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Use of antibiotics in the treatment of human brucellosis
CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 3, MARCH 1996
USE OF ANTIBIOTICS IN THE TREATMENT OF HUMAN BRUCELLOSIS SULAIMAN A. AL-MAJED, ABDUL KARIM AL-ASKA, AHMED AL-MITWALLI, ABDULLAH AL-WAZZAN, HUSSAIN AL-ARFAJ, AND AWAD AL-ANAZI Department
of Medicine,
College of Medicine, King Saud University, Riyadh, Saudi Arabia
ABSTRACT
Over a 3-year period (from 1987 through 1989), the medical charts of 346 patients (between 14 and 89 years of age with a male to female ratio of 1.6:l) with brucellosis were reviewed to determine the efficacy of various treatment regimens. Of 92 positive blood cultures, all the isolates were sensitive to tetracycline, streptomycin, and rifampicin; however, 17 isolates were resistant to co-trimoxazole. Various combinations of tetracycline, streptomycin, co-trimoxazole, and rifampicin were used for a prolonged period (3 months). Drugs were equally available to all patients. The best results were obtained with tetracycline plus streptomycin. Co-trimoxazole, when used alone, was found to be the least effective, with more failures and relapses. INTRODUCTION
Brucellosis is a zoonotic disease of major economic and public health significance. Despite the growing number of countries declared brucella free, the disease remains widespread in many parts of the world. Although there has been great progress in the use of antimicrobial drugs during the past 2 decades, there is still controversy regarding the treatment of brucellosis. Tetracycline is one of the early antibiotics used for the treatment of human brucellosis,’ with a recommended treatment course of at least 21 days.2 However, it soon became necessary to combine tetracycline and streptomycin to reduce the rates of failure and relapse.3 Co-trimoxazole, which is thought to penetrate very well into the tissues, has also been used for the treatment of brucellosis with varying success rates.3*4The inhibitory effect of rifampicin on the growth of Brucella organisms has been demonstrated.5 Recent experience with rifampicin combined with doxycycline cured 95% and deoxycycline alone cured 84% of cases.6*7 Reports from Saudi Arabia suggest that if a <6-week course of a single or compound antibiotic regimen is used, a significant proportion of failures
Address correspondence to: Dr. Suleiman Al-wed, Department of Medicine (38). College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. Rem&d for public&n on October 11, i99.5. Printed in the U.S.A. Reproduction in whole or part is not permitted. 175
OrJll-393xKws3.50
ANTIBIOTICS
IN THE TREATMENT
OF BRUCELLOSIS
or relapses occurs.8 Therefore, a prolonged antibiotic course was suggested to decrease the relapse and failure rates.g The current study was conducted to assess the response of patients with brucellosis to a 3-month course of different antibiotic regimens.
PATIENTS AND METHODS
Hospital charts of 346 patients diagnosed as having brucellosis were reviewed. Only patients with completed charts and regular follow-ups of at least l-year’s duration were included. The diagnosis of brucellosis was made either on the basis of a positive blood culture or symptoms and signs compatible with brucellosis along with a positive standard tuber agglutination test indicating an antibody titer of l/320 or more. Antibiotic sensitivity in bacteria was determined by Stokes’ disk diffusion method. Bacteria were considered to be sensitive if the radius of the inhibition zone was ~3 mm smaller than the control and resistant if the inhibition radius was G2 mm.l” A protocol was designed for the study, but patients were not strictly randomized. This trial was not blinded. The following antibiotic regimens were used: (1) a combination of tetracycline and streptomycin for 3 weeks, followed by tetracycline alone for the remainder of the 3-month regimen; (2) a combination of tetracycline and co-trimoxazole for 3 weeks, after which either of the two drugs was continued for the remainder of the 3-month regimen; (3) co-trimoxazole and streptomycin combined for 3 weeks, followed by co-trimoxazole for the remainder of the 3-month regimen; (4) co-trimoxazole and rifampicin for 3 weeks, followed by cotrimoxazole for the remainder of the 3-month regimen; or (5) either tetracycline or co-trimoxazole alone for 3 months. All patients were questioned at every visit about their symptoms, and compliance was determined by counting tablets remaining in the bottle. Patients were seen every 2 weeks in the first month, then monthly for 2 months, and then every 3 months for 1 year. Treatment was considered to be a success if signs and symptoms subsided and there was defervescence of fever. Treatment was considered to be a failure if symptoms or signs of brucellosis persisted after 1 week of starting the treatment. Relapse was defined as the appearance of symptoms (such as fever and joint pain) or signs of the disease after an initial good response during the 12 months after therapy. Spondylitis, sacroiliitis, and infection or the hip were diagnosed by appropriate findings on physical examination or by radiologic appearance during bone isotope studies. Peripheral or focal disease, such as arthritis, was defined by the presence of symptoms or signs in a particular site. 176
S. AL-MATED ET AL.
Statistical
Analysis
The data were analyzed using the chi-square and Student’s t test. P < 0.05 was considered to be statistically significant. RESULTS
The ages of the 346 patients ranged between 14 and 89 years, with a male to female ratio of 1.6:1. The clinical manifestations in the patients are shown in Table I. Blood cultures were positive in 92 blood samples (26.6%), and all isolates were sensitive to tetracycline, streptomycin, and rifampitin; however, 17 isolates showed resistance to co-trimoxazole. Of the total, 102 patients received tetracycline plus streptomycin, 96 received tetracycline plus co-trimoxazole, 42 received tetracycline alone, 31 received co-trimoxazole plus streptomycin, 4 received co-trimoxazole plus rifampicin, and 71 received co-trimoxazole alone. Table II summarizes the results of treatment of 346 patients with brucellosis by various antibiotic regimens. Because the numbers of failures and relapses were small, it was not possible to perform any statistical comparisons. However, when the number of relapses and failures were combined, the difference between the combination of tetracycline plus streptomycin versus tetracycline plus co-
Table I. Clinical manifestation in 346 patients with brucellosis. Manifestation
Percentage
Symptoms Fever/chills Sweating Backache Joint pain Anorexia Weight loss General weakness Abdominal pain Vomiting Diarrhea Dysuria Constipation Meningitis Abortion Signs Joint tenderness lliosacral joint tenderness He atomegaly Sp Penomegaly Lymphadenopathy Epigastric tenderness
177
ANTIBIOTICS
Table
II. Results of treatment regimens.
IN THE TREATMENT
of 346 patients
with brucellosis
Antibiotics Tetracycline + Co-trimoxazole Tetracycline + Co-trimoxazole Co-trimoxazole Tetracycline Total
Streptomycin Co-trimoxazole + Streptomycin + Rifampicin
OF BRUCELLOSIS
Success 102
with various
Failure
antibiotic
Relame
1; ;!$/a’
;A 31
1 I3.2; I
4: 346
302
2 (4.8%) 17
27
trimoxazole was significant, with x2 = 20.82 on 5 degrees of freedom (P < 0.001). DISCUSSION
Because of their intracellular localization, Brucella organisms are relatively inaccessible to agents that are otherwise effective in vitro. Therefore, prolonged exposure may be necessary to lower the relapse and failure rates. The patients in this study had a 3-month course of treatment with different antibiotic regimens, and the outcome varied accordingly. The combination of tetracycline and streptomycin gave the best results (96.1% cure rate), which is in agreement with previous reports,l’ and there were no failures. The four patients who showed symptoms of relapse responded well to the sameiregimen observed by others.12 However, the benefits of this regimen cannot be fully achieved because of the daily painful injections of streptomycin and the adverse effects on children, pregnant women, and the elderly.13 Co-trimoxazole alone did not give good results, confirming the results of a previous study.14 Furthermore, cotrimoxazole was the only drug in this study to which in vitro resistant strains were observed, as noted in an earlier report.15 However, with a co-trimoxazoleketracycline or co-trimoxazolektreptomycin combination the response was much better, and comparable results were obtained by Kambal et al. l1 A combination of co-trimoxazole and rifampicin was used in a selected group of patients but did not prove to be superior to the other treatment regimens (75.0% cure rate). As tuberculosis is also a common disease in Saudi Arabia,” and rifampicin-resistant strains may emerge,17 the regular use of a combination of co-trimoxazole and rifampicin for the treatment of brucellosis is not advised. Although Acocella et al7 obtained comparable results in a group receiving the combination of tetracycline and streptomycin, their follow-up period was 6 months, and relapses might have been missed. Tetracycline alone is still widely used, and Rizzo-Naudi 178
S. AL-MAJED
ET AL
et all’ reported a cure rate of 76%; however, in this current study the response was much better @5.7%), with P > 0.0005. However, the relapse/ failure rate in the tetracycline-alone group is unacceptable as a mode of treatment in human brucellosis. CONCLUSION This study shows the effectiveness of a tetracycline/streptomycin combination. Alternative regimens are co-trimoxazoleketracycline or cotrimoxazolektreptomycin combinations. The prolonged course appears to improve the success rate of the treatment regimens. Because of the design limitations of this study, which still showed a reduction in the relapse rate associated with all the regimens, a randomized, comparative study to evaluate the effects of prolonged and standard short treatment is needed. Acknowledgment This study was supported by King Khalid University Hospital, Riyadh, Saudi Arabia. References: 1. Young EJ. Human brucellosis. 2. Spink WW. Current 172-174.
Rev Infect Dis. 1983;5:821-842.
status of therapy of brucellosis
in human beings. JAMA.
1960;6:
3. Smith JM. Brucella species (brucellosis). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases. New York: Wiley Medical; 1979:1782. 4. Hassan H, Erian MM, Farid Z, et al. Trimethoprim-sulfamethoxazole sis. BMJ. 1971;3:159-160. 5. Hall WH, Manion RE. In vitro susceptibility Microbial. 1970;20:600-604.
of Brucella
to various
in acute brucelloantibodies.
Appl
6. Kosmidis J. Comparative therapeutic trials in human brucellosis. In: Daikos GK, Gramarellou G, eds. Proceedings of the IV Mediterranean Congress of Chemotherapy, Rhodes. Chemioterapia. 1985;4(Suppl 2):669-670. 7. Acocella G, Bertand A, Beytout J, et al. Comparison of three different regimens in the treatment of acute brucellosis: A multicentre multinational study. J Antimicrob Chemother. 1989;23:433-439. 8. Rajapakse CN, Al-Aska 1987;26:28-31.
AK, Al-Orainey
9. Al-Kawi S232.
of neuro brucellosis.
MZ. Treatment
I, et al. Spinal brucellosis.
Ann Saudi Med. 1988;9(Suppl
10. Stokes EG, Ridgway GL. In: Clinical Bacteriology. Arnold; 1987:204-221. 179
Br J Rheumatol. 2):S230-
Chapter 9, 6th ed. London: Edward
ANTIBIOTICS
IN THE TREATMENT
OF BRUCELLOSIS
11. Kambal AM, Mahgoub ES, Jamjoon GA, Chowdhury MN. Brucellosis in Riyadh, Saudi Arabia: A microbiological and clinical study. Trans R Sac Trop Med Hyg. 1983;77:820829. 12. Montejo JM, Alberola I, Glez-Zarate P, et al. Open, randomized therapeutic trial of six antimicrobial regimens in the treatment of human brucellosis. Clin Infect Dis. 1993;16: 671-676. 13. World Health Organization. A Guide to the Diagnosis, man Brucellosis. Geneva: World Health Organization;
Treatment and Prevention 1981.
14. Alkan M, Gross EM. Possible failure of trimethoprim-sulfamethoxazole of brucellosis. In: Proceedings of the IV Mediterranean Congress Rhodes. Chemioterapia. 1985;4(Suppl 2):670-671. Abstract.
of Hu-
in the treatment of Chemotherapy;
15. Viladrich PF, Ruli G, Corredoira J, Miravitlles MR. Treatment of human brucellosis with doxycycline plus rifampicin or doxycycline plus streptomycin. A randomized, doubleblind study. Ann Zntern Med. 1992;117:25-30. 16. Aneja VS. Tuberculosis in Saudi Arabia. Health Organization; 1984.
WHO Assignment
Report.
Geneva:
World
17. Rindom SC, Engbaek HC, Vergmann B, et al. Incidence of drug resistance among isolates of mycobacterium tuberculosis recovered in the Gizan area, Saudi Arabia. Saudi Med J. 1985;6:375-378. 18. Rizzo-Naudi J, Griscti-Solar N, Ganado W. Human brucellosis: An evaluation otics in the treatment of brucellosis. Postgrad Med J. 1967;43:520-526.
180
of antibi-
USE OF ANTIBIOTICS IN THE TREATMENT OF HUMAN BRUCELLOSIS SULAIMAN A. AL-MAJED, ABDUL KARIM AL-ASKA, AHMED AL-MITWALLI, ABDULLAH AL-WAZZAN, HUSSAIN AL-ARFAJ, AND AWAD AL-ANAZI Department
of Medicine,
College of Medicine, King Saud University, Riyadh, Saudi Arabia
ABSTRACT
Over a 3-year period (from 1987 through 1989), the medical charts of 346 patients (between 14 and 89 years of age with a male to female ratio of 1.6:l) with brucellosis were reviewed to determine the efficacy of various treatment regimens. Of 92 positive blood cultures, all the isolates were sensitive to tetracycline, streptomycin, and rifampicin; however, 17 isolates were resistant to co-trimoxazole. Various combinations of tetracycline, streptomycin, co-trimoxazole, and rifampicin were used for a prolonged period (3 months). Drugs were equally available to all patients. The best results were obtained with tetracycline plus streptomycin. Co-trimoxazole, when used alone, was found to be the least effective, with more failures and relapses. INTRODUCTION
Brucellosis is a zoonotic disease of major economic and public health significance. Despite the growing number of countries declared brucella free, the disease remains widespread in many parts of the world. Although there has been great progress in the use of antimicrobial drugs during the past 2 decades, there is still controversy regarding the treatment of brucellosis. Tetracycline is one of the early antibiotics used for the treatment of human brucellosis,’ with a recommended treatment course of at least 21 days.2 However, it soon became necessary to combine tetracycline and streptomycin to reduce the rates of failure and relapse.3 Co-trimoxazole, which is thought to penetrate very well into the tissues, has also been used for the treatment of brucellosis with varying success rates.3*4The inhibitory effect of rifampicin on the growth of Brucella organisms has been demonstrated.5 Recent experience with rifampicin combined with doxycycline cured 95% and deoxycycline alone cured 84% of cases.6*7 Reports from Saudi Arabia suggest that if a <6-week course of a single or compound antibiotic regimen is used, a significant proportion of failures
Address correspondence to: Dr. Suleiman Al-wed, Department of Medicine (38). College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. Rem&d for public&n on October 11, i99.5. Printed in the U.S.A. Reproduction in whole or part is not permitted. 175
OrJll-393xKws3.50
ANTIBIOTICS
IN THE TREATMENT
OF BRUCELLOSIS
or relapses occurs.8 Therefore, a prolonged antibiotic course was suggested to decrease the relapse and failure rates.g The current study was conducted to assess the response of patients with brucellosis to a 3-month course of different antibiotic regimens.
PATIENTS AND METHODS
Hospital charts of 346 patients diagnosed as having brucellosis were reviewed. Only patients with completed charts and regular follow-ups of at least l-year’s duration were included. The diagnosis of brucellosis was made either on the basis of a positive blood culture or symptoms and signs compatible with brucellosis along with a positive standard tuber agglutination test indicating an antibody titer of l/320 or more. Antibiotic sensitivity in bacteria was determined by Stokes’ disk diffusion method. Bacteria were considered to be sensitive if the radius of the inhibition zone was ~3 mm smaller than the control and resistant if the inhibition radius was G2 mm.l” A protocol was designed for the study, but patients were not strictly randomized. This trial was not blinded. The following antibiotic regimens were used: (1) a combination of tetracycline and streptomycin for 3 weeks, followed by tetracycline alone for the remainder of the 3-month regimen; (2) a combination of tetracycline and co-trimoxazole for 3 weeks, after which either of the two drugs was continued for the remainder of the 3-month regimen; (3) co-trimoxazole and streptomycin combined for 3 weeks, followed by co-trimoxazole for the remainder of the 3-month regimen; (4) co-trimoxazole and rifampicin for 3 weeks, followed by cotrimoxazole for the remainder of the 3-month regimen; or (5) either tetracycline or co-trimoxazole alone for 3 months. All patients were questioned at every visit about their symptoms, and compliance was determined by counting tablets remaining in the bottle. Patients were seen every 2 weeks in the first month, then monthly for 2 months, and then every 3 months for 1 year. Treatment was considered to be a success if signs and symptoms subsided and there was defervescence of fever. Treatment was considered to be a failure if symptoms or signs of brucellosis persisted after 1 week of starting the treatment. Relapse was defined as the appearance of symptoms (such as fever and joint pain) or signs of the disease after an initial good response during the 12 months after therapy. Spondylitis, sacroiliitis, and infection or the hip were diagnosed by appropriate findings on physical examination or by radiologic appearance during bone isotope studies. Peripheral or focal disease, such as arthritis, was defined by the presence of symptoms or signs in a particular site. 176
S. AL-MATED ET AL.
Statistical
Analysis
The data were analyzed using the chi-square and Student’s t test. P < 0.05 was considered to be statistically significant. RESULTS
The ages of the 346 patients ranged between 14 and 89 years, with a male to female ratio of 1.6:1. The clinical manifestations in the patients are shown in Table I. Blood cultures were positive in 92 blood samples (26.6%), and all isolates were sensitive to tetracycline, streptomycin, and rifampitin; however, 17 isolates showed resistance to co-trimoxazole. Of the total, 102 patients received tetracycline plus streptomycin, 96 received tetracycline plus co-trimoxazole, 42 received tetracycline alone, 31 received co-trimoxazole plus streptomycin, 4 received co-trimoxazole plus rifampicin, and 71 received co-trimoxazole alone. Table II summarizes the results of treatment of 346 patients with brucellosis by various antibiotic regimens. Because the numbers of failures and relapses were small, it was not possible to perform any statistical comparisons. However, when the number of relapses and failures were combined, the difference between the combination of tetracycline plus streptomycin versus tetracycline plus co-
Table I. Clinical manifestation in 346 patients with brucellosis. Manifestation
Percentage
Symptoms Fever/chills Sweating Backache Joint pain Anorexia Weight loss General weakness Abdominal pain Vomiting Diarrhea Dysuria Constipation Meningitis Abortion Signs Joint tenderness lliosacral joint tenderness He atomegaly Sp Penomegaly Lymphadenopathy Epigastric tenderness
177
ANTIBIOTICS
Table
II. Results of treatment regimens.
IN THE TREATMENT
of 346 patients
with brucellosis
Antibiotics Tetracycline + Co-trimoxazole Tetracycline + Co-trimoxazole Co-trimoxazole Tetracycline Total
Streptomycin Co-trimoxazole + Streptomycin + Rifampicin
OF BRUCELLOSIS
Success 102
with various
Failure
antibiotic
Relame
1; ;!$/a’
;A 31
1 I3.2; I
4: 346
302
2 (4.8%) 17
27
trimoxazole was significant, with x2 = 20.82 on 5 degrees of freedom (P < 0.001). DISCUSSION
Because of their intracellular localization, Brucella organisms are relatively inaccessible to agents that are otherwise effective in vitro. Therefore, prolonged exposure may be necessary to lower the relapse and failure rates. The patients in this study had a 3-month course of treatment with different antibiotic regimens, and the outcome varied accordingly. The combination of tetracycline and streptomycin gave the best results (96.1% cure rate), which is in agreement with previous reports,l’ and there were no failures. The four patients who showed symptoms of relapse responded well to the sameiregimen observed by others.12 However, the benefits of this regimen cannot be fully achieved because of the daily painful injections of streptomycin and the adverse effects on children, pregnant women, and the elderly.13 Co-trimoxazole alone did not give good results, confirming the results of a previous study.14 Furthermore, cotrimoxazole was the only drug in this study to which in vitro resistant strains were observed, as noted in an earlier report.15 However, with a co-trimoxazoleketracycline or co-trimoxazolektreptomycin combination the response was much better, and comparable results were obtained by Kambal et al. l1 A combination of co-trimoxazole and rifampicin was used in a selected group of patients but did not prove to be superior to the other treatment regimens (75.0% cure rate). As tuberculosis is also a common disease in Saudi Arabia,” and rifampicin-resistant strains may emerge,17 the regular use of a combination of co-trimoxazole and rifampicin for the treatment of brucellosis is not advised. Although Acocella et al7 obtained comparable results in a group receiving the combination of tetracycline and streptomycin, their follow-up period was 6 months, and relapses might have been missed. Tetracycline alone is still widely used, and Rizzo-Naudi 178
S. AL-MAJED
ET AL
et all’ reported a cure rate of 76%; however, in this current study the response was much better @5.7%), with P > 0.0005. However, the relapse/ failure rate in the tetracycline-alone group is unacceptable as a mode of treatment in human brucellosis. CONCLUSION This study shows the effectiveness of a tetracycline/streptomycin combination. Alternative regimens are co-trimoxazoleketracycline or cotrimoxazolektreptomycin combinations. The prolonged course appears to improve the success rate of the treatment regimens. Because of the design limitations of this study, which still showed a reduction in the relapse rate associated with all the regimens, a randomized, comparative study to evaluate the effects of prolonged and standard short treatment is needed. Acknowledgment This study was supported by King Khalid University Hospital, Riyadh, Saudi Arabia. References: 1. Young EJ. Human brucellosis. 2. Spink WW. Current 172-174.
Rev Infect Dis. 1983;5:821-842.
status of therapy of brucellosis
in human beings. JAMA.
1960;6:
3. Smith JM. Brucella species (brucellosis). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases. New York: Wiley Medical; 1979:1782. 4. Hassan H, Erian MM, Farid Z, et al. Trimethoprim-sulfamethoxazole sis. BMJ. 1971;3:159-160. 5. Hall WH, Manion RE. In vitro susceptibility Microbial. 1970;20:600-604.
of Brucella
to various
in acute brucelloantibodies.
Appl
6. Kosmidis J. Comparative therapeutic trials in human brucellosis. In: Daikos GK, Gramarellou G, eds. Proceedings of the IV Mediterranean Congress of Chemotherapy, Rhodes. Chemioterapia. 1985;4(Suppl 2):669-670. 7. Acocella G, Bertand A, Beytout J, et al. Comparison of three different regimens in the treatment of acute brucellosis: A multicentre multinational study. J Antimicrob Chemother. 1989;23:433-439. 8. Rajapakse CN, Al-Aska 1987;26:28-31.
AK, Al-Orainey
9. Al-Kawi S232.
of neuro brucellosis.
MZ. Treatment
I, et al. Spinal brucellosis.
Ann Saudi Med. 1988;9(Suppl
10. Stokes EG, Ridgway GL. In: Clinical Bacteriology. Arnold; 1987:204-221. 179
Br J Rheumatol. 2):S230-
Chapter 9, 6th ed. London: Edward
ANTIBIOTICS
IN THE TREATMENT
OF BRUCELLOSIS
11. Kambal AM, Mahgoub ES, Jamjoon GA, Chowdhury MN. Brucellosis in Riyadh, Saudi Arabia: A microbiological and clinical study. Trans R Sac Trop Med Hyg. 1983;77:820829. 12. Montejo JM, Alberola I, Glez-Zarate P, et al. Open, randomized therapeutic trial of six antimicrobial regimens in the treatment of human brucellosis. Clin Infect Dis. 1993;16: 671-676. 13. World Health Organization. A Guide to the Diagnosis, man Brucellosis. Geneva: World Health Organization;
Treatment and Prevention 1981.
14. Alkan M, Gross EM. Possible failure of trimethoprim-sulfamethoxazole of brucellosis. In: Proceedings of the IV Mediterranean Congress Rhodes. Chemioterapia. 1985;4(Suppl 2):670-671. Abstract.
of Hu-
in the treatment of Chemotherapy;
15. Viladrich PF, Ruli G, Corredoira J, Miravitlles MR. Treatment of human brucellosis with doxycycline plus rifampicin or doxycycline plus streptomycin. A randomized, doubleblind study. Ann Zntern Med. 1992;117:25-30. 16. Aneja VS. Tuberculosis in Saudi Arabia. Health Organization; 1984.
WHO Assignment
Report.
Geneva:
World
17. Rindom SC, Engbaek HC, Vergmann B, et al. Incidence of drug resistance among isolates of mycobacterium tuberculosis recovered in the Gizan area, Saudi Arabia. Saudi Med J. 1985;6:375-378. 18. Rizzo-Naudi J, Griscti-Solar N, Ganado W. Human brucellosis: An evaluation otics in the treatment of brucellosis. Postgrad Med J. 1967;43:520-526.
180
of antibi-