In the recent years treatment of typhoid fever with existing popular drugs has been unsatisfactory, because of the emergent resistant strains of Salmonella typhi throughout the world including Pakistan. Third generation cephalosporins, such as ceftriaxone and cefixime, have emerged as a satisfactory alternative drugs to previous oral typhoid fever therapies. Previous studies in Pakistan have shown a cure rate of more than 95% with parenteral ceflriaxone in children with MDR typhoid fever (Naqvi et aI., 1992). The major limitations for available third generation cephalosporins are cost and the necessity for parenteral administration.
Many studies have reported changes in clinical responses to many drugs due to the effects of age, liver dysfunction, malnutrition and fever on the kinetics of these drugs. However, new anti-typhoidal drugs have not been extensively studied. Therefore, this study was undertaken to examine the effects of age and/or concomitant complications with typhoid fever (liver dysfunction, malnutrition and fever) on the pharmacokinetics (absorption, distribution, metabolism and excretion) of new anti-typhoidal drugs, which may ultimately alter drug activity.
Children with MDR typhoid fever were administered either ceftriaxone (65mg/ Kg once daily) for 14 days or cefixime (10, 15 and 20mg/ Kg/day in two divided doses) for 14 days. Similar previous study on cefixime (I0mg/ Kg) had been conducted by us in children with MDR typhoid fever. Serum levels of ceftriaxone and cefixime were determined using high performance liquid chromatography (HPLC) technique. The pharmacokinetic parameters i.e.maximum serum concentration (Cmax), minimum serum concentration (Cmin), halflife (t1/2), area under the serum concentration versus time curve (AVC), volume of distribution (V d) and serum clearance (ClS) were calculated.
Salmonella typhi was isolated from blood obtained from 119 children (64 in the ceftriaxone study, 30 in the first cefixime study and 25 in second study of cefixime) and these isolates were found to be resistant to the first line oral therapies (ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole) of typhoid fever. All patients successfully completed the study as per protocol. The relapse rate was 5% in ceftriaxone study and 2% in cefixime studies. The time to deffervescence in ceftriaxone study was 5.5 days, whereas in first cefixime study it was 9.5, 6.4 and 11.1 days for the dose levels of 10, 15 and 20mg/ Kg body weight respectively and in cefixime previous study was 14.9 days. However, there was no mortality or any other complication observed during the course all studies.
On day three of treatment, the pharmacokinetic parameters including Cmax, Cmin, t1/2, AUC, Vd, and Cls were estimated for both drugs (ceftriaxone and cefixime) in children with MDR typhoid fever. Compared with the published data in children, the results of this study showed that ceftriaxone has lower Cmax and higher t1/2, AUC, Vd and Cls values. The mean peak serum cefixime concentrations in the two studies were fairly linear in pediatric patients on doses of 10 to 20mg/ Kg. However, the values of Cmax, t1/2, AUC, Vd were higher, whereas Cls was lower than that reported in previously in children and adults.
To determine the effects of age on the pharmacokinetic parameters of ceftriaxone and cefixime were investigated in children with MDR typhoid fever. Pediatric patients in this study were divided into two groups (group one included all children ages 5 years, and group two were those> 5 years of age). The effects of age on the pharmacokinetic parameters of ceftriaxone and cefixime (previous study) were not significant. Whereas, it is significantly affected the V d and Cls of cefixime.
The influence of the transient liver dysfunction (in some patients) due to typhoid fever on the pharmacokinetics of ceftriaxone and cefixime was also examined. In ceftriaxone study, the Cm.. and AVC were significantly lower and Vd was significantly higher in children with liver dysfunction than those of children with normal liver function. Whereas, the Cmax, t1/2 CIs were not significantly affected. However, in both cefixime studies, liver dysfunction had no significant effects on their pharmacokinetic parameters.
In order to assess the effects of malnutrition on the pharmacokinetics of cefixime in children with typhoid fever, data was analyzed by comparing data obtained from children with or without malnutrition. The mean values of pharmacokinetic parameters in children with malnutrition were not significantly different form those of children with normal nutritional status.
The effects of fever duration on ceftriaxone and cefixime pharmacokinetics were examined in children with MDR typhoid fever. Children were divided into two groups (Le., group one included all children with < I week of fever duration, and group two were those> I week of fever duration). The Cls of cefixime (previous study) was significantly lower in group one than that of group two. Whereas, other pharmacokinetic parameters of this study and the ceftriaxone and cefixime studies were not significantly affected by duration of fever.
In conclusion based on the above data, it can be safely that 14 days course of once-daily ceftriaxone (65mg/ Kg body weight), showed a safe and effective alternative therapy to first line therapies for the treatment of MDR typhoid fever in children. In addition, ceftriaxone shortens duration of fever substantially, thus reducing the hospital stay.
In addition, this study also suggests that a 14 days course of twice-daily cefixime 15mg/ Kg provides safe and effective therapy than that of 10 and 20mg/ Kg, and also provides alternative therapy to first line therapy. In addition, cefixime is an oral formulation, so can be prescribed on an outpatient basis for children experiencing MDR typhoid fever. Therefore, its use would be preferable for patients that not require hospitalization.
Since the transient liver dysfunction significantly affects the pharmacokinetic parameters of ceftriaxone, therefore dosage adjustment may be required in children requiring ceftriaxone. Whereas, the affects of liver dysfunction on the pharmacokinetic parameters of cefixime were not significant, therefore dosage adjustment may be not required in children requiring cefixime. Hoever, age, malnutrition and fever related changes in the pharmacokinetic parameters of ceftriaxone and cefixime were not satisticaly significant. Therefore, it is concluded that dosage adjustment would not be necessary in children requiring ceftriaxone as well as cefixime.