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Ciprofloxacin plus doxycycline versus rifampicin plus doxycycline in the treatment of acute brucellosis
M6d Mal Infect. 1996 ; 26, RICAI : 587-9
Ciprofloxacin plus doxycyclineversus rifampicin plus doxycycline in the treatment of acute brucellosis* T. KALO**, S. NOVI**, A. NUSHI** and S. DEDJA**
SUMMARY
The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of ciprofloxacin plus doxycycline, versus rifampicin plus doxycycline was analysed by a prospective study of 24 patients. Subjects with central nervous system involvement, endocarditis, or spondyfitis were not included in this study. All patients completed the full treatment and became afebrile in 5 days of therapy. Two patients (one in each group) suffered relapses during the follow-up period. We conclude that the combination ciprofloxacin and doxycycline versus rifampicin and docycycline, is an effective treatment for the types of brucellosis included in this study, and they haven't any difference between these two therapeutic combinations. Key-words : Acute brucellosis - Ciprofloxacin - Doxycycline - Rifampicin.
Brucellosis, although almonst eradicated in many parts of the world, remains widespread and endemic disease, particularly in developing countries where is an important ongoing public health problem. The mediterranean region is one of the most heavily affected from human brucellosis. In the last three years, the incidence of acute brucellosis in Albania varies between 2 and 2.1/100.000 habitants, and the region most heavily affected is the south of country. The present prospective and randomised study was undertaken to evaluate efficacy, safety and patient acceptability of two antibiotic regimens : ciprofloxacin plus doxycycline versus rifampicin plus doxycycline, for acute brucellosis.
MATERIALS AND METHODS From January 1992 to December 1994, a prospective and randomised study of 24 patients at UHC of Tirana, was carried out to evaluate the e f f i c a c y of two therapeutic combinations : ciprofloxacin plus
* 15° Rdunion Interdisciplinaire de Chimioth6rapie Anti-Infectieuse. Paris, 7 et 8 d6cembre 1995. ** Department of Infectious Diseases, UniversityHospital Centre of Tirana, Albania.
doxycycline versus rifampicin plus doxycycline, in eliminating symptoms and preventig relapses of the disease. The diagnostic criteria were positive serology and/or isolation of a Brucella sp. from blood in the presence of compatible epidemiological and clinical findings. The serological criteria were the following : Wright seroagglutination assay titers equal to or higher than 1/160 and/or indirect immunofluorescence assay titers higher than 1/100. Individuals who received antimicrobial therapy prior to the study, patients allergic to the drugs employed, children, under 15 years of age and pregnant women were excluded from the study. We have also eliminated the patients with brucellosis and severe complications of this disease, such as central nervous system involvement, endocarditis or spondilitis. The first twelve patients were treated with orally ciprofloxacin (1 gr/d) plus doxycycline (200 mg/d), and the second twelve patients were treated with orally rifampicin (900 mg/d) plus doxycycline (200 mg/d), administered for a period of 6 weeks. The patients were reassessed at 3 and 6 months following the end of the treatment. Relapse was diagnosed if symptoms persisted after 7 days of the treatment, and new blood samples for cultures were collected from patients suspected of having a relapse. The statistical analysis was carried
587
out using a statistics package elaborated by Epi-Info (Atlanta, USA). RESULTS
Ten women (41.67 %) and fourteen men (58.33 %), ranging in age from 18 to 56 years (mean + standard derivation; 31.76 + 13.5 years), were included in this study. All patients were suffering from acute brucellosis clinically and biologically proven. On the average, the diagnosis was confirmed 21.42 + 14.52 days (mean + SD), after the onset of symptoms. The majority of patients lived in rural districts (72.8 %). More than half of them had ingested unpasteurized milk (70.26 %), and had contact with goats (60.1%). Both risk factors were present in 40.1% of patients. We haven't try any risk factor in patients (12.5 %). Among 24 patients, 6 (25 %) had localised disease : 3 cases of osteoarticular involvement (2 cases of sacroilitis, 1 case of arthritis), and 3 cases of orchitis. One patient had two complications. The blood cultures from 11 of 19 patients were positive (57.9 %), and Brucella melitensis was isolated in all of them. The Wright seroagglutination assay was positive for 23 of 24 patients (95.83 %) and indirect immunofluorescence was positive in 21 of 24 patients (87.5 %). Relapses were suffered by 2 (8.33 %) of the patients (one in each group), who were monitored for 6 months after the end of treatment. The regimen A (cipro + doxy) presented the same efficacy rate (91.66 %) as regimen B (rifam + doxy), and they haven't any difference in the treatment of complicated or not, acute brucellosis (table I). DISCUSSION Tetracyclines, TMP-SMZ, streptomycin and rifampicin are reputed to be the best drugs for brucellosis : the high possibility for relapses makes combination
therapy necessary. These combinations have a synergic effect on Brucella organisms. Most comparative studies have shown that the combination of rifampicin and tetracycline (or doxycycline), recommended by the World Health Organisation (1), is less effective than tetracycline (or doxycycline) plus streptomycin (2, 3, 4, 5), but more effective than rifampicin, ceftriaxone (6, 7), or ciprofloxacin (8, 9) administered alone. Two randomised trials compared the efficacy of rifampicin plus doxycycline with that of streptomycin plus doxycycline, which were administered over a period of 6 weeks, and which resulted in a relapse rate of 0-13 % with doxy. + rifam., and 0-7 % with stre. + doxy. (2, 5). Thus the combination of tetracycline (doxycycline) and streptomycin remains the therapy of choice of brucellosis without complications, as well as for the focal forms (2, 3, 4, 5). The initial response in our study was excellent. We haven't any therapeutic failure and all patients became afebrile and asymptomatic during the first week of treatment (table I). Our study showed that ciprofloxacin plus doxycycline and rifampicin plus doxycycline, were safe and well tolerated by most patients; additionally, only two patients (8.33 %) suffered from slight secondary effects (headache and epigastric pain), that did not necessitate suspension of treatment. The risk of relapse is the most important parameter to consider when a therapy of human brucellosis is being assessed. We know that ninety percent of the recurrences appear within the first 4 months after treatment is discontinued. The treatment with ciprofloxacin alone, although effective for the acute symptoms, is associated with an appreciable rate of relapse (26.6 to 39 %) (8, 9). Ciprofloxacin, administered alone twice daily, does not appear to constitute adequate therapy for acute brucellosis. It
TABLE I : Selected antibiotics used and relapse rate in brucellosis
Antibiotic
Treatment regimen
Defervecs. p6riod (day)
Doxycycline (D) Rifampicin (R)
D = 42 d (200 mg/d) R = 42 d (900 mg/d)
5
1
8.33
Ciprofloxacin (C) Doxycycline (D)
C = 42 d (1 gr/d) D = 42 d (200 mg/d)
4
1
8.33
588
Relapse rate N° %
should be given with other agent for t r e a t m e n t o f brucellosis. In our study o f 12 patients treated with ciprofloxacin and doxycycline, who were monitored for a period o f 6 months after concluding treatment, only one (8.33 %) suffered relapse.
RESUME
On the basis o f our results, we c o n c l u d e that the combination o f a 6 weeks course of ciprofloxacin and doxycycline is well tolerated, and this combination has the same effigacy than rifampicin and d o x y c y c l i n e , r e c o m m a n d e d by the W H O (1).
CIPROFLOXACINE PLUS DOXYCYCLINE VERSUS RIFAMPICINE PLUS DOXYCYCLINE DANS LE TRAITEMENT DE LA BRUCELLOSE AIGUE
Entre janvier 1992 et d6cembre 1994, 24 malades atteints de brucellose aigufi due ~ Brucella melitensis, ont 6t6 inclus dans une 6tude prospective et randomis6e. Les 12 premiers ont re~u pendant 6 semaines ciprofloxacine 1 gr/j et doxycycline 200 mg/j, et les 12 autres ont 6t6 trait6s par rifampicine 900 mg/j et doxycycline 200 mg/j. N'ont pas 6t6 inclus dans cette 6tude les malades avec des atteintes neurom6ning6es, une endocardite ou une spondylodiscite. Tous ont bien to16r6 le traitement et ils sont devenus apyr6tiques en 5 jours. On n'a observ6 que deux rechutes (une dans chaque groupe, 8,33 %), au cours des 6 mois apr6s l'arr& du traitement. En conclusion, la bi-th6rapie par ciprofloxacine et doxycycline est aussi efficace que l'association de rifampicine et de doxycycline, pr6conis6e par I'OMS. Mots-cl6s : Brucellose aigu~ - Ciprofloxacine - Doxycycline - Rifampicine.
REFERENCES 1. 2.
3.
4.
5.
W o r l d Health Organisation-Expert C o m m i t t e e on Brucellosis - 5th report. W H O Tech Rep Ser. 1986 ; 740 : 56-7. A R I Z A J., GUDID F., PALLARS R. - Comparative trial of rifampicindoxycycline versus tetracycline-streptomycin in the therapy of human brucellosis. Antimicrob Agents Chemother. 1985 ; 28 : 548-51. A C O C E L L A G., B E R T R A N D A., B E Y T O U T J. - C o m p a r i s o n of three different r e g i m e n s in the treatment of acute b r u c e l l o s i s : a multicenter multinational study. J Antimicrob Chemother. 1989 ; 23 : 433-9. C I S N E R O S J.M., V I C I A N A P., C O L M E R O J. - M n l t i c e n t e r prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks. Antimicrob Agents Chemother. 1990 ; 34 : 881-3. R O D R I G U E Z M., G A M O A., M O R E N O J. - E v a l u a c i o n de dos
589
6.
7. 8.
9.
r6gimenes diferentes en el tratamiento de la brucelosis : rifampicinadixiciclina vs. estreptomieina-doxiciclina. Resultados preliminares. N Arch Fac Med. 1985 ; 43 : 171-5. A L - I D R I S S I H.Y., U W A Y D A H A.K., D A N S O K.T. - Ceftriaxone in the treatment of acute and subacute human brucellosis. J Int Med Res. 1989 ; 17 : 363-8. L A N G R., D A G A N R., P O T A S M A N J. - Failure of ceftriaxone in the treatment of acute brucellosis. Clin Infect Dis. 1992 ; 14 : 506-9. L A N G R., R A Z R., SACKS T., SHAPIRO M. - Failure of prolonged treatment w i t h c i p r o f l o x a c i n in acute infections due to Brucella melitensis. J Antimicrob Chemother. 1990 ; 26 : 841-6. A L - S I B A I M.B., H A L I M M.A., E L - S H A K E R M.M. - Efficacy of ciprofloxacin for treatment of Brucella melitensis infections. Antimicrob Agents Chemother. 1992 ; 1 : 150-2.
Ciprofloxacin plus doxycyclineversus rifampicin plus doxycycline in the treatment of acute brucellosis* T. KALO**, S. NOVI**, A. NUSHI** and S. DEDJA**
SUMMARY
The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of ciprofloxacin plus doxycycline, versus rifampicin plus doxycycline was analysed by a prospective study of 24 patients. Subjects with central nervous system involvement, endocarditis, or spondyfitis were not included in this study. All patients completed the full treatment and became afebrile in 5 days of therapy. Two patients (one in each group) suffered relapses during the follow-up period. We conclude that the combination ciprofloxacin and doxycycline versus rifampicin and docycycline, is an effective treatment for the types of brucellosis included in this study, and they haven't any difference between these two therapeutic combinations. Key-words : Acute brucellosis - Ciprofloxacin - Doxycycline - Rifampicin.
Brucellosis, although almonst eradicated in many parts of the world, remains widespread and endemic disease, particularly in developing countries where is an important ongoing public health problem. The mediterranean region is one of the most heavily affected from human brucellosis. In the last three years, the incidence of acute brucellosis in Albania varies between 2 and 2.1/100.000 habitants, and the region most heavily affected is the south of country. The present prospective and randomised study was undertaken to evaluate efficacy, safety and patient acceptability of two antibiotic regimens : ciprofloxacin plus doxycycline versus rifampicin plus doxycycline, for acute brucellosis.
MATERIALS AND METHODS From January 1992 to December 1994, a prospective and randomised study of 24 patients at UHC of Tirana, was carried out to evaluate the e f f i c a c y of two therapeutic combinations : ciprofloxacin plus
* 15° Rdunion Interdisciplinaire de Chimioth6rapie Anti-Infectieuse. Paris, 7 et 8 d6cembre 1995. ** Department of Infectious Diseases, UniversityHospital Centre of Tirana, Albania.
doxycycline versus rifampicin plus doxycycline, in eliminating symptoms and preventig relapses of the disease. The diagnostic criteria were positive serology and/or isolation of a Brucella sp. from blood in the presence of compatible epidemiological and clinical findings. The serological criteria were the following : Wright seroagglutination assay titers equal to or higher than 1/160 and/or indirect immunofluorescence assay titers higher than 1/100. Individuals who received antimicrobial therapy prior to the study, patients allergic to the drugs employed, children, under 15 years of age and pregnant women were excluded from the study. We have also eliminated the patients with brucellosis and severe complications of this disease, such as central nervous system involvement, endocarditis or spondilitis. The first twelve patients were treated with orally ciprofloxacin (1 gr/d) plus doxycycline (200 mg/d), and the second twelve patients were treated with orally rifampicin (900 mg/d) plus doxycycline (200 mg/d), administered for a period of 6 weeks. The patients were reassessed at 3 and 6 months following the end of the treatment. Relapse was diagnosed if symptoms persisted after 7 days of the treatment, and new blood samples for cultures were collected from patients suspected of having a relapse. The statistical analysis was carried
587
out using a statistics package elaborated by Epi-Info (Atlanta, USA). RESULTS
Ten women (41.67 %) and fourteen men (58.33 %), ranging in age from 18 to 56 years (mean + standard derivation; 31.76 + 13.5 years), were included in this study. All patients were suffering from acute brucellosis clinically and biologically proven. On the average, the diagnosis was confirmed 21.42 + 14.52 days (mean + SD), after the onset of symptoms. The majority of patients lived in rural districts (72.8 %). More than half of them had ingested unpasteurized milk (70.26 %), and had contact with goats (60.1%). Both risk factors were present in 40.1% of patients. We haven't try any risk factor in patients (12.5 %). Among 24 patients, 6 (25 %) had localised disease : 3 cases of osteoarticular involvement (2 cases of sacroilitis, 1 case of arthritis), and 3 cases of orchitis. One patient had two complications. The blood cultures from 11 of 19 patients were positive (57.9 %), and Brucella melitensis was isolated in all of them. The Wright seroagglutination assay was positive for 23 of 24 patients (95.83 %) and indirect immunofluorescence was positive in 21 of 24 patients (87.5 %). Relapses were suffered by 2 (8.33 %) of the patients (one in each group), who were monitored for 6 months after the end of treatment. The regimen A (cipro + doxy) presented the same efficacy rate (91.66 %) as regimen B (rifam + doxy), and they haven't any difference in the treatment of complicated or not, acute brucellosis (table I). DISCUSSION Tetracyclines, TMP-SMZ, streptomycin and rifampicin are reputed to be the best drugs for brucellosis : the high possibility for relapses makes combination
therapy necessary. These combinations have a synergic effect on Brucella organisms. Most comparative studies have shown that the combination of rifampicin and tetracycline (or doxycycline), recommended by the World Health Organisation (1), is less effective than tetracycline (or doxycycline) plus streptomycin (2, 3, 4, 5), but more effective than rifampicin, ceftriaxone (6, 7), or ciprofloxacin (8, 9) administered alone. Two randomised trials compared the efficacy of rifampicin plus doxycycline with that of streptomycin plus doxycycline, which were administered over a period of 6 weeks, and which resulted in a relapse rate of 0-13 % with doxy. + rifam., and 0-7 % with stre. + doxy. (2, 5). Thus the combination of tetracycline (doxycycline) and streptomycin remains the therapy of choice of brucellosis without complications, as well as for the focal forms (2, 3, 4, 5). The initial response in our study was excellent. We haven't any therapeutic failure and all patients became afebrile and asymptomatic during the first week of treatment (table I). Our study showed that ciprofloxacin plus doxycycline and rifampicin plus doxycycline, were safe and well tolerated by most patients; additionally, only two patients (8.33 %) suffered from slight secondary effects (headache and epigastric pain), that did not necessitate suspension of treatment. The risk of relapse is the most important parameter to consider when a therapy of human brucellosis is being assessed. We know that ninety percent of the recurrences appear within the first 4 months after treatment is discontinued. The treatment with ciprofloxacin alone, although effective for the acute symptoms, is associated with an appreciable rate of relapse (26.6 to 39 %) (8, 9). Ciprofloxacin, administered alone twice daily, does not appear to constitute adequate therapy for acute brucellosis. It
TABLE I : Selected antibiotics used and relapse rate in brucellosis
Antibiotic
Treatment regimen
Defervecs. p6riod (day)
Doxycycline (D) Rifampicin (R)
D = 42 d (200 mg/d) R = 42 d (900 mg/d)
5
1
8.33
Ciprofloxacin (C) Doxycycline (D)
C = 42 d (1 gr/d) D = 42 d (200 mg/d)
4
1
8.33
588
Relapse rate N° %
should be given with other agent for t r e a t m e n t o f brucellosis. In our study o f 12 patients treated with ciprofloxacin and doxycycline, who were monitored for a period o f 6 months after concluding treatment, only one (8.33 %) suffered relapse.
RESUME
On the basis o f our results, we c o n c l u d e that the combination o f a 6 weeks course of ciprofloxacin and doxycycline is well tolerated, and this combination has the same effigacy than rifampicin and d o x y c y c l i n e , r e c o m m a n d e d by the W H O (1).
CIPROFLOXACINE PLUS DOXYCYCLINE VERSUS RIFAMPICINE PLUS DOXYCYCLINE DANS LE TRAITEMENT DE LA BRUCELLOSE AIGUE
Entre janvier 1992 et d6cembre 1994, 24 malades atteints de brucellose aigufi due ~ Brucella melitensis, ont 6t6 inclus dans une 6tude prospective et randomis6e. Les 12 premiers ont re~u pendant 6 semaines ciprofloxacine 1 gr/j et doxycycline 200 mg/j, et les 12 autres ont 6t6 trait6s par rifampicine 900 mg/j et doxycycline 200 mg/j. N'ont pas 6t6 inclus dans cette 6tude les malades avec des atteintes neurom6ning6es, une endocardite ou une spondylodiscite. Tous ont bien to16r6 le traitement et ils sont devenus apyr6tiques en 5 jours. On n'a observ6 que deux rechutes (une dans chaque groupe, 8,33 %), au cours des 6 mois apr6s l'arr& du traitement. En conclusion, la bi-th6rapie par ciprofloxacine et doxycycline est aussi efficace que l'association de rifampicine et de doxycycline, pr6conis6e par I'OMS. Mots-cl6s : Brucellose aigu~ - Ciprofloxacine - Doxycycline - Rifampicine.
REFERENCES 1. 2.
3.
4.
5.
W o r l d Health Organisation-Expert C o m m i t t e e on Brucellosis - 5th report. W H O Tech Rep Ser. 1986 ; 740 : 56-7. A R I Z A J., GUDID F., PALLARS R. - Comparative trial of rifampicindoxycycline versus tetracycline-streptomycin in the therapy of human brucellosis. Antimicrob Agents Chemother. 1985 ; 28 : 548-51. A C O C E L L A G., B E R T R A N D A., B E Y T O U T J. - C o m p a r i s o n of three different r e g i m e n s in the treatment of acute b r u c e l l o s i s : a multicenter multinational study. J Antimicrob Chemother. 1989 ; 23 : 433-9. C I S N E R O S J.M., V I C I A N A P., C O L M E R O J. - M n l t i c e n t e r prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks. Antimicrob Agents Chemother. 1990 ; 34 : 881-3. R O D R I G U E Z M., G A M O A., M O R E N O J. - E v a l u a c i o n de dos
589
6.
7. 8.
9.
r6gimenes diferentes en el tratamiento de la brucelosis : rifampicinadixiciclina vs. estreptomieina-doxiciclina. Resultados preliminares. N Arch Fac Med. 1985 ; 43 : 171-5. A L - I D R I S S I H.Y., U W A Y D A H A.K., D A N S O K.T. - Ceftriaxone in the treatment of acute and subacute human brucellosis. J Int Med Res. 1989 ; 17 : 363-8. L A N G R., D A G A N R., P O T A S M A N J. - Failure of ceftriaxone in the treatment of acute brucellosis. Clin Infect Dis. 1992 ; 14 : 506-9. L A N G R., R A Z R., SACKS T., SHAPIRO M. - Failure of prolonged treatment w i t h c i p r o f l o x a c i n in acute infections due to Brucella melitensis. J Antimicrob Chemother. 1990 ; 26 : 841-6. A L - S I B A I M.B., H A L I M M.A., E L - S H A K E R M.M. - Efficacy of ciprofloxacin for treatment of Brucella melitensis infections. Antimicrob Agents Chemother. 1992 ; 1 : 150-2.