ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1990, p. 1809-1811
0066-4804/90/091809-03$02.00/0 Copyright ©) 1990, American Society for Microbiology
Vol. 34, No. 9
Chloramphenicol Concentrations in Sera of Patients with Typhoid Fever Being Treated with Oral or Intravenous Preparation Department
TEOW-YEE TI,l* EDMUND H. MONTEIRO,2 SELENA LAM,3 AND HOW-SUNG LEE1 Faculty of Medicine, National University of Singapore,' Department of Communicable Diseases, Tan Tock Seng Hospital,2 and Enteric Laboratory, Ministry of Health,3 Singapore
of Pharmacology,
Received 6 December 1989/Accepted 26 June 1990
Serum chloramphenicol and chloramphenicol succinate concentrations in patients given equivalent doses of chloramphenicol base either intravenously or orally for typhoid fever were measured by high-performance liquid chromatography. The mean serum chloramphenicol concentrations were significantly lower in the 11 patients treated with intravenous chloramphenicol succinate than in the 15 patients treated with oral chloramphenicol capsules.
Chloramphenicol is an effective drug in the treatment of typhoid fever caused by susceptible strains of Salmonella typhi. The recommended route of administration of chloramphenicol is usually oral for the treatment of typhoid fever (2, 4, 5, 7). The intravenous route is used with severely ill patients, in whom absorption may be poor. In adults, chloramphenicol can be given as the base orally, and absorption is rapid and complete. The intravenous preparation is chloramphenicol succinate, an inactive precursor, which is hydrolyzed to chloramphenicol in the body. Although the drug has been used to treat typhoid fever for the past four decades, there are scanty data on serum drug concentrations in patients with typhoid fever treated via the oral or intravenous route of administration. The same dose of chloramphenicol, 50 mg/kg of body weight per day, is recommended for both oral and intravenous routes of administration (2, 4, 5, 7). One questions the rationale of such a dosage recommendation since various investigators have shown that a significant percentage of intravenous chloramphenicol succinate is excreted in the urine before its conversion to chloramphenicol (3, 9). In a study on healthy volunteers given equivalent doses of chloramphenicol, Glazko et al. reported that the area under the plasma concentration-time curve of chloramphenicol given intravenously as chloramphenicol succinate was only 60 to 70%o that obtained with oral chloramphenicol (3). The objective of our study was to measure the serum chloramphenicol and chloramphenicol succinate concentrations in patients with typhoid fever who were being treated with either oral chloramphenicol or intravenous chloramphenicol succinate and to assess the clinical outcome of the treatment. Patients who were being treated by their physicians for typhoid fever with oral chloramphenicol or intravenous chloramphenicol succinate were included in the study. The decision to initiate chloramphenicol therapy and the dose and route of administration of the drug were determined by the patients' physicians. Fifteen patients received chloramphenicol capsules orally. Intravenous chloramphenicol succinate was infused via a microdrip over 5 to 15 min to 11 patients. All patients were dosed every 6 h except for seven patients (four in the oral group and three in the intravenous group) who were given *
Corresponding author. 1809
the drug every 8 h. Within the first 3 days of therapy, 10 ml of clotted blood was collected from the patients just before the dose and 1 and 2.5 h postdose. The blood samples were immediately centrifuged, and the serum was stored at -20°C until assay. One of us monitored the progress of the patients in hospital daily. The responses to therapy were divided into four categories: cure (clinical response with stool and urine cultures negative for S. typhi posttreatment, and the patient remained well during follow-up), failure (lack of defervescence), clinical response with continued excretion of S. typhi in the stool posttreatment (convalescent carrier), and relapse (initial response followed by recurrence of fever with blood cultures positive for S. typhi within 2 months posttherapy and with no evidence of reexposure). Chloramphenicol and chloramphenicol succinate were measured simultaneously by high-performance liquid chromatography, using the method reported by Aravind et al. (1). The lower limit of detection of chloramphenicol and chloramphenicol succinate was 0.8 jig/ml. The day-to-day coefficients of variation of the analysis over the study period were 16.4 and 18.7% for the lower limits of detection of chloramphenicol and chloramphenicol succinate, respectively. For the rest of the calibration from 4 to 32 ,ug/ml, the range of variation was between 6.2 and 9.3%. The differences between the intravenous and oral treatment groups in the dose of chloramphenicol administered and the serum drug concentrations were analyzed by the nonparametric Wilcoxon rank-sum test. The patient characteristics, dosages, and serum chloramphenicol and chloramphenicol succinate concentrations are shown in Tables 1 and 2 and Fig. 1. The doses administered were calculated as the chloramphenicol base for both treatment groups. The mean daily dose of chloramphenicol base in the intravenous treatment group was not statistically different from that in the oral treatment group (P > 0.05). The mean trough chloramphenicol concentration in the intravenous treatment group was significantly lower than that obtained in those treated orally (P < 0.001). In those treated intravenously the 1- and 2.5-h-postdose concentrations were significantly lower than those in the oral treatment group (P < 0.001; P < 0.005). There were no treatment failures in either group. Although the patients on intravenous therapy responded well, it is difficult to comment on the adequacy of the concentration in serum, since the number of patients was small. The optimum
1810
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Characteristics of patients on intravenous chloramphenicol succinate Patient
1 2 3 4 5 6 7 8 9 10 11
Mean ± SD
Age (yr)/sexa
Wtt(g (kg)
12/M 26/M 42/F 22/F 17/F 24/F 29/M 26/F 48/F 29/F 29/F
25.3 59.8 47.5 64.0 57.6 44.0 64.0 53.8 45.5 41.8 48.0
27.6 ± 10.2
50.1
+
Chloramphenday base
dose/kg per day (mg) 49.4 50.2 63.2 46.9 69.4 51.1 46.9 55.8 49.5 53.8 62.5
11.4
Serum creatinine
Blood culture
Chloramphenicol in serum (p.g/ml)d
ALTIC (U/liter)
1 h postTrough rab radose
an
an
+ + + + + + + +
N
70
N N N N N
365 39
+ -
N
114
70
54.4 ± 7.5
1.5 (0) 3.0 (0) 8.7 (0)
6 (2.2) 8.0 (11.8) 20.0 (12.5) 8.2 (4.4) 9.6 (3.6) 6.8 (0.8) 7.2 (1.0) 7.0 (1.6) 7.6 (6.0) 11.5 (4.6) 11.1 (5.7)
2.6 (0) 4.3 (0) 5.7 (0) 1.4 (0) 2.6 (0) 1.8 (0) 9.5 (3.9)
9.4 (4.9) ± 3.9 (4.0)
4.1 ± 2.9
2.5 h postdose
Outcome
2.5 4.2 8.2 6.3
Cure Cure Cure Cure Cure Relapse Cure Cure Cure Cure Cure
(0) (0.8) (0.8) (0)
5.3 (0.4) ± 2.5 (0.5)
a M, Male; F, female. b N, Normal range (creatinine, 0.5 to 1.6 mg/dl; urea, 17 to 46 mg/dl). ALT, Alanine aminotransferase (normal range, 5 to 40 U/liter). d Values in parentheses are those of chloramphenicol succinate.
serum chloramphenicol concentration for the treatment of typhoid fever is not known. Generally, it is reasonable to try to attain a trough concentration that is at least as high as the MIC for the pathogen and below 10 p.g/ml, as suggested by Lietman (8). Thirty-two strains of S. typhi were randomly selected from the isolates in our enteric laboratory, and the MIC of chloramphenicol was determined. The range of MICs of chloramphenicol was 2 to 4 ,ug/ml. In the patients treated intravenously, the trough chloramphenicol concentrations ranged from 1.4 to 9.5 ,ug/ml and in 6 of 11 patients the trough concentrations were below 4 ,ug/ml. In contrast, all the patients in the oral treatment group had trough chloramphenicol concentrations above 4 jxg/ml, with a range of 6.3 to 15.3 ,ug/ml. Several investigators found that a significant amount of
chloramphenicol succinate was excreted in the urine before its hydrolysis to chloramphenicol (3, 9). Therefore, renal function may influence the serum chloramphenicol concentration in patients on chloramphenicol succinate but is unlikely to have any significant effect in patients on oral chloramphenicol, since only 5 to 10% of the drug is excreted in the unchanged form. The patients in our study who had their renal function assessed all had serum creatinine or urea within the normal range. The rest of the patients were young and had no clinical suggestion of renal dysfunction. It is unlikely that renal impairment was a factor in causing a difference in serum chloramphenicol concentrations in the two groups of patients. Renal excretion of chloramphenicol succinate prior to its hydrolysis to chloramphenicol is a more likely cause of the lower serum drug concentrations.
TABLE 2. Characteristics of patients on oral chloramphenicol
(yte/tAge
Patlent (yr)/sexl
ChloramphenWt (kg)
icol base
dose/kg per
Blood culture
day (mg)
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Mean ± SD
13/M 18/M 16/M 12/M 14/F 26/M 35/F 38/M 14/M 34/M 35/M 13/M 14/M 41/M 15/M
45.0 45.0 58.6 40.0 32.8 49.9
67.8 91.0
44.4 50.0 51.9 50.0 61.0 45.1 40.5 56.6 50.0 37.5 36.3 54.6 52.2 44.2 33.0
22.5 ± 10.9
58.0 ± 18.2
47.2 ± 7.9
74.0 53.0 60.0 80.5 82.6 32.0 57.5
+ + + + + + +
+ + + +
+
a M, Male; F, female. b N, Normal range (creatinine, 0.5 to 1.6 mg/dl; urea, 17 to 46 mg/dl). c ALT, Alanine aminotransferase (normal range, 5 to 40 U/liter).
Serum
ea. and ureab
ALTc
(U/liter)
Trough
1 h postdose
33
11.2 20.0
79 38
7.0 7.6 11.7 11.1 7.6
86 127 141 206 292 158
11.7 10.2 12.8 7.3 15.3 7.4 9.6 6.3 6.4
N N N N N
N N
Chloramphenicol in serum (,ug/ml) Truh
9.4 ± 2.8
15.7 20.8 10.8 11.0 20.2 25.0 17.8 17.3 20.5
2.5 h postdose
Cure Cure
19.2
9.8 19.0 20.8 10.0 11.4
20.4 17.6 ± 4.6
Outcome
15.0 ± 5.1
Cure Cure Cure Cure Relapse Relapse Cure Cure Cure Cure Cure Cure Convalescent carrier
NOTES
VOL. 34, 1990 0
1811
oral therapy. Therefore, where facilities are available, it may be prudent to measure serum chloramphenicol concentrations, especially in patients who are treated with intravenous chloramphenicol succinate, to ensure that failure to respond is not due to low serum drug concentrations.
.I0
25 .0 r-
8
E 20 0
0a
Z
E
0
S.. .E
C)
15
Cl)
rC
c
O
l
10
0
0
0
-C a
0
0
0
E
Pre-Dose
lh Post-Dose
2.5h Post-Dose
FIG. 1. Predose and 1- and 2.5-h-postdose serum chloramphenicol concentrations (mean standard deviation) in patients treated with oral chloramphenicol (l) and intravenous chloramphenicol succinate (B). F 1, Serum chloramphenicol succinate concentration. n, Number of patients.
Abnormal liver function tests are not uncommon in patients with typhoid fever (6). In our study, the patients in both the oral and intravenous treatment groups who had their liver function evaluated showed mild elevation in liver enzymes. However, there did not seem to be any correlation between the levels of alanine aminotransferase and serum chloramphenicol concentrations. In summary, in the treatment of typhoid fever, it is important to realize that with equivalent doses of chloramphenicol, the serum drug concentration of patients treated intravenously is significantly lower than that of patients on
LITERATURE CITED 1. Aravind, M. K., J. N. Miceli, R. E. Kauffman, L. E. Strebel, and A. K. Done. 1980. Simultaneous measurement of chloramphenicol and chloramphenicol succinate by high-performance liquid chromatography. J. Chromatogr. 221:176-181. 2. Butler, T. 1988. Typhoid fever, p. 1641-1643. In J. B. Wyngaarden and L. H. Smith (ed.), Cecil textbook of medicine, 18th ed. The W. B. Saunders Co., Philadelphia. 3. Glazko, A. J., W. A. Dill, A. W. Kinkel, J. R. Goulet, W. J. Holloway, and R. A. Buchanan. 1977. Absorption and excretion of parenteral doses of chloramphenicol sodium succinate (CMS) in comparison with peroral doses of chloramphenicol (CM). Clin. Pharmacol. Ther. 21:104. 4. Guerrant, R. L. 1987. Salmonella infection, p. 592-5%. In R. G. Petersdoff, R. D. Adams, E. Braunwald, K. J. Isselbachek, J. B. Martin, and J. B. Wilson (ed.), Harrison's principle of internal medicine, 11th ed. McGraw-Hill Book Co., New York. 5. Hook, E. W. 1985. Salmonella species, p. 1256-1268. In G. L. Mandell, R. G. Douglas, and J. E. Bennett (ed.), Principles and practice of infectious diseases, 2nd ed. John Wiley & Sons, Inc., New York. 6. Klotz, S. A., J. H. Jorgensen, F. J. Buckwold, and P. C. Craven. 1984. Typhoid fever. Arch. Intern. Med. 144:533-537. 7. Kucers, A., and N. M. Bennett. 1987. The use of antibiotics, 4th ed., p. 757-807. William Heinemann Medical Books Ltd., London. 8. Lietman, P. S. 1981. Oral chloramphenicol therapy. J. Pediatr. 99:905-906.
9. Slaughter, R. L., J. A. Pieper, F. B. Cerra, B. Brodsky, and J. R. Kaup. 1980. Chloramphenicol sodium succinate kinetics in critically ill patients. Clin. Pharmacol. Ther. 28:69-77.
0066-4804/90/091809-03$02.00/0 Copyright ©) 1990, American Society for Microbiology
Vol. 34, No. 9
Chloramphenicol Concentrations in Sera of Patients with Typhoid Fever Being Treated with Oral or Intravenous Preparation Department
TEOW-YEE TI,l* EDMUND H. MONTEIRO,2 SELENA LAM,3 AND HOW-SUNG LEE1 Faculty of Medicine, National University of Singapore,' Department of Communicable Diseases, Tan Tock Seng Hospital,2 and Enteric Laboratory, Ministry of Health,3 Singapore
of Pharmacology,
Received 6 December 1989/Accepted 26 June 1990
Serum chloramphenicol and chloramphenicol succinate concentrations in patients given equivalent doses of chloramphenicol base either intravenously or orally for typhoid fever were measured by high-performance liquid chromatography. The mean serum chloramphenicol concentrations were significantly lower in the 11 patients treated with intravenous chloramphenicol succinate than in the 15 patients treated with oral chloramphenicol capsules.
Chloramphenicol is an effective drug in the treatment of typhoid fever caused by susceptible strains of Salmonella typhi. The recommended route of administration of chloramphenicol is usually oral for the treatment of typhoid fever (2, 4, 5, 7). The intravenous route is used with severely ill patients, in whom absorption may be poor. In adults, chloramphenicol can be given as the base orally, and absorption is rapid and complete. The intravenous preparation is chloramphenicol succinate, an inactive precursor, which is hydrolyzed to chloramphenicol in the body. Although the drug has been used to treat typhoid fever for the past four decades, there are scanty data on serum drug concentrations in patients with typhoid fever treated via the oral or intravenous route of administration. The same dose of chloramphenicol, 50 mg/kg of body weight per day, is recommended for both oral and intravenous routes of administration (2, 4, 5, 7). One questions the rationale of such a dosage recommendation since various investigators have shown that a significant percentage of intravenous chloramphenicol succinate is excreted in the urine before its conversion to chloramphenicol (3, 9). In a study on healthy volunteers given equivalent doses of chloramphenicol, Glazko et al. reported that the area under the plasma concentration-time curve of chloramphenicol given intravenously as chloramphenicol succinate was only 60 to 70%o that obtained with oral chloramphenicol (3). The objective of our study was to measure the serum chloramphenicol and chloramphenicol succinate concentrations in patients with typhoid fever who were being treated with either oral chloramphenicol or intravenous chloramphenicol succinate and to assess the clinical outcome of the treatment. Patients who were being treated by their physicians for typhoid fever with oral chloramphenicol or intravenous chloramphenicol succinate were included in the study. The decision to initiate chloramphenicol therapy and the dose and route of administration of the drug were determined by the patients' physicians. Fifteen patients received chloramphenicol capsules orally. Intravenous chloramphenicol succinate was infused via a microdrip over 5 to 15 min to 11 patients. All patients were dosed every 6 h except for seven patients (four in the oral group and three in the intravenous group) who were given *
Corresponding author. 1809
the drug every 8 h. Within the first 3 days of therapy, 10 ml of clotted blood was collected from the patients just before the dose and 1 and 2.5 h postdose. The blood samples were immediately centrifuged, and the serum was stored at -20°C until assay. One of us monitored the progress of the patients in hospital daily. The responses to therapy were divided into four categories: cure (clinical response with stool and urine cultures negative for S. typhi posttreatment, and the patient remained well during follow-up), failure (lack of defervescence), clinical response with continued excretion of S. typhi in the stool posttreatment (convalescent carrier), and relapse (initial response followed by recurrence of fever with blood cultures positive for S. typhi within 2 months posttherapy and with no evidence of reexposure). Chloramphenicol and chloramphenicol succinate were measured simultaneously by high-performance liquid chromatography, using the method reported by Aravind et al. (1). The lower limit of detection of chloramphenicol and chloramphenicol succinate was 0.8 jig/ml. The day-to-day coefficients of variation of the analysis over the study period were 16.4 and 18.7% for the lower limits of detection of chloramphenicol and chloramphenicol succinate, respectively. For the rest of the calibration from 4 to 32 ,ug/ml, the range of variation was between 6.2 and 9.3%. The differences between the intravenous and oral treatment groups in the dose of chloramphenicol administered and the serum drug concentrations were analyzed by the nonparametric Wilcoxon rank-sum test. The patient characteristics, dosages, and serum chloramphenicol and chloramphenicol succinate concentrations are shown in Tables 1 and 2 and Fig. 1. The doses administered were calculated as the chloramphenicol base for both treatment groups. The mean daily dose of chloramphenicol base in the intravenous treatment group was not statistically different from that in the oral treatment group (P > 0.05). The mean trough chloramphenicol concentration in the intravenous treatment group was significantly lower than that obtained in those treated orally (P < 0.001). In those treated intravenously the 1- and 2.5-h-postdose concentrations were significantly lower than those in the oral treatment group (P < 0.001; P < 0.005). There were no treatment failures in either group. Although the patients on intravenous therapy responded well, it is difficult to comment on the adequacy of the concentration in serum, since the number of patients was small. The optimum
1810
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Characteristics of patients on intravenous chloramphenicol succinate Patient
1 2 3 4 5 6 7 8 9 10 11
Mean ± SD
Age (yr)/sexa
Wtt(g (kg)
12/M 26/M 42/F 22/F 17/F 24/F 29/M 26/F 48/F 29/F 29/F
25.3 59.8 47.5 64.0 57.6 44.0 64.0 53.8 45.5 41.8 48.0
27.6 ± 10.2
50.1
+
Chloramphenday base
dose/kg per day (mg) 49.4 50.2 63.2 46.9 69.4 51.1 46.9 55.8 49.5 53.8 62.5
11.4
Serum creatinine
Blood culture
Chloramphenicol in serum (p.g/ml)d
ALTIC (U/liter)
1 h postTrough rab radose
an
an
+ + + + + + + +
N
70
N N N N N
365 39
+ -
N
114
70
54.4 ± 7.5
1.5 (0) 3.0 (0) 8.7 (0)
6 (2.2) 8.0 (11.8) 20.0 (12.5) 8.2 (4.4) 9.6 (3.6) 6.8 (0.8) 7.2 (1.0) 7.0 (1.6) 7.6 (6.0) 11.5 (4.6) 11.1 (5.7)
2.6 (0) 4.3 (0) 5.7 (0) 1.4 (0) 2.6 (0) 1.8 (0) 9.5 (3.9)
9.4 (4.9) ± 3.9 (4.0)
4.1 ± 2.9
2.5 h postdose
Outcome
2.5 4.2 8.2 6.3
Cure Cure Cure Cure Cure Relapse Cure Cure Cure Cure Cure
(0) (0.8) (0.8) (0)
5.3 (0.4) ± 2.5 (0.5)
a M, Male; F, female. b N, Normal range (creatinine, 0.5 to 1.6 mg/dl; urea, 17 to 46 mg/dl). ALT, Alanine aminotransferase (normal range, 5 to 40 U/liter). d Values in parentheses are those of chloramphenicol succinate.
serum chloramphenicol concentration for the treatment of typhoid fever is not known. Generally, it is reasonable to try to attain a trough concentration that is at least as high as the MIC for the pathogen and below 10 p.g/ml, as suggested by Lietman (8). Thirty-two strains of S. typhi were randomly selected from the isolates in our enteric laboratory, and the MIC of chloramphenicol was determined. The range of MICs of chloramphenicol was 2 to 4 ,ug/ml. In the patients treated intravenously, the trough chloramphenicol concentrations ranged from 1.4 to 9.5 ,ug/ml and in 6 of 11 patients the trough concentrations were below 4 ,ug/ml. In contrast, all the patients in the oral treatment group had trough chloramphenicol concentrations above 4 jxg/ml, with a range of 6.3 to 15.3 ,ug/ml. Several investigators found that a significant amount of
chloramphenicol succinate was excreted in the urine before its hydrolysis to chloramphenicol (3, 9). Therefore, renal function may influence the serum chloramphenicol concentration in patients on chloramphenicol succinate but is unlikely to have any significant effect in patients on oral chloramphenicol, since only 5 to 10% of the drug is excreted in the unchanged form. The patients in our study who had their renal function assessed all had serum creatinine or urea within the normal range. The rest of the patients were young and had no clinical suggestion of renal dysfunction. It is unlikely that renal impairment was a factor in causing a difference in serum chloramphenicol concentrations in the two groups of patients. Renal excretion of chloramphenicol succinate prior to its hydrolysis to chloramphenicol is a more likely cause of the lower serum drug concentrations.
TABLE 2. Characteristics of patients on oral chloramphenicol
(yte/tAge
Patlent (yr)/sexl
ChloramphenWt (kg)
icol base
dose/kg per
Blood culture
day (mg)
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Mean ± SD
13/M 18/M 16/M 12/M 14/F 26/M 35/F 38/M 14/M 34/M 35/M 13/M 14/M 41/M 15/M
45.0 45.0 58.6 40.0 32.8 49.9
67.8 91.0
44.4 50.0 51.9 50.0 61.0 45.1 40.5 56.6 50.0 37.5 36.3 54.6 52.2 44.2 33.0
22.5 ± 10.9
58.0 ± 18.2
47.2 ± 7.9
74.0 53.0 60.0 80.5 82.6 32.0 57.5
+ + + + + + +
+ + + +
+
a M, Male; F, female. b N, Normal range (creatinine, 0.5 to 1.6 mg/dl; urea, 17 to 46 mg/dl). c ALT, Alanine aminotransferase (normal range, 5 to 40 U/liter).
Serum
ea. and ureab
ALTc
(U/liter)
Trough
1 h postdose
33
11.2 20.0
79 38
7.0 7.6 11.7 11.1 7.6
86 127 141 206 292 158
11.7 10.2 12.8 7.3 15.3 7.4 9.6 6.3 6.4
N N N N N
N N
Chloramphenicol in serum (,ug/ml) Truh
9.4 ± 2.8
15.7 20.8 10.8 11.0 20.2 25.0 17.8 17.3 20.5
2.5 h postdose
Cure Cure
19.2
9.8 19.0 20.8 10.0 11.4
20.4 17.6 ± 4.6
Outcome
15.0 ± 5.1
Cure Cure Cure Cure Relapse Relapse Cure Cure Cure Cure Cure Cure Convalescent carrier
NOTES
VOL. 34, 1990 0
1811
oral therapy. Therefore, where facilities are available, it may be prudent to measure serum chloramphenicol concentrations, especially in patients who are treated with intravenous chloramphenicol succinate, to ensure that failure to respond is not due to low serum drug concentrations.
.I0
25 .0 r-
8
E 20 0
0a
Z
E
0
S.. .E
C)
15
Cl)
rC
c
O
l
10
0
0
0
-C a
0
0
0
E
Pre-Dose
lh Post-Dose
2.5h Post-Dose
FIG. 1. Predose and 1- and 2.5-h-postdose serum chloramphenicol concentrations (mean standard deviation) in patients treated with oral chloramphenicol (l) and intravenous chloramphenicol succinate (B). F 1, Serum chloramphenicol succinate concentration. n, Number of patients.
Abnormal liver function tests are not uncommon in patients with typhoid fever (6). In our study, the patients in both the oral and intravenous treatment groups who had their liver function evaluated showed mild elevation in liver enzymes. However, there did not seem to be any correlation between the levels of alanine aminotransferase and serum chloramphenicol concentrations. In summary, in the treatment of typhoid fever, it is important to realize that with equivalent doses of chloramphenicol, the serum drug concentration of patients treated intravenously is significantly lower than that of patients on
LITERATURE CITED 1. Aravind, M. K., J. N. Miceli, R. E. Kauffman, L. E. Strebel, and A. K. Done. 1980. Simultaneous measurement of chloramphenicol and chloramphenicol succinate by high-performance liquid chromatography. J. Chromatogr. 221:176-181. 2. Butler, T. 1988. Typhoid fever, p. 1641-1643. In J. B. Wyngaarden and L. H. Smith (ed.), Cecil textbook of medicine, 18th ed. The W. B. Saunders Co., Philadelphia. 3. Glazko, A. J., W. A. Dill, A. W. Kinkel, J. R. Goulet, W. J. Holloway, and R. A. Buchanan. 1977. Absorption and excretion of parenteral doses of chloramphenicol sodium succinate (CMS) in comparison with peroral doses of chloramphenicol (CM). Clin. Pharmacol. Ther. 21:104. 4. Guerrant, R. L. 1987. Salmonella infection, p. 592-5%. In R. G. Petersdoff, R. D. Adams, E. Braunwald, K. J. Isselbachek, J. B. Martin, and J. B. Wilson (ed.), Harrison's principle of internal medicine, 11th ed. McGraw-Hill Book Co., New York. 5. Hook, E. W. 1985. Salmonella species, p. 1256-1268. In G. L. Mandell, R. G. Douglas, and J. E. Bennett (ed.), Principles and practice of infectious diseases, 2nd ed. John Wiley & Sons, Inc., New York. 6. Klotz, S. A., J. H. Jorgensen, F. J. Buckwold, and P. C. Craven. 1984. Typhoid fever. Arch. Intern. Med. 144:533-537. 7. Kucers, A., and N. M. Bennett. 1987. The use of antibiotics, 4th ed., p. 757-807. William Heinemann Medical Books Ltd., London. 8. Lietman, P. S. 1981. Oral chloramphenicol therapy. J. Pediatr. 99:905-906.
9. Slaughter, R. L., J. A. Pieper, F. B. Cerra, B. Brodsky, and J. R. Kaup. 1980. Chloramphenicol sodium succinate kinetics in critically ill patients. Clin. Pharmacol. Ther. 28:69-77.
