Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=yjoc20
Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: https://www.tandfonline.com/loi/yjoc20
Comparison of Five Antimicrobial Regimens for the
Treatment of Brucellar Spondylitis: A Prospective,
Randomized Study
Y. Bayindir, E. Sonmez, A. Aladag & N. Buyukberber
To cite this article: Y. Bayindir, E. Sonmez, A. Aladag & N. Buyukberber (2003) Comparison of Five Antimicrobial Regimens for the Treatment of Brucellar Spondylitis: A Prospective, Randomized Study, Journal of Chemotherapy, 15:5, 466-471, DOI: 10.1179/joc.2003.15.5.466
To link to this article: https://doi.org/10.1179/joc.2003.15.5.466
Published online: 18 Jul 2013.
Submit your article to this journal
Article views: 26
View related articles
Journal of Chemotherapy Vol. 15 - n. 5 (466-471) - 2003
© E.S.I.F.T. srl - Firenze ISSN 1120-009X
INTRODUCTION
Brucellosis exists worldwide and is a systemic infection caused by facultative intracellular bacteria
of the genus Brucella that can involve many organs and tissues 1,2. The disease has limited geographic distribution 3, but remains an important public health problem in the Mediterranean region, including
Comparison of Five Antimicrobial Regimens
for the Treatment of Brucellar Spondylitis:
A Prospective, Randomized Study
Y. BAYINDIR1 - E. SONMEZ2- A. ALADAG3 - N. BUYUKBERBER4
1 Inonu University, Medical Faculty, Department of Infectious Diseases, 3Neurosurgery, Malatya, Turkey. 2 Kadir Has University, Medical Faculty, Department of Infectious Diseases, Istanbul, Turkey.
4 Gaziantep University, Medical Faculty, Department of Microbiology, Gaziantep, Turkey.
Correspondence: Yrd. Doç. Dr. Yasar Bayindir, Inönü Üniversitesi Tıp Fakültesi, Infeksiyon Hastalıkları AD,
Malatya, Turkey. Phone: +90 422 341 06 60; Fax: +90 422 341 07 28. E-mail: yasarb@inonu.edu.tr - buyukberber@gantep.edu.tr
Summary
Brucellosis, a zoonosis with worldwide distribution, is a systemic infection and still an important public health problem in Turkey. The best antimicrobial combina-tion and schedule for the treatment of brucellosis with spondylitis has not yet been clearly determined. In a prospective and randomized study, we compared the effica-cy of five antimicrobial regimens for treatment of 102 patients with lumbar brucel-lar spondylitis. Patients were randomly assigned to receive antimicrobial combina-tion therapy. Twenty patients received streptomycin 1 g/day intramuscularly for 15 days and tetracycline-HCl, 500 mg every 6 h orally for 45 days (ST), 21 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally for 45 days (SD), 20 patients received doxycycline 100 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (DR), 19 patients received ofloxacin, 200 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (OR), and 22 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally for 45 days plus rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (SDR). Initial therapeutic failure occurred in 2 patients (10%) in the ST regimen group, 4 patients (19%) in the SD group, 3 patients (15%) in the DR group and 5 patients (26%) in the OR regimen. In addi-tion, 2 patients (10%) in the DR group and 5 patients (26%) in the OR regimen relapsed during the follow-up period. There was no relapse in any patients in the ST, SD, and SDR groups. The response rates were 90% in the ST and 81% in the SD groups. In contrast, there was a maximum good response (100%) and no relapse in the SDR group. In conclusion, a combination of doxycycline, strepto-mycin, and rifampicin can be recommended as therapy for brucellar spondylitis and to reduce relapse rates.
Key words: Brucellar spondylitis, doxycycline, streptomycin, rifampicin,
brucel-losis.
REVIEW
COMPARISON OF FIVE ANTIMICROBIAL REGIMENS FOR THE TREATMENT OF BRUCELLAR SPONDYLITIS: A PROSPECTIVE... 467 Eastern Turkey 4-7. Osteoarticular complications are
common in brucellosis and have been described in 20-60% of cases 1. Especially lumbar spondylitis is the most prevalent and important clinical form of osteoarticular involvement in adults with brucellosis 8,9. Spondylitis may be difficult to diagnose and can be complicated by potentially devastating neurologi-cal or vascular conditions because of failure in diag-nosis 10-12. On the other hand, even though a combi-nation of effective antimicrobial agents is the treat-ment of choice, managetreat-ment of brucellar spondylitis still remains controversial in terms of drug selection, duration of treatment, and the role of surgery 13-18.
In our study, we performed a prospective ran-domized study to compare several combination antimicrobial regimens for patients with brucellar spondylitis.
MATERIALS AND METHODS
This study is a prospective, randomized trial comparing the efficacy of some combinations of antimicrobial agents known to be effective against brucellar spondylitis. Fifty-six males and 46 females (mean age 40.5 years, range 21 to 69 years) with brucellar spondylitis were treated and followed-up at Turgut Ozal Medical Center, Inonu University, Malatya, Turkey, between 1992 and 2001. The patients were randomly categorized according to given combinations of antimicrobial agents and final outcomes. Five different combinations of antimicro-bial agents, which were left to the discretion of our trials and approved by the institutional review board, were given to the patients with brucellar spondylitis. All the patients signed an informed consent.
The brucellosis diagnosis was established by using the following criteria: 1. consumption of un-pasteurized milk or other dairy products in history, 2. compatible clinical picture (fever, sweating, arthralgia, hepatomegaly, splenomegaly or other signs and symptoms), 3. detection of anti-Brucella antibodies at significant titer (1/160 or more) in a standard tube agglutination test (SAT), 4. isolation of Brucella species in blood culture.
Blood cultures were performed and incubated up to 3 weeks using BACTEC 9120 (Becton Dickinson, Madrid, Spain). Presumptive identification was made on the basis of colony morphology, Gram staining, oxidase, and urea test. Brucella species appeared as non-pigmented, non-hemolytic, and punctate colonies after 48 h incubation. All suspicious colonies were examined by Gram staining and posi-tive oxidase and urea test 19. As serological tests, the standard tube agglutination (SAT) and rose Bengal tests were done by standard methods. We used SAT for all patients and 98 patients were found to be positive according to SAT. However, only in 4
patients with SAT seronegativity, we had performed SAT with AHG for whom brucellosis was suspected clinically. For spondylitis, the radiographic findings were recorded by determining epiphysitis of the anterosuperior angle of the vertebra, narrowing of the disc space, erosion, sclerosis, vertebral collapse and osteomyelitis. All patients with suspected spondylitis on plain radiograph were scanned by CT. Brucellar spondylitis is considered as focal and dif-fuse by CT or MRI. Focal spondylitis was defined as focal areas of abnormal signal intensity, usually local-ized in the anterior aspect of an end plate of a verte-bra at the diskoverteverte-bral junction. Diffuse spondylitis was defined as diffuse abnormal signal intensity of adjacent vertebrae and the intervening disk. Although radiography is sufficient for demonstrating focal spondylitis, MR imaging is preferred for assess-ing diffuse disease 20. MRI was performed in 64 patients.
Treatment groups
Twenty patients received streptomycin 1 g/day i.m. for 15 days and tetracycline-HCl, 500 mg every 6 h orally for 45 days (ST group); 21 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally (SD group) for 45 days; 20 patients received doxycycline 100 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (DR group); 19 patients received ofloxacin, 200 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (OR group) and 22 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally for 45 days plus rifampicin 15 mg/kg per day in a single morn-ing dose orally for 45 days (SDR group). Maximum rifampicin dose was 900 mg/day. All patients were followed up for at least 6 months after stopping the therapy (Table 1).
Patients were monitored for therapy efficacy and toxicity using clinical and laboratory data. Complete blood count, erythrocyte sedimentation rate (ESR), serum transaminase, creatinine, lactate dehydroge-nase, gamma-glutamyl transpeptidase, alkaline phos-phatase, albumin, bilirubin and electrolyte levels were measured on days 7, 14 and at the end of the therapy. Control serology for brucellosis was per-formed at the end of therapy. Blood culture, brucel-losis serology and radiological and other diagnostic imaging methods were re-performed according to the symptoms of the patients’ duration of follow-up. After the end of therapy, patients were reassessed as outpatients at months 1, 3, 6, and 12, as well as whenever clinical symptoms reappeared. Drug safety was assessed on the basis of clinical adverse events and laboratory tests. Table 2 shows the
demograph-ic characteristdemograph-ics and clindemograph-ical-symptomatdemograph-ic findings of patients at baseline in the five combination antimi-crobial agents groups.
The patients receiving five different combination regimens were classified into 3 groups according to the clinical outcome of brucellar spondylitis at the end of follow-up. The response was considered good if the patient recovered and did not have any clinical or bacteriological signs of infection. If the patient continued to have clinical and bacteriological signs that suggested persistent infection after 45 days of treatment, this was considered to be therapeutic fail-ure. If the patient had initially recovered, but clinical signs reoccurred and at least a four-fold rise in spe-cific IgG antibodies was detected in SAT with 2-mer-captoethanol, this was considered relapse.
Statistical analysis
Statistical analysis was performed by using the Statistical Package for the Social Sciences (SPSS). The results are presented as mean ± SEM. κ2 test for qualitative variables and Student’s t-test for quan-titative variables was used for statistical analysis. A p value of <0.05 was considered statistically signifi-cant.
RESULTS
One hundred and two patients (56 males and 46 females) with brucellar spondylitis were evaluated. There were no significant differences in age, sex, and duration of the symptoms prior to therapy, serological test positivity and extent of spondylitis. Low back pain was the most common symptom (100%). Constitutional symptoms and fever were the other common symptoms (77.4% and 57.8%, respectively). The time from onset of symptoms to diagnosis of spondylitis was 16 months (median, 8 weeks). All patients were followed-up for at least 6 months.
Standard tube agglutination testing of initial sam-ples from 98 of the 102 (96%) patients was positive for antibodies to Brucella spp (titer≥1:160). Blood cultures from 12 (11.7%) of 102 patients were posi-tive. ESRs were measured for all patients (mean ESRs 40.5 mm/h). Mean WBC was 7780/mm3. Leukocytosis (>10,500/mm3) was found in 20 patients. Four patients (3.9%) had focal spondylitis and 98 had diffuse disease (96.1%). Three patients had epidural abscess and one had paravertebral abscess by CT and MRI.
Fourteen (13.7%) initial therapeutic failures and 7 (6.8%) relapses occurred during the study period. Initial therapeutic failure occurred in 2 patients (10%) in the ST regimen, in 4 patients (19%) in the SD group, in 3 patients (15%) in the DR group, and in 5 patients (26%) in the OR group. In addition, 2 patients (10%) in the DR regimen and 5 patients (26%) in the OR group relapsed during the follow-up period. The organism could not be isolated from any of these patients. There was no relapse in any patients in groups ST, SD, and SDR. Good response occurred in the ST (90%) and SD (81%) groups. In contrast, there was a maximum good response (100%) and no relapse in the SDR group (p<0.05). Treatment outcomes are shown in Table 3. There were no differences between patients with therapeutic failure and relapses in terms of age, sex, duration of the symptoms, blood culture positivity and extent of spondylitis. The patients with thera-peutic failure and relapses were treated with an alternative regimen.
All antimicrobial regimens were generally well tolerated. Severe toxic effects were uncommon in all five antimicrobial regimens. The most commonly observed adverse effects were gastrointestinal com-plaints (12%-17% for all groups); including heart-burn, epigastric pain, nausea, and vomiting. Therapy was not interrupted in any patient due to severe hypersensitivity reaction and elevated liver transaminase levels (more than five times the base-line levels).
TABLE1 - Antimicrobial combinations, dosage and schedule.
Groups N. Combination of antibiotics Dosage and duration of therapy
ST 20 Streptomycin + Tetracycline-HCl 1 g/d i.m.* (15 d) +500 x4 mg/d p.o. (45 d) SD 21 Streptomycin + Doxycycline 1 g/d i.m. (15 d) + 100 x2 mg/d p.o. (45 d) SDR 22 Streptomycin + Doxycycline + Rifampicin 1 g/d i.m. (15 d) + 100 x2 mg/d p.o. (45 d) +
15 mg/kg (600-900 mg/d) x 1 p.o. (45 d)
DR 20 Doxycycline + Rifampicin 100 x 2 mg/d p.o. (45 d) + 15 mg/kg (600-900 mg/d) x 1 p.o. (45 d)
OR 19 Ofloxacin + Rifampicin 200 x2 mg/d p.o. (45d) + 15 mg/ kg (600-900 mg/d) x 1 p.o. (45 d)
COMPARISON OF FIVE ANTIMICROBIAL REGIMENS FOR THE TREATMENT OF BRUCELLAR SPONDYLITIS: A PROSPECTIVE... 469
TABLE2 - Characteristics of patients with brucellar spondylitis divided into five antimicrobial combination groups.
Characteristics Groups
ST SD SDR DF OF Total
Number (%) 20 (19.6%) 21 (20.6%) 22 (21.6%) 20 19.6%) 19 (18.6%) 102 (100%) Mean age 44.6 38.5 41.8 40.7 37.1 40.5 Male/female 12/8 11/10 12/10 11/9 10/9 56/46 Living in urban/rural area 15/5 11/10 12/10 11/9 10/9 59/43 Risk factors
Occupational exposure 2 5 1 0 3 11 Ingestion of unpasteurized milk 18 15 10 9 9 61 / dairy products
Mean duration of symptoms 7 8 7 7 9 before therapy (weeks)
Symptoms
Lower back pain 20 21 22 20 19 102
Fever 17 10 7 8 8 50
Constitutional symptoms 18 17 19 15 10 79
Positive cultures 4 3 5 3 1 16
Serological tests
SAT ≥1/160 20 21 20 18 19 98 SAT with AHG ≥1/160 0 0 2 2 0 4 Four-fold rise titer 12 17 11 9 11 60 Other laboratory tests
WBC ( /mm3) <4000 9 8 10 8 9 44 4000-10,000 5 7 9 10 7 38 >10,000 6 5 5 4 6 20 Hemoglobin <12g/dl 0 2 7 2 2 13 >12g/dl 20 19 15 18 17 89 ESR <50 mm/h 20 20 18 20 18 96 >50 mm/h 0 1 4 0 1 6 Elevated ALT/AST 10 5 12 8 9 44 CRP positivity (mg/L) 20 21 22 20 19 102 Radiological findings Focal spondylitis 1 1 0 1 1 4 Diffuse spondylitis 19 20 22 19 18 98 Epidural abscess 0 0 3 0 0 3 Paravertebral abscess 0 0 1 0 0 1 SAT: Standard tube agglutination test, AHG: anti-human globulin, WBC: white blood cells,
ESR: erythrocyte sedimentation rate, ALT: alanine aminotransferase, AST: aspartate aminotransferase, CRP: C-reactive protein, MRI: magnetic resonance imaging
DISCUSSION
Diagnosis of brucellosis needs to be confirmed by laboratory tests. Blood culture is still the standard method. Automated incubation-detection methods are effective but allowance should be made for the relatively slow growth of the organism 3,21. In our cases, we detected blood culture positivity in 7 patients (6.9%) for B. melitensis, and in 5 patients (4.9%) for B. abortus (total: 11.7%). In our cases, a brucella SAT titer of more than 1/160 was detected in 100% and a four-fold rise titer was found in 59%. Al Soub et al reported the importance of serological brucellar tests in developing countries 22. Serological tests were also helpful in the diagnosis of brucellar spondylitis. Spondylitis is one of the major manifes-tations of osteoarticular brucellosis. The incidence of spondylitis reported in the literature varies signifi-cantly, ranging from 10% to >50% 8,9,13. Brucellar spondylitis occurs most commonly in adults aged between 50 and 60 years. The lumbar spine is the most frequently involved area for spondylitis 20,22-26. It can be either focal or diffuse 9,13. In our series, the mean age was 40.5 years and our patients were younger than other series. The other demographic and clinical characteristics of our patients were simi-lar to those of previously described groups of patients with brucellar spondylitis 13,22-26.
The aim of an antimicrobial regimen is to con-trol the acute symptoms of brucellosis and to pre-vent complications and relapses. The choice of regi-men and duration of therapy should be based on the presence of focal disease. Treatment with a single antibiotic and of short duration carries a high risk for relapse 14,27. The treatment recommended by the World Health Organization (WHO) for acute brucel-losis in adults is rifampicin 600 to 900 mg and doxycycline 200 mg daily for a minimum of 6 weeks 28. Nevertheless, there are very few comparative tri-als on this issue and none of them has shown the advantages of the DR regimen over the DS regimen. In most of studies, the DR regimen showed higher relapse rates than the DS 14,17,29,30. Ariza et al reported that the DR regimen is a less efficacious combination therapy to prevent brucellosis relapses than is the classical ST combination when both are administered for 30 days 31.
Early diagnosis and optimal treatment are known to be effective and surgical procedures are rarely required in brucellar spondylitis. However, treatment of brucellar spondylitis remains controversial with regard to the selection of antibiotics and treatment duration. The most widely used antibiotic combina-tion for therapy is tetracycline or doxycycline and streptomycin; this combination provides sustained improvement in the condition of 60%–90% of patients 13,16. In previous trials, most therapeutic fail-ures in patients treated with the DR regimen consist-ed of clinical lesions in the spine. Ariza et al report-ed that doxycycline plus rifampicin might be less effective in patients with brucellar spondylitis 14. The regimens containing streptomycin yielded statistically more favorable results than other combinations 30. Mousa et al reported that prolonged treatment with a combination of three anti-brucella drugs was nec-essary 11. Ariza et al recommended the combined antibiotic regimen of streptomycin plus doxycycline for good clinical improvement in brucellar spondylitis cases 13. Some studies also recommended strepto-mycin plus doxycycline plus rifampicin combination in brucellosis complicated with neurobrucellosis, endocarditis and unresponsive or low responding spondylitis 2,3.
The duration of antibiotic therapy for brucellar spondylitis is longer than for systemic brucellosis without spondylitis 32. Although the duration varies considerably in different studies, treatment includes antibiotics administered for a period between 6 and 12 weeks 13,16. On the other hand, the ST regimen seems superior to the SD regimen in our study. The reason for such a superior result is unknown. However, the higher toxicity profile of tetracycline compared to doxycycline makes less use of it in the standard regimens in many diseases including brucel-losis. Therefore, tetracycline resistance may decline through the years with less use of the drug.
In our study, the streptomycin plus doxycycline plus rifampicin combination was found to be the most effective combination for treatment of brucellar spondylitis, as we observed no therapeutic failure or relapse in this group. Complete response was also achieved in the SDR group in 3 patients with epidural abscess and 1 patient with paravertebral
TABLE3 - Outcomes of the antimicrobial therapy.
Group N. Good response (%) Failure (%) Relapse (%) Total (%) ST 20 18 (90) 2 (10) 0 20 (100) SD 21 17 (81) 4 (19) 0 21 (100)
SDR 22 22 (100) 0 0 22 (100)
DR 20 15 (75) 3 (15) 2 (10) 20 (100) OR 19 9 (48) 5 (26) 5 (26) 19 (100)
COMPARISON OF FIVE ANTIMICROBIAL REGIMENS FOR THE TREATMENT OF BRUCELLAR SPONDYLITIS: A PROSPECTIVE... 471 abscess. Therefore, triple combination is more
effec-tive especially in patients with complicated brucellar spondylitis. The highest therapeutic failure and relapse rates were observed with the OR regimen in our study (26% both of them). Despite their in vitro activity against Brucella spp., quinolones do not appear to constitute adequate therapy for acute bru-cellosis 33-35.
In conclusion, brucellar spondylitis is an impor-tant disease in eastern Turkey and other developing countries. The SDR combination is very effective therapy and this triple drug regimen reduces failure and relapse rates in brucellar spondylitis.
REFERENCES
1Young EJ. Brucella species. In: Mandell GL, Bennet JE,
Dolin R (eds). Principles and Practice of Infectious Diseases. Fifth ed. New York: Churchill Livingstone 2000: 2386-2393.
2Young EJ. An overview of human brucellosis. Clin Infect
Dis 1995; 21: 283289.
3Corbel MJ. Brucellosis: an Overview. Emerg Infect Dis
1997; 3(2): 213-221.
4Sonmez E, Durmaz B, Aladag M, Sahin K, Ozbilge H,
Gunal S. Prevalence of brucellosis in Malatya Region. Turk J Med 1997; 2: 102-105.
5 Durmaz R, Durmaz B, Refik M, Sonmez E.
Seropositivity of brucellosis in Malatya, Turkey. Tr J Med Sci 1997; 27: 125-128.
6 Sari R, Buyukberber N, Sevinc A, Bayindir Y,
Buyukberber S. Brucellosis in the etiology of febrile neutrope-nia: case report. J Chemother 2002;14: 88-91.
7Sevinc A, Kutlu NO, Kuku I, Ozgen U, Aydogdu I,
Soylu H. Severe epistaxis in brucellosis-induced isolated thrombocytopenia: a report of two cases. Clin Lab Haematol 2000; 22: 373-375.
8Colmenero JD, Reguera JM, Martos F,
Sanchez-De-Mora D, Delgado M, Causse M, et al. Complications associat-ed with Brucella melitensis infection: a study of 530 cases. Medicine 1996; 75(4): 195-211.
9Gonzalez-Gay MA, Porrua C, Ibanez D,
Garcia-Pais MJ. Osteoarticular complications of brucellosis in an Atlantic area of Spain. J Rheumatol 1999; 26:141-145.
10 Lopez-Arlandis JM, Benedito J, Barcia Marino C,
Hernandez M. Epidural spinal cord compression in brucellar spondylitis. Rev Clin Esp 1989; 185: 165-166.
11Mousa AM, Bahar RH, Araj GF, Koshy TS, Muhtaseb
SA, al-Mudallal DS, Marafie AA. Neurological complications of Brucella spondylitis. Acta Neurol Scand 1990; 81: 16-23.
12 Sanchez-Gonzalez J, García-Delange T, Martos F,
Colmenero JD. Thrombosis of the abdominal aorta secondary to Brucella spondylitis. Infection 1996; 24: 261-262.
13 Ariza J, Gudiol F, Valverde J, Pallares R,
Fernandez-Viladrich P, Rufi G, et al. Brucellar spondylitis. A detailed analysis based on current findings. Rev Infect Dis 1985; 7: 656-664.
14 Ariza J, Gudiol F, Pallares R, Viladrich PF, Rufi G,
Corredoira J, Miravitlles MR. Treatment of human brucellosis with doxycycline plus rifampin or doxycycline plus strepto-mycin: a randomized, double-blind study. Ann Intern Med 1992; 117: 25-30.
15 Al-Sibai MB, Halim MA, El-Shaker MM, Khan BA,
Qadri SM. Efficacy of ciprofloxacin for treatment of Brucella
melitensis infections. Antimicrob Agents Chemother 1992;
36: 150-152.
16 Colmenero JD, Jimenez-Mejias ME, Sanchez-Lora FJ,
Reguera JM, Palomino-Nicas J, Martos F, et al. Pyogenic, tuberculous, and brucellar vertebral osteomyelitis: a descriptive and comparative study of 219 cases. Ann Rheum Dis 1997; 56: 709-715.
17 Solera J, Rodriguez-Zapata M, Geijo P, Largo J,
Paulino J, Saez L, et al. Doxycycline-rifampin versus doxycy-cline-streptomycin in treatment of human brucellosis due to
Brucella melitensis. Antimicrob Agents Chemother 1995;
39: 2061-2067.
18Tekkok IH, Berker M, Ozcan OE, Ozgen T, Akalin E.
Brucellosis of the spine. Neurosurgery 1993; 33: 838-844.
19Shapiro DS, Wong JD. Brucella. In: Murray PR, Baron
EJ, Pfaller MA, Tenover FC, Yolken RH (ed.). Manual of clin-ical microbiology, 7thed. ASM Press, Washington DC, 1999,
pp 625-631.
20 Al-Shabed MS, Sharif HS, Haddad MC, Aabed MY,
Sammak BM, Mutairi MA. Imaging features of musculoskeletal brucellosis. Radiographics 1994; 14:333-348
21Solomoon HM, Jackson D. Rapid diagnosis of Brucella
melitensis in blood; some operational characteristics of
BACT/ ALERT. J Clin Microbiol 1992; 28: 2139-2141.
22 Al Soub H, Uwaydah AK, Hussain AH. Vertebral
osteomyelitis in Katar: Br J Clin Pract 1994; 48 (3): 130-132.
23 Rajapakse CN. Bacterial infections: osteoarticular
bru-cellosis. Clin Rheumatol 1995; 9(1): 161-167.
24 Lopes C, Oliveira J, Malcata L, Pombo V, Da Cunha
S, Corte-Real R, et al. Spinal brucellosis. 4 years of experi-ence. Acta Med Port 1992; 5: 419-423.
25 Samra Y, Hertz M, Shaked Y, Zwas S, Altman G.
Brucellosis of the spine: a report of 3 cases. J Bone Joint Surg Br 1982; 64: 429-431.
26 Solera J, Lozano E, Martinez-Alfaro E, Espinosa A,
Castillejos ML, Abad L. Brucellar spondylitis: review of 35 cases and literature survey. Clin Infect Dis 1999; 29(6): 1440-1449.
27 Hall WH. Modern chemotherapy for brucellosis in
humans. Rev Infect Dis 1990; 12:1060-1099.
28 Food and Agriculture Organization: World Health
Organization. FAO-WHO Expert Committee on Brucellosis. WHO Technical Report Series, 6threport, 1986; 740: 56-57. 29 Colmenero Castillo JD, Hernandez Marquez S,
Reguera Iglesias JM, Cabrera Franquelo F, Rius Diaz F, Alonso A. Comparative trial of doxycycline plus streptomycin versus doxycycline plus rifampin for the therapy of human brucellosis. Chemotherapy 1989; 35(2): 146-152.
30 Montejo JM, Alberola I, Glez-Zarate P, Alvarez A,
Alonso J, Canovas A, et al. Open randomized therpeutic trial of six antimicrobial regimens in the treatment of human bru-cellosis. Clin Infect Dis 1993; 16(5): 671-676.
31 Ariza J, Gudiol F, Pallares R, Rufi G,
Fernandez-Viladrich P. Comparative trial of rifampin-doxycycline versus tetracycline-streptomycin in the therapy of human brucellosis. Antimicrob Agents Chemother 1985; 28 (4): 548-551.
32 Solera J, Martinez-Alfaro E, Espinosa A. Recognition
and optimum treatment of brucellosis. Drug 1997; 53: 245-256.
33 Lang R, Raz R, Sacks T, Shapiro M. Failure of
pro-longed treatment with ciprofloxacin in acute brucellosis. J Antimicrobial Chemother 1990; 26: 841-846.
34 Garcia Rodriguez JA, Garcia Sanchez JE, Trujillano I.
Lack of effective bactericidal activity of new quinolones against
Brucella spp. Antimicrob Agents Chemother 1991; 35:
756-759.
35Kocagoz S, Akova M, Altun B, Gur D, Hascelik G. In
vitro activities of new quinolones against Brucella melitensis isolated in a tertiary-care hospital in Turkey. Clin Microbiol Infect 2002; 8: 240-242.
