Z. A. BHLTTTA ET AL.
Brief Report
Chloramphenicol Therapy of Typhoid Fever and its Relationship to Hepatic Dysfunction by Z. A. Bhutta, S. H. Naqvi, S. Durrani* and A. Suria* Departments of Paediatrics and * Pharmacology, Faculty of Health Sciences, The Aga Khan University, Karachi, Pakistan
Materials and Methods The study was conducted over an 18-month period (May 1987-September 1988) at the Aga Khan University Hospital (AKUH), Karachi. The protocol of the study was approved by the Human Subjects Protection Committee at AKUH. All children (age 6 months-14 years) presenting to the Department of Paediatrics at AKUH with suspected typhoid were prospectively randomized for the study. Children with neutropenia (neutrophils < 1000/mm3) and those who had received chloramphenicol therapy in the preceding 7 days, were excluded from the study. Informed consent was obtained from the parents/guardians of the children. Patients were randomized to receive intravenous Correspondence: Dr Zulfiquar Ahmed Bhutta, Department of Paediatrics, Faculty of Health Sciences, The Aga Khan University, Karachi, Pakistan. 320
©Oxford University Press 1991
CS, either 100 mg/kg/day (Group A) or 75 mg/kg/day (Group B) in a 6-hourly dosage for 48 hours. The drug was administered after dilution in normal saline as an infusion over 30 minutes. A daily record of clinical status, including temperature, mental status, hydration, jaundice, abdominal discomfort, visceromegaly, diarrhoea, and vomiting was maintained. The patients were discharged home on oral chloramphenicol palmitate in the same dosage after remaining afebrile for 24 hours. Baseline investigations including complete blood count (CBC), differential count, reticulocyte count, serum bilirubin, SGPT (alanine aminotransferase), alkaline phosphatase, and bicarbonate were obtained at admission, and were repeated after 48 hours. Chloramphenicol sampling and assay Blood samples (3 ml) were obtained by venepuncture 48 hours after initiation of therapy, before, and 1 hour after cessation of chloramphenicol infusion. Plasma was frozen at — 80°C until analysis by high pressure liquid chromatography (HPLC) using the method of Nielsson-Ehle et al.1 Results Twenty-five children enrolled in the study had culture proven typhoid. Table 1 lists the clinical details for the two groups of patients studied. There was no significant difference between the two groups for age, weight, severity of illness, or baseline liver function. Although hepatomegaly was seen in 15/25 (60 per cent) patients at admission, significant hepatic dysfunction as evidenced by hepatomegaly and two-fold elevation of SGPT was found in 4/15 (27 per cent) and 6/10 (60 per cent) patients in groups A and B, respectively, at initiation of therapy. There was a wide range of trough concentration values in group A who had received 100 mg/kg/day. Two children developed trough levels of chloramphenicol in excess of 30 mcg/ml. However, there was no significant difference in the mean trough concentrations of the two groups (11.5 ±10.9 versus 5.4 ±2.6 mcg/ml, mean±SD, x =0.2, />=NS). Journal of Tropical Pediatrics
Vol.37
December 1991
Downloaded from http://tropej.oxfordjournals.org/ at University of Birmingham on May 29, 2015
Chloramphenicol is considered the treatment of choice in enteric fever.1 Although wide variations have been reported, 2 there is little data on chloramphenicol phannacokinetics in enteric fever. Less still is known about appropriate dosage in children with typhoid and dosage schedules ranging from 50 to 100 mg/kg/ day have been recommended. 3 Free chloramphenicol, produced after the cleavage of the succinate or palmitate group from the intravenous or oral preparations, is the biologically active form and is excreted following glucuronidation in the liver. As free chloramphenicol is principally conjugated in the liver, chloramphenicol clearance and potentially toxic serum levels may develop in patients with liver dysfunction.4 The association of hepatic dysfunction with typhoid has also been demonstrated previously in adults and children. 6 The use of chloramphenicol, therefore, in children with typhoid and concomitant hepatic dysfunction may also be associated with the potential risk of toxicity. We conducted a prospective study to compare two different regimens of chloramphenicol succinate (CS) in pediatric cases of enteric fever and their relationship to hepatic dysfunction.
Z. A. BHUTTA ET AL.
TABLE 1
Comparison of patients characteristics at admission Mean±SD Group B 75 mg/kg/day n=10
11:4 8.2±4.7 9.7 ±5.8
8.4±4.7 13.5±12
63.5 ±35.8
56.9±22.1
176.7±63.4
147.2 ±52.9
18.0±2.4
19.2±2.6
M:F
Age (yrs) Duration of illness (days) SGPT (Alanine Aminotransferase) (IU/L) Alkaline phospbatase (IU/L) Bicarbonate (mmol/L)
6:4
All differences are non significant. Similarly, there was a wider range of peak serum concentrations in group A. Three children (20 percent) on 100 mg/kg/day dosage, developed peak levels of chloramphenicol in excess of 30 mcg/ml (Fig. 1). 60
50
Discussion E 40(A
"5
.8
30-
20
o
10
Group B Group A (100 mg/kg/day) (75 mg/kg/day)
FIG. 1. Shaded area represents the therapeutic range for chlororamphenicol in blood. The horizontal bars and box represent the mean and range, respectively. Journal of Tropical Pediatrics
Vol. 37
December 1991
Although we chose to study the intravenous preparation of chloramphenicol, the post-hydrolytic metabolism, and pharmacokinetics of the oral form, viz. chloramphenicol palmitate 8 is similar to CS, and the results would be equally applicable. The minimal inhibitory concentration of chloramphenicol against most susceptible organisms is 0.5-2.0 mcg/dl 9 and the usual serum levels required to achieve satisfactory antibacterial activity range from 5 to 20 mcg/dl. 10 The dose related bone marrow toxicity of chloramphenicol occurs with serum levels exceeding 25 mcg/ml" and it is, therefore, imperative that every effort should be made to ensure that the levels remain in the therapeutic range. Of the various liver disorders studied by Narang et al.,12 hepatitis was associated with the highest serum chloramphenicol levels, suggesting a specific relationship with hepatocellular derangement. Other studies in adults have shown decreased clearance of chloramphenicol and toxicity with hepatic dysfunction.' 3 However, no clear association has been found between different liver function tests and chloramphenicol levels.14-15 Hepatic dysfunction in typhoid may be severe enough to manifest as clinical jaundice, 16 but is 321
Downloaded from http://tropej.oxfordjournals.org/ at University of Birmingham on May 29, 2015
Group A 100 mg/kg/day n=15
However, the mean peak serum concentrations for both dosage groups were comparable (18.4±14.4 versus 14.2±6.9 mcg/dl, mean±SD, ^ = 0.23. P= NS). Most of the high levels of chloramphenicol were found in children with significant hepatic dysfunction. Four of the five children with chloramphenicol levels greater than 30 mcg/ml, had SGPT values > 100IU/1. A significant correlation was also found between chloramphenicol trough levels at 48 hours and corresponding serum SGPT values (y= - 2 . 5 + 0.19oc, r=0.68, P
Brief Report
Chloramphenicol Therapy of Typhoid Fever and its Relationship to Hepatic Dysfunction by Z. A. Bhutta, S. H. Naqvi, S. Durrani* and A. Suria* Departments of Paediatrics and * Pharmacology, Faculty of Health Sciences, The Aga Khan University, Karachi, Pakistan
Materials and Methods The study was conducted over an 18-month period (May 1987-September 1988) at the Aga Khan University Hospital (AKUH), Karachi. The protocol of the study was approved by the Human Subjects Protection Committee at AKUH. All children (age 6 months-14 years) presenting to the Department of Paediatrics at AKUH with suspected typhoid were prospectively randomized for the study. Children with neutropenia (neutrophils < 1000/mm3) and those who had received chloramphenicol therapy in the preceding 7 days, were excluded from the study. Informed consent was obtained from the parents/guardians of the children. Patients were randomized to receive intravenous Correspondence: Dr Zulfiquar Ahmed Bhutta, Department of Paediatrics, Faculty of Health Sciences, The Aga Khan University, Karachi, Pakistan. 320
©Oxford University Press 1991
CS, either 100 mg/kg/day (Group A) or 75 mg/kg/day (Group B) in a 6-hourly dosage for 48 hours. The drug was administered after dilution in normal saline as an infusion over 30 minutes. A daily record of clinical status, including temperature, mental status, hydration, jaundice, abdominal discomfort, visceromegaly, diarrhoea, and vomiting was maintained. The patients were discharged home on oral chloramphenicol palmitate in the same dosage after remaining afebrile for 24 hours. Baseline investigations including complete blood count (CBC), differential count, reticulocyte count, serum bilirubin, SGPT (alanine aminotransferase), alkaline phosphatase, and bicarbonate were obtained at admission, and were repeated after 48 hours. Chloramphenicol sampling and assay Blood samples (3 ml) were obtained by venepuncture 48 hours after initiation of therapy, before, and 1 hour after cessation of chloramphenicol infusion. Plasma was frozen at — 80°C until analysis by high pressure liquid chromatography (HPLC) using the method of Nielsson-Ehle et al.1 Results Twenty-five children enrolled in the study had culture proven typhoid. Table 1 lists the clinical details for the two groups of patients studied. There was no significant difference between the two groups for age, weight, severity of illness, or baseline liver function. Although hepatomegaly was seen in 15/25 (60 per cent) patients at admission, significant hepatic dysfunction as evidenced by hepatomegaly and two-fold elevation of SGPT was found in 4/15 (27 per cent) and 6/10 (60 per cent) patients in groups A and B, respectively, at initiation of therapy. There was a wide range of trough concentration values in group A who had received 100 mg/kg/day. Two children developed trough levels of chloramphenicol in excess of 30 mcg/ml. However, there was no significant difference in the mean trough concentrations of the two groups (11.5 ±10.9 versus 5.4 ±2.6 mcg/ml, mean±SD, x =0.2, />=NS). Journal of Tropical Pediatrics
Vol.37
December 1991
Downloaded from http://tropej.oxfordjournals.org/ at University of Birmingham on May 29, 2015
Chloramphenicol is considered the treatment of choice in enteric fever.1 Although wide variations have been reported, 2 there is little data on chloramphenicol phannacokinetics in enteric fever. Less still is known about appropriate dosage in children with typhoid and dosage schedules ranging from 50 to 100 mg/kg/ day have been recommended. 3 Free chloramphenicol, produced after the cleavage of the succinate or palmitate group from the intravenous or oral preparations, is the biologically active form and is excreted following glucuronidation in the liver. As free chloramphenicol is principally conjugated in the liver, chloramphenicol clearance and potentially toxic serum levels may develop in patients with liver dysfunction.4 The association of hepatic dysfunction with typhoid has also been demonstrated previously in adults and children. 6 The use of chloramphenicol, therefore, in children with typhoid and concomitant hepatic dysfunction may also be associated with the potential risk of toxicity. We conducted a prospective study to compare two different regimens of chloramphenicol succinate (CS) in pediatric cases of enteric fever and their relationship to hepatic dysfunction.
Z. A. BHUTTA ET AL.
TABLE 1
Comparison of patients characteristics at admission Mean±SD Group B 75 mg/kg/day n=10
11:4 8.2±4.7 9.7 ±5.8
8.4±4.7 13.5±12
63.5 ±35.8
56.9±22.1
176.7±63.4
147.2 ±52.9
18.0±2.4
19.2±2.6
M:F
Age (yrs) Duration of illness (days) SGPT (Alanine Aminotransferase) (IU/L) Alkaline phospbatase (IU/L) Bicarbonate (mmol/L)
6:4
All differences are non significant. Similarly, there was a wider range of peak serum concentrations in group A. Three children (20 percent) on 100 mg/kg/day dosage, developed peak levels of chloramphenicol in excess of 30 mcg/ml (Fig. 1). 60
50
Discussion E 40(A
"5
.8
30-
20
o
10
Group B Group A (100 mg/kg/day) (75 mg/kg/day)
FIG. 1. Shaded area represents the therapeutic range for chlororamphenicol in blood. The horizontal bars and box represent the mean and range, respectively. Journal of Tropical Pediatrics
Vol. 37
December 1991
Although we chose to study the intravenous preparation of chloramphenicol, the post-hydrolytic metabolism, and pharmacokinetics of the oral form, viz. chloramphenicol palmitate 8 is similar to CS, and the results would be equally applicable. The minimal inhibitory concentration of chloramphenicol against most susceptible organisms is 0.5-2.0 mcg/dl 9 and the usual serum levels required to achieve satisfactory antibacterial activity range from 5 to 20 mcg/dl. 10 The dose related bone marrow toxicity of chloramphenicol occurs with serum levels exceeding 25 mcg/ml" and it is, therefore, imperative that every effort should be made to ensure that the levels remain in the therapeutic range. Of the various liver disorders studied by Narang et al.,12 hepatitis was associated with the highest serum chloramphenicol levels, suggesting a specific relationship with hepatocellular derangement. Other studies in adults have shown decreased clearance of chloramphenicol and toxicity with hepatic dysfunction.' 3 However, no clear association has been found between different liver function tests and chloramphenicol levels.14-15 Hepatic dysfunction in typhoid may be severe enough to manifest as clinical jaundice, 16 but is 321
Downloaded from http://tropej.oxfordjournals.org/ at University of Birmingham on May 29, 2015
Group A 100 mg/kg/day n=15
However, the mean peak serum concentrations for both dosage groups were comparable (18.4±14.4 versus 14.2±6.9 mcg/dl, mean±SD, ^ = 0.23. P= NS). Most of the high levels of chloramphenicol were found in children with significant hepatic dysfunction. Four of the five children with chloramphenicol levels greater than 30 mcg/ml, had SGPT values > 100IU/1. A significant correlation was also found between chloramphenicol trough levels at 48 hours and corresponding serum SGPT values (y= - 2 . 5 + 0.19oc, r=0.68, P
