not double-blind and the patients were not followed-up for more than 6 months. In addition, because the patients were ambulatory, we did not perform blood cultures for all patients. Another limitation was the scarcity of fever in our cases, so we were not able to include fever as a criterion for clinical response in the follow-up of the patients. Another noticeable point in our study was the exclusion of patients with special forms of localized brucellosis including endocarditis, spondylitis, and neurobrucellosis. Therefore, we recommend more research regarding the treatment of these complications.
      According to the results of the worst and the best case scenarios in our study, there were no significant differences among the three regimen groups, so we recommend more research on these regimens.
      In conclusion, the DOX–STR combination should remain the first-line regimen for the treatment of brucellosis in our region; we recommend the DOX–RIF and OFX–RIF combinations as the second-line regimens.

      Acknowledgements

      This study was supported in part by the Vice-Chancellor of Research and Technology, Hamedan University of Medical Sciences, Hamedan, Iran. The contributions of L. Gachkar were supported by a fund from the Research Center for Infectious Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran (grant No. A-G-991).
      Ethical approval: The study was approved by the ethics committee of Hamedan University of Medical Sciences and subjects gave informed consent to participate.
      Conflict of interest: None declared.

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