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Treatment of typhoid fever in children with a flexible-duration of ceftriaxone, compared with 14-day treatment with chloramphenicol
International Journal of Antimicrobial Agents 21 (2003) 350 /353 www.ischemo.org
Treatment of typhoid fever in children with a flexible-duration of ceftriaxone, compared with 14-day treatment with chloramphenicol Mustafa Mansur Tatli a,*, Guler Aktas a, Mustafa Kosecik a, Abdulkadir Yilmaz b a
Department of Pediatrics, Faculty of Medicine, Harran University, Sanliurfa, Turkey b Sanliurfa Childrens’ Hospital, Sanliurfa, Turkey Received 21 February 2002; accepted 8 August 2002
Abstract Although the efficacy of ceftriaxone in typhoid fever is well documented, the precise duration of ceftriaxone therapy in children with typhoid fever is not established and varies from 3 to 14 days in the literature. In a prospective, randomized study ceftriaxone was compared with chloramphenicol for treatment of 72 children who had bacteriologically confirmed typhoid fever. Ceftriaxone was given at a dose of 75 mg/kg per day (maximally 2 g/day) intravenously, in two doses until defervescence and continued 5 days after that time. Chloramphenicol was given at a dose of 75 mg/kg per day (maximally 2 g/day) in four doses for 14 days. Mean defervescence time was in 5.4 days in the ceftriaxone group and 4.2 days in the chloramphenicol group (P /0.04). Clinical cure without complications was achieved in all patients in both groups. No patient relapsed in the ceftriaxone group, and four patients relapsed in the chloramphenicol group (P /0.048). The overall results of this study suggest that a flexible-duration of ceftriaxone therapy given until defervescence time, followed by an additional 5 days of therapy is a reasonable alternative to conventional 14day chloramphenicol treatment in children with typhoid fever. # 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ceftriaxone; Children; Chloramphenicol; Typhoid fever
1. Introduction Approximately 16 million cases of typhoid fever occur annually in the developing world [1 /3]. Typhoid fever has been treated with chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole for many years [4]. Over the last decade, strains of Salmonella typhi multiply resistant to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole have been reported from Southeast Asia, the Indian subcontinent and certain countries in the Middle East [5 /8]. Chloramphenicol is not an ideal drug for treatment of typhoid fever because of the risk of aplastic anaemia (1/10 000), a relapse rate of approximately 10%, and because it requires a prolonged course of treatment (14 days) [9]. Ceftriaxone has a minimum inhibitory concentration of 0.05 mg/l for * Corresponding author. Present address: Onur Mahallesi, Sarmasik Sokak, Kayhan Apt. No: 33 B-Blok, Daire: 4, 35340 Balcova, Izmir, Turkey. Fax: /90-232-259-9723. E-mail address: [email protected] (M.M. Tatli).
most strains of S. typhi . It exhibits better b lactamase stability, less nephrotoxicity and longer half-life than other cephalosporins [10]. Although it has been successfully used for more than 15 years [8], there is no established duration of treatment in children with typhoid fever and regimens in typhoid fever vary between 3 and 14 days [3,11/14]. Short courses (3 /7 days) of ceftriaxone therapy have unacceptable relapse rates. Fourteen days course of ceftriaxone therapy has a lower relapse rate, but carries a considerable cost. In this study we aimed to evaluate a flexible-duration course of ceftriaxone, compared with conventional chloramphenicol courses in the therapy of typhoid fever in children.
2. Patients and methods The study was conducted in the Harran University Research Hospital, and the Children’s Hospital, Sanliurfa, Turkey. Between September 1998, and July 2001, children (below16 years of age) with suspected typhoid
0924-8579/03/$30 # 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(02)00388-6
M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353
fever were included in the study. Patients were thought to have typhoid fever if they had no obvious source of infection and high-grade fever (]/39 8C) persisted for more than 5 days. Patients with negative blood cultures or with history of antimicrobial therapy in previous 10 days were excluded. Informed consent was obtained from parents of all patients. Patients were randomized to receive ceftriaxone or chloramphenicol treatments, using sealed envelopes. Ceftriaxone was administered 75 mg/kg per day (maximally 2 g/day) in two divided doses until the axillary temperature remained below 37.5 8C for at least 24 h, followed by 5 days therapy at the same dose. Chloramphenicol was administered at 75 mg/kg per days (maximally 2 g/day) in four divided doses for 14 days. The criterion for failure was persistence of fever on the seventh day of therapy. All data were recorded on previously prepared special forms. Patients were examined twice daily; symptoms and signs were recorded. Axillary temperature, arterial blood pressure, respiratory and pulse rate were recorded every 6 h. Blood was taken for complete blood count, electrolytes and tube Widal test on admission. Stool and urine were cultured using standard methods before treatment. Further blood and stool cultures were done if patients had not responded by the seventh day of therapy. Susceptibilities of all S. typhi isolates were tested to ceftriaxone, chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole by disk diffusion technique, using the Kirby/Bauer method. The response to treatment was assessed by improvement in symptoms and signs of typhoid fever. An infection was considered clinically cured if clinical signs and symptoms resolved and the patient remained well during follow-up. A clinical treatment failure was defined as persistence of symptoms or impairment in clinical condition. A microbiological failure was defined as a blood culture positive for S. typhi after completion of therapy. A relapse was defined as high fever (/ 38.5 8C) and blood culture positive for S. typhi during the 28 days after discharge. Defervescence time was defined as the time from the onset of treatment until the fever was 37.5 8C or below for at least 24 h. Normally distributed data for the two treatment groups were compared by the Student’s t-test. Differences between proportions were tested by Fisher’s exact test. Defervescence times in the two groups were compared using Kaplan/Meier survival analysis.
3. Results A total of 72 children with typhoid fever were enrolled in the study, thirty-six patients in each group. The sex ratios and means of ages were comparable in both groups. The most common presenting symptoms after
351
high-grade fever were headache, myalgia, anorexia, irritability and cough. Hepatomegaly was present in 54 (75%) and splenomegaly in 39 (54%) patients. Relative bradycardia was encountered in two patients and no rose spots were seen. The duration of illness before admission ranged from 5 to 12 days (mean, 7.3 days) in the ceftriaxone and 5 /10 days (mean, 7.1 days) in the chloramphenicol group. Consciousness was impaired in two patients in the ceftriaxone group. There were no differences in presenting clinical features between the two treatment groups. Demographic, clinical and laboratory data are shown in Table 1. The prevalence of low total leukocyte counts and mild anaemia were comparable between groups. Of the 72 typhoid patients entered into the study, 16 (22.2%) also had positive pre-treatment stool cultures for S. typhi . All isolates of S. typhi were susceptible to ceftriaxone, chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole. All of the patients in both groups were cured. Defervescence was achieved within 5.4 days in the ceftriaxone group versus 4.2 days in chloramphenicol group and the difference was statistically significant (P /0.04). Headache, myalgia, anorexia and irritability disappeared between 3 and 6 days in both groups. Mean duration of therapy in the ceftriaxone group was 10.4 (8 /12) days. No side effects were observed clinically and biochemically in either group of patients. Thirty patients in the ceftriaxone group and 28 patients in the choramphenicol group were assessed at follow-up; no patient in the former and four patients in the latter group relapsed. Six patients in the ceftriaxone and eight patients in the chloramphenicol group were not assessed because of communication failure. Relapsed patients were successfully treated with ceftriaxone. Relapse rates were significantly different (P /0.04). All follow-up Table 1 Demographic, clinical, and laboratory features of patients, by treatment groups on admission Features of patients
Ceftriaxone (n /36) mean (range)
Age (years) 10.7 (4.5 /015) Sex (male/female) 20/16 Duration of ill7.3 (5 /12) ness (days) Fever ( ]/39 8C) 36 (100%) Headache 27 (75%) Myalgia 18 (50%) Anorexia 17 (47%) Irritability 14 (39%) Cough 10 (27%) Haemoglobin (g/ 10.79/2.1 dl) (mean9/S.D.) WBC (109 per l) 6.89/4.3 (mean9/S.D.)
Chloramphenicol (n / 36) Mean (range) 9.8 21/15 7.1 (5 /10) 36 (100%) 22 (61%) 20 (56%) 20 (56%) 16 (46%) 6 (17%) 10.49/1.8 6.59/4.7
None of these differences were statistically significant.
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M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353
Table 2 Responses of the patients to the therapies Features of patients
Ceftriaxone mean (range)
Chloramphenicol mean (range)
Duration of therapy (day) Time to defervescence (day) Clinical failure Bacteriological failure Relapse Carrier state
10.4 (8 /12) 5.4 (3 /7) None None 0/30 None
14 4.2 (2 /6) None None 4/28 None
stool cultures were negative. Results are shown in Table 2.
4. Discussion The length of therapy in typhoid fever is intended to prevent relapses [15], but there is no defined duration of ceftriaxone therapy. Some authors recommend short courses of therapy (3 /7 days) [3,4,16,17] and the others recommend a long course therapy (7 /14 days) [8,14]. Recently, it has been reported that short duration of ceftriaxone therapy (3, 5 or 7 days) has been associated with a high relapse rate in children with typhoid [14,18]. Long-term ceftriaxone therapy has better relapse rates than short-term therapy, but was not cost effective [14]. In our study ceftriaxone was used on average for 10 days and no relapse occurred during follow-up. These results suggested that the regimen used in this study had a better relapse rate than short time ceftriaxone or chloramphenicol therapy and was as effective as long course ceftriaxone therapy in children with typhoid fever [3,4,11]. Average times to defervescence in ceftriaxone group were slightly longer than the chloramphenicol group (5.4 vs. 4.2 days, P /0.04). Chloramphenicol is the most frequently used drug for treatment of typhoid fever in Turkey; defervescence is usually seen within the first week of treatment. However, 14 days of therapy are needed [4]. Shorter courses of chloramphenicol are not advised because relapses occur in 10 /20% of treated cases 1/2 weeks after the therapy [10]. Although chloramphenicol has some advantages such as low cost and more rapid defervescence, but it is not a perfect drug because of its potentially serious adverse effects. However, we have not observed bone marrow suppression in patients treated with chloramphenicol. Haemoglobin levels of patients in the chloramphenicol group did not decrease at the end of treatment and were comparable with patients treated with ceftriaxone. The mean leukocyte count was not significantly lower in patients treated with chloramphenicol than those treated with ceftriaxone. Another disadvantages of chloramphenicol treatment of typhoid fever is a high rate of relapse after treatment [16]. Nineteen percent of followed patients in chloram-
Significance (P )
0.04
0.048
phenicol group relapsed, a rate consistent with previous studies [3,12]. We did not observe any serious side effects of ceftriaxone or chloramphenicol; both drugs were generally well tolerated. We defined the seventh day of therapy as the cut-off time for fever, i.e. decision for effects of therapy, because the persistence of fever during the first week of therapy, despite improvement in other clinical parameters, has been described previously [6,9]. It has been postulated that continuing fever might be due to the residual intracellular S. typhi that are gradually being eliminated by the immune response. Another explanation for prolonged fever was that the delay in defervescence might be due to elevated levels of cytokines [6,7]. We concluded that a flexible-duration of ceftriaxone therapy-given until defervescence occurs, followed by an additional 5 days at the same dose-seems to be an ideal regimen in children with typhoid fever.
References [1] Unal S, Hayran M, Tuncer S, et al. Treatment of enteric fever with pefloxacin for 7 days versus 5 days: a randomized clinical trial, Antimicrob Agents Chemother 1996;40:2898 /2900. [2] Bhutta ZA, Mansoorali N, Hussain R. Plasma cytokines in paediatric typhoidal salmonellosis: correlation with clinical course and outcome. J Infect 1997;35:253 /6. [3] Acharya G, Butler T, Ho M, Sharma P, et al. Treatment of typhoid fever: randomized trial of a 3-day course of ceftriaxone versus a 14-day course of chloramphenicol. Am J Trop Med Hyg 1995;52:162 /5. [4] Islam A, Butler T, Kabir I, Alam NH. Treatment of typhoid fever with ceftriaxone for 5 days or chloramphenicol for 14 days: a randomized clinical trial. Antimicrob Agents Chemother 1993;37:1572 /5. [5] Rathore MH, Bux D, Hasan M. Multidrug-resistant Salmonella typhi in Pakistani children: clinical features and treatment. South Med J 1996;89:235 /7. [6] Memon IA, Billoo AG, Memon HI. Cefixime: an oral option for the treatment of multidrug-resistant enteric fever in children. South Med J 1997;90:1204 /7. [7] Ha V, Wain J, Vo THN, et al. Two or three days of ofloxacin treatment for uncomplicated multidrug-resistant typhoid fever in children. Antimicrob Agents Chemother 1996;40:958 /61. [8] Ti TY, Monteiro EH, Lam S, Lee HS. Ceftriaxone therapy in bacteremic typhoid fever. Antimicrob Agents Chemother 1985;28:540 /3.
M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353 [9] Islam A, Butler T, Nath SK, et al. Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol. J Infect Dis 1988;158:742 /7. [10] Acharya G, Crevisier C, Butler T, et al. Pharmacokinetics of ceftriaxone in patients with typhoid fever. Antimicrob Agents Chemother 1994;38:24185 /8. [11] Smith MD, Nguyen MD, Nguyen TH, et al. Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever. Antimicrob Agents Chemother 1994;38:1716 /20. [12] Lasserre R, Sangalang RP, Santiago L. Three-day treatment of typhoid fever with two different doses of ceftriaxone, compared to 14-day therapy with chloramphenicol: a randomized trial. J Antimicrob Chemother 1991;28:765 /72. [13] Bhutta ZA, Khan IA, Molla AM. Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone. Pediatr Infect Dis J 1994;13:990 /4.
353
[14] Bhutta ZA, Khan IA, Shadmani M. Failure of short-course ceftriaxone chemotherapy for multidrug-resistant typhoid fever in children: a randomized controlled trial in Pakistan. Antimicrob Agents Chemother 2000;44:450 /2. [15] Lasserre R, Sangalang RP, Santiago L. Three-day of typhoid fever with two different doses of ceftriaxone, compared to 14-day therapy with chloramphenicol: a randomized trial. J Antimicrob Chemother 1991;28:765 /72. [16] Girgis NI, Kilpatrick ME, Farid Z, Mikhail IA, Bishay E. Ceftriaxone versus chloramphenicol in the treatment of enteric fever. Drugs Exp Clin Res 1990;16:607 /9. [17] Moosa A, Rubidge CJ. Once daily ceftriaxone vs. chloramphenicol for treatment of typhoid fever in children. Pediatr Infect Dis J 1989;8:696 /9. [18] Frenck RW, Nakhla I, Sultan Y, et al. Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin Infect Dis 2000;31:1134 /8.
Treatment of typhoid fever in children with a flexible-duration of ceftriaxone, compared with 14-day treatment with chloramphenicol Mustafa Mansur Tatli a,*, Guler Aktas a, Mustafa Kosecik a, Abdulkadir Yilmaz b a
Department of Pediatrics, Faculty of Medicine, Harran University, Sanliurfa, Turkey b Sanliurfa Childrens’ Hospital, Sanliurfa, Turkey Received 21 February 2002; accepted 8 August 2002
Abstract Although the efficacy of ceftriaxone in typhoid fever is well documented, the precise duration of ceftriaxone therapy in children with typhoid fever is not established and varies from 3 to 14 days in the literature. In a prospective, randomized study ceftriaxone was compared with chloramphenicol for treatment of 72 children who had bacteriologically confirmed typhoid fever. Ceftriaxone was given at a dose of 75 mg/kg per day (maximally 2 g/day) intravenously, in two doses until defervescence and continued 5 days after that time. Chloramphenicol was given at a dose of 75 mg/kg per day (maximally 2 g/day) in four doses for 14 days. Mean defervescence time was in 5.4 days in the ceftriaxone group and 4.2 days in the chloramphenicol group (P /0.04). Clinical cure without complications was achieved in all patients in both groups. No patient relapsed in the ceftriaxone group, and four patients relapsed in the chloramphenicol group (P /0.048). The overall results of this study suggest that a flexible-duration of ceftriaxone therapy given until defervescence time, followed by an additional 5 days of therapy is a reasonable alternative to conventional 14day chloramphenicol treatment in children with typhoid fever. # 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ceftriaxone; Children; Chloramphenicol; Typhoid fever
1. Introduction Approximately 16 million cases of typhoid fever occur annually in the developing world [1 /3]. Typhoid fever has been treated with chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole for many years [4]. Over the last decade, strains of Salmonella typhi multiply resistant to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole have been reported from Southeast Asia, the Indian subcontinent and certain countries in the Middle East [5 /8]. Chloramphenicol is not an ideal drug for treatment of typhoid fever because of the risk of aplastic anaemia (1/10 000), a relapse rate of approximately 10%, and because it requires a prolonged course of treatment (14 days) [9]. Ceftriaxone has a minimum inhibitory concentration of 0.05 mg/l for * Corresponding author. Present address: Onur Mahallesi, Sarmasik Sokak, Kayhan Apt. No: 33 B-Blok, Daire: 4, 35340 Balcova, Izmir, Turkey. Fax: /90-232-259-9723. E-mail address: [email protected] (M.M. Tatli).
most strains of S. typhi . It exhibits better b lactamase stability, less nephrotoxicity and longer half-life than other cephalosporins [10]. Although it has been successfully used for more than 15 years [8], there is no established duration of treatment in children with typhoid fever and regimens in typhoid fever vary between 3 and 14 days [3,11/14]. Short courses (3 /7 days) of ceftriaxone therapy have unacceptable relapse rates. Fourteen days course of ceftriaxone therapy has a lower relapse rate, but carries a considerable cost. In this study we aimed to evaluate a flexible-duration course of ceftriaxone, compared with conventional chloramphenicol courses in the therapy of typhoid fever in children.
2. Patients and methods The study was conducted in the Harran University Research Hospital, and the Children’s Hospital, Sanliurfa, Turkey. Between September 1998, and July 2001, children (below16 years of age) with suspected typhoid
0924-8579/03/$30 # 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(02)00388-6
M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353
fever were included in the study. Patients were thought to have typhoid fever if they had no obvious source of infection and high-grade fever (]/39 8C) persisted for more than 5 days. Patients with negative blood cultures or with history of antimicrobial therapy in previous 10 days were excluded. Informed consent was obtained from parents of all patients. Patients were randomized to receive ceftriaxone or chloramphenicol treatments, using sealed envelopes. Ceftriaxone was administered 75 mg/kg per day (maximally 2 g/day) in two divided doses until the axillary temperature remained below 37.5 8C for at least 24 h, followed by 5 days therapy at the same dose. Chloramphenicol was administered at 75 mg/kg per days (maximally 2 g/day) in four divided doses for 14 days. The criterion for failure was persistence of fever on the seventh day of therapy. All data were recorded on previously prepared special forms. Patients were examined twice daily; symptoms and signs were recorded. Axillary temperature, arterial blood pressure, respiratory and pulse rate were recorded every 6 h. Blood was taken for complete blood count, electrolytes and tube Widal test on admission. Stool and urine were cultured using standard methods before treatment. Further blood and stool cultures were done if patients had not responded by the seventh day of therapy. Susceptibilities of all S. typhi isolates were tested to ceftriaxone, chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole by disk diffusion technique, using the Kirby/Bauer method. The response to treatment was assessed by improvement in symptoms and signs of typhoid fever. An infection was considered clinically cured if clinical signs and symptoms resolved and the patient remained well during follow-up. A clinical treatment failure was defined as persistence of symptoms or impairment in clinical condition. A microbiological failure was defined as a blood culture positive for S. typhi after completion of therapy. A relapse was defined as high fever (/ 38.5 8C) and blood culture positive for S. typhi during the 28 days after discharge. Defervescence time was defined as the time from the onset of treatment until the fever was 37.5 8C or below for at least 24 h. Normally distributed data for the two treatment groups were compared by the Student’s t-test. Differences between proportions were tested by Fisher’s exact test. Defervescence times in the two groups were compared using Kaplan/Meier survival analysis.
3. Results A total of 72 children with typhoid fever were enrolled in the study, thirty-six patients in each group. The sex ratios and means of ages were comparable in both groups. The most common presenting symptoms after
351
high-grade fever were headache, myalgia, anorexia, irritability and cough. Hepatomegaly was present in 54 (75%) and splenomegaly in 39 (54%) patients. Relative bradycardia was encountered in two patients and no rose spots were seen. The duration of illness before admission ranged from 5 to 12 days (mean, 7.3 days) in the ceftriaxone and 5 /10 days (mean, 7.1 days) in the chloramphenicol group. Consciousness was impaired in two patients in the ceftriaxone group. There were no differences in presenting clinical features between the two treatment groups. Demographic, clinical and laboratory data are shown in Table 1. The prevalence of low total leukocyte counts and mild anaemia were comparable between groups. Of the 72 typhoid patients entered into the study, 16 (22.2%) also had positive pre-treatment stool cultures for S. typhi . All isolates of S. typhi were susceptible to ceftriaxone, chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole. All of the patients in both groups were cured. Defervescence was achieved within 5.4 days in the ceftriaxone group versus 4.2 days in chloramphenicol group and the difference was statistically significant (P /0.04). Headache, myalgia, anorexia and irritability disappeared between 3 and 6 days in both groups. Mean duration of therapy in the ceftriaxone group was 10.4 (8 /12) days. No side effects were observed clinically and biochemically in either group of patients. Thirty patients in the ceftriaxone group and 28 patients in the choramphenicol group were assessed at follow-up; no patient in the former and four patients in the latter group relapsed. Six patients in the ceftriaxone and eight patients in the chloramphenicol group were not assessed because of communication failure. Relapsed patients were successfully treated with ceftriaxone. Relapse rates were significantly different (P /0.04). All follow-up Table 1 Demographic, clinical, and laboratory features of patients, by treatment groups on admission Features of patients
Ceftriaxone (n /36) mean (range)
Age (years) 10.7 (4.5 /015) Sex (male/female) 20/16 Duration of ill7.3 (5 /12) ness (days) Fever ( ]/39 8C) 36 (100%) Headache 27 (75%) Myalgia 18 (50%) Anorexia 17 (47%) Irritability 14 (39%) Cough 10 (27%) Haemoglobin (g/ 10.79/2.1 dl) (mean9/S.D.) WBC (109 per l) 6.89/4.3 (mean9/S.D.)
Chloramphenicol (n / 36) Mean (range) 9.8 21/15 7.1 (5 /10) 36 (100%) 22 (61%) 20 (56%) 20 (56%) 16 (46%) 6 (17%) 10.49/1.8 6.59/4.7
None of these differences were statistically significant.
352
M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353
Table 2 Responses of the patients to the therapies Features of patients
Ceftriaxone mean (range)
Chloramphenicol mean (range)
Duration of therapy (day) Time to defervescence (day) Clinical failure Bacteriological failure Relapse Carrier state
10.4 (8 /12) 5.4 (3 /7) None None 0/30 None
14 4.2 (2 /6) None None 4/28 None
stool cultures were negative. Results are shown in Table 2.
4. Discussion The length of therapy in typhoid fever is intended to prevent relapses [15], but there is no defined duration of ceftriaxone therapy. Some authors recommend short courses of therapy (3 /7 days) [3,4,16,17] and the others recommend a long course therapy (7 /14 days) [8,14]. Recently, it has been reported that short duration of ceftriaxone therapy (3, 5 or 7 days) has been associated with a high relapse rate in children with typhoid [14,18]. Long-term ceftriaxone therapy has better relapse rates than short-term therapy, but was not cost effective [14]. In our study ceftriaxone was used on average for 10 days and no relapse occurred during follow-up. These results suggested that the regimen used in this study had a better relapse rate than short time ceftriaxone or chloramphenicol therapy and was as effective as long course ceftriaxone therapy in children with typhoid fever [3,4,11]. Average times to defervescence in ceftriaxone group were slightly longer than the chloramphenicol group (5.4 vs. 4.2 days, P /0.04). Chloramphenicol is the most frequently used drug for treatment of typhoid fever in Turkey; defervescence is usually seen within the first week of treatment. However, 14 days of therapy are needed [4]. Shorter courses of chloramphenicol are not advised because relapses occur in 10 /20% of treated cases 1/2 weeks after the therapy [10]. Although chloramphenicol has some advantages such as low cost and more rapid defervescence, but it is not a perfect drug because of its potentially serious adverse effects. However, we have not observed bone marrow suppression in patients treated with chloramphenicol. Haemoglobin levels of patients in the chloramphenicol group did not decrease at the end of treatment and were comparable with patients treated with ceftriaxone. The mean leukocyte count was not significantly lower in patients treated with chloramphenicol than those treated with ceftriaxone. Another disadvantages of chloramphenicol treatment of typhoid fever is a high rate of relapse after treatment [16]. Nineteen percent of followed patients in chloram-
Significance (P )
0.04
0.048
phenicol group relapsed, a rate consistent with previous studies [3,12]. We did not observe any serious side effects of ceftriaxone or chloramphenicol; both drugs were generally well tolerated. We defined the seventh day of therapy as the cut-off time for fever, i.e. decision for effects of therapy, because the persistence of fever during the first week of therapy, despite improvement in other clinical parameters, has been described previously [6,9]. It has been postulated that continuing fever might be due to the residual intracellular S. typhi that are gradually being eliminated by the immune response. Another explanation for prolonged fever was that the delay in defervescence might be due to elevated levels of cytokines [6,7]. We concluded that a flexible-duration of ceftriaxone therapy-given until defervescence occurs, followed by an additional 5 days at the same dose-seems to be an ideal regimen in children with typhoid fever.
References [1] Unal S, Hayran M, Tuncer S, et al. Treatment of enteric fever with pefloxacin for 7 days versus 5 days: a randomized clinical trial, Antimicrob Agents Chemother 1996;40:2898 /2900. [2] Bhutta ZA, Mansoorali N, Hussain R. Plasma cytokines in paediatric typhoidal salmonellosis: correlation with clinical course and outcome. J Infect 1997;35:253 /6. [3] Acharya G, Butler T, Ho M, Sharma P, et al. Treatment of typhoid fever: randomized trial of a 3-day course of ceftriaxone versus a 14-day course of chloramphenicol. Am J Trop Med Hyg 1995;52:162 /5. [4] Islam A, Butler T, Kabir I, Alam NH. Treatment of typhoid fever with ceftriaxone for 5 days or chloramphenicol for 14 days: a randomized clinical trial. Antimicrob Agents Chemother 1993;37:1572 /5. [5] Rathore MH, Bux D, Hasan M. Multidrug-resistant Salmonella typhi in Pakistani children: clinical features and treatment. South Med J 1996;89:235 /7. [6] Memon IA, Billoo AG, Memon HI. Cefixime: an oral option for the treatment of multidrug-resistant enteric fever in children. South Med J 1997;90:1204 /7. [7] Ha V, Wain J, Vo THN, et al. Two or three days of ofloxacin treatment for uncomplicated multidrug-resistant typhoid fever in children. Antimicrob Agents Chemother 1996;40:958 /61. [8] Ti TY, Monteiro EH, Lam S, Lee HS. Ceftriaxone therapy in bacteremic typhoid fever. Antimicrob Agents Chemother 1985;28:540 /3.
M.M. Tatli et al. / International Journal of Antimicrobial Agents 21 (2003) 350 /353 [9] Islam A, Butler T, Nath SK, et al. Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol. J Infect Dis 1988;158:742 /7. [10] Acharya G, Crevisier C, Butler T, et al. Pharmacokinetics of ceftriaxone in patients with typhoid fever. Antimicrob Agents Chemother 1994;38:24185 /8. [11] Smith MD, Nguyen MD, Nguyen TH, et al. Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever. Antimicrob Agents Chemother 1994;38:1716 /20. [12] Lasserre R, Sangalang RP, Santiago L. Three-day treatment of typhoid fever with two different doses of ceftriaxone, compared to 14-day therapy with chloramphenicol: a randomized trial. J Antimicrob Chemother 1991;28:765 /72. [13] Bhutta ZA, Khan IA, Molla AM. Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone. Pediatr Infect Dis J 1994;13:990 /4.
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