Enteric fever is caused by fecal oral transmission of Salmonella enteric serotypes Typhi or Para typhi A. About 27 million people suffer from enteric fever each year, with about 200 000 deaths almost exclusively in the developing world.1 In western countries, the disease has been brought very close to eradication levels. In the UK, there is approximately one case per 100,000 population per year. Each year, the world over, there are at least 13- 17 million cases of typhoid fever, resulting in 600,000 deaths; 80% of these cases and deaths occur in Asia alone. Antibiotics resistance, particularly emergence of multidrug resistant (MDR) strains among Salmonellae is a rising concern and has been linked to antibiotic use in livestock.2
Recent reports suggest that the clinical symptoms and complication rates are similar in Typhi and Paratyphi A infections, in contrast to the belief that Paratyphi A was a milder infection. Hence, the treatment of paratyphoid fever needs to be carried out as aggressively as treatment for typhoid fever. Crucially, current typhoid vaccines do not protect against paratyphoid fever—a major drawback of the present vaccine, especially because paratyphoid is on the rise in South Asia.1 Moreover, a transferable plasmid encoding resistance to chloramphenicol, co-trimoxazole, and ampicillin has spread to Salmonella enterica serovar Typhi in many countries.
β-lactams have been considered ineffective against organisms growing inside mammalian cells because of their poor penetration into cells. However, cefixime has been shown to be clinically effective against typhoid fever. Cefixime, the first orally extended-spectrum cephalosporin, has strong activity against serovar Typhi [Minimum inhibitory concentration (MIC) at which 90% of the strains are inhibited – 0.25 mg/ml], and its clinical usefulness has also been proven in several studies.
In a study, the probable mechanism of therapeutic effectiveness of cefixime against typhoid fever was investigated using Salmonella enterica serovar Typhimurium in a cellular and in an experimental model. The result showed that cefixime inhibited the growth of serovar Typhimurium inhabiting monocyte- derived THP-1 cells. Elongation of serovar Typhimurium in THP-1 cells was observed microscopically. Apparent morphological changes of serovar Typhimurium in THP-1 cells were also observed by electron microscopy. The concentration of cefixime inside THP-1 cells was almost half (46 to 48%) of the concentration outside the cells when serovar Typhimurium coexisted in the solution (Figure 1).
The length of time after oral dosing (8 mg/kg) that cefixime was present was calculated from levels in serum. At a concentration above the MIC at which 90% of the serovar Typhi organisms inside human cells were inhibited was presumed to be more than 12 hrs.
An interventional study was carried out to compare the clinical efficacy of cefixime in the treatment of childhood typhoid fever with that of azithromycin for a period of one year. It was a randomized clinical trial with a total of 60 cases of typhoid fever, divided into two groups. The inclusion criteria of the cases were; documented fever for more than 4 days plus two or more of the following clinical features; toxic physical appearance, intestinal complaints, coated tongue, ceacal gurgling, hepatomegaly and splenomegaly, diarrhoea and constipation plus positive Widal test and/or blood culture positivity. Data was collected in a structured questionnaire. Cefixime was given at a dose of 20mg/ kg/day in two divided doses for 14 days whereas azithromycin was given at a dose of 10mg/kg/day for a period of 7 days The mean time of defervesence was 3.41 ± 0.95 with cefixime and 4.05 ± 1.14 days with azithromycin respectively. The minimum defervesence time was 2 days and maximum defervesence time was 7 days. The clinical effect rate was 87% in azithromycin group and 93% in cefixime group.
The highest disease burden of typhoid fever caused by Salmonella enterica serotype Typhi (S. Typhi) is seen in children below five years of age in endemic areas. The immunological responses and clinical characteristics in young children with S. Typhi bacteremia have till date remained poorly characterized. To address this issue a study to compare cefixime with chloramphenicol for treatment of children with culture positive typhoid fever was conducted, that showed treatment with cefixime was a better option.
Twenty children were given cefixime 10 mg/kg/day orally for 14 days and twenty received chloramphenicol 50 mg/kg/day orally for 14 days. The clinical characteristics were compared in both the groups. Clinical effect was observed in 18 (90%) patients treated with cefixime and 9 (45%) treated with chloramphenicol. Of 11 patients who did not respond to chloramphenicol, 10 were switched over to cefixime and all were cured. Overall 28 out of 30 cases (93.3%) were cured by cefixime.
Cefixime has been shown to be effective in multi drug resistant enteric fever in children. In a study carried out to assess the efficacy safety, and cost effectiveness of cefixime in the treatment of multidrug-resistant enteric fever, it was shown that it is safe and effective, oral option. The study included 85 patients 5 years of age or less, with culture-proven enteric fever. The patients were randomly assigned to two groups.
Group A (n = 41) received cefixime at a dosage of 10 mg/kg to 12 mg/kg per day in two divided doses. Group B (n = 44) received chloramphenicol at a dosage of 100 mg/kg daily in four divided doses. Both groups were treated for 2 weeks. The results showed that in group A, 95% (39/41) of the patients receiving cefixime responded favorably, whereas in group B, 30% (14/45) responded to chloramphenicol. The 31 patients not cured in group B were then successfully treated with cefixime. Overall, cefixime was well tolerated.
Management of typhoid fever continues to pose a challenge. Therapy with newer quinolones and -lactams has been introduced to cope with multidrug-resistant Salmonella serovar Typhi. Cefixime has been proven to be one of the potent drugs that inhibits strains of serovar Typhi and shows a strong activity against the organism. While quinolones are not recommended in children with enteric fever, cefixime has been successfully used and has been proven to be safe and better tolerable in pediatrics patients.