Study comparing ceftriaxone with azithromycin for the treatment of uncomplicated typhoid fever in children of India

Introduction: The typhoid fever is one of the most common and serious infections in a developing country like India. An increase in the occurrence of typhoid fever in Indian children has stimulated the evaluation of alternative drugs for treatment in the Out Patient Department (OPD) without hospitalisation. Objective: To study the feasibility of using oral azithromycin for treating blood culture positive uncomplicated typhoid fever instead of intravenous ceftriaxone in a resource poor setting. Materials and Methods: We performed a randomised controlled trial to compare the efficacy and safety of azithromycin (20 mg/kg/day) as a once daily oral dose with intravenous ceftriaxone for 7 days for the treatment of uncomplicated typhoid fever in children and adolescents in India. A total of 124 children aged 3-18 years who were suspected to have typhoid fever were randomized and studied. Statistical analysis used: Data analysis was performed using Epi Info version 7 (Centers for Disease Control, Atlanta, GA.) and SPSS for Windows version 7.5 (SPSS, Inc., Chicago, Il.). Results: Our study showed that clinical cure was achieved in 30 (100%) of 30 patients in the azithromycin group and in 30 (88.2%) of 34 patients in the ceftriaxone group. The mean time taken for clearance of bacteraemia was longer in the azithromycin group than in the ceftriaxone. No patient who received azithromycin had a relapse as compared to 5 patients who received ceftriaxone. No serious side effects occurred in any subject under study. Conclusion: Oral azithromycin could be a convenient and cheap alternative for the treatment of typhoid fever, especially in children in developing countries where medical resources are scarce.

Keywords: Azithromycin, ceftriaxone, resource poor, Typhoid fever
Key messages: Oral azithromycin in single dosing can improve compliance and decrease economic burden in uncomplicated typhoid fever in developing countries.

The typhoid fever caused by  Salmonella ^{More Details} typhi remains a serious problem in developing countries like India. It is estimated that more than 26.9 million typhoid fever cases occur annually out of which 1% result in death.^[1]The vast majority of this infectious disease is mainly witnessed in Asia. These figures are representing the clinical syndrome rather than the culture-proven typhoid fever cases. The typhoid infection is predominantly seen in school age children and young adults. However, this infection is reported to be milder in infants and very young children. There is a wide range of presentation with involvement of various organs. Besides, there is also a paucity of microbiology facilities in developing countries.

The choice of oral antimicrobial regimens for uncomplicated typhoid fever caused by Salmonella typhi is unclear. An increase in the incidence of Salmonella typhi strains resistant to fluoroquinolones, chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole causing typhoid fever in Indian children, stimulated us to evaluate alternative drugs for treatment of uncomplicated typhoid fever in the Out Patient Department (OPD) without hospitalisation. A macrolide like azithromycin given in a high dose for 7 days is the most affordable first-line option for these infections in areas of endemicity. The injectable cephalosporin (ceftriaxone) and / or hospitalisation would prove to be a great economic drain and resource burden in a developing country like India.

The aim of this study was to compare use of oral azithromycin with intravenous ceftriaxone to treat uncomplicated blood culture positive typhoid fever in a resource poor country like India.

Study site: The study was conducted at a 999 bedded primary care as well as a referral hospital in New Delhi (India).

Study population: The children between 3-18 years of age who were suspected of having typhoid fever, were admitted to the paediatric ward. The patients with documented fever (a rectal temperature >38.0°C or an oral temperature >37.5°C) of more than 4 days and having more than any 2 of the above symptoms or signs were included in the study. The additional symptoms or signs considered were splenomegaly, hepatomegaly, abdominal tenderness, and/or a coated tongue. Only patients with blood and/or stool cultures positive for S. typhi were evaluated.

We excluded patients who had inability to swallow oral medications and were also having major typhoid complications like pneumonia, shock, coma, intestinal haemorrhage, perforation, or significant underlying illness. We also excluded patients who had received antibiotics that were effective against S. Typhi in the past 4 days or who were known to be allergic to either ceftriaxone or azithromycin.

The parents or guardians who were willing to enrol their child were explained in detail about the study. Any doubts or questions related to the study were clarified to their satisfaction. Illiterate parents and guardians had the consent documents read to them and explained in the language they understood, by interpreters who were not associated with the study in any manner. After the informed consent was taken, the patients were randomly assigned to a treatment group.

Sample size: The study was designed to detect a 50% difference in clinical success rates between the two groups. We assumed that at least 50% of the subjects treated with azithromycin would respond to therapy (response is defined as becoming afebrile within 7 days of starting treatment). Accepting a type 1 error of 0.05 and a type 2 error of 0.2, it was projected that 30 evaluable subjects (positive blood or stool culture) would be needed for each treatment arm.^[2] Assuming that 50% of the patients with clinical typhoid fever would have blood cultures positive for S. typhi, a total of 62 subjects were initially enrolled for each treatment group of azithromycin and ceftriaxone.

Randomization and treatment: The patients were screened for eligibility to be enrolled in the study. Thereafter, the informed consent was obtained and each patient was randomly assigned to a treatment group. Neither subjects nor investigators knew before randomization which medication each subject would receive. Treatment assignments were determined by block randomization based on a random number list. These were sealed in envelopes by a medical professional uninvolved in the treatment trial. At the time of enrolment, the investigator unsealed the envelope to determine which treatment the subject would receive. After randomization, subjects were treated in an open-label format with either azithromycin (20 mg/kg/day; maximum, 1000 mg/day) or ceftriaxone (75 mg/kg/day; maximum, 2.5 g/day). All doses of both study medications were administered in the hospital by the nursing staff.

Procedures: The blood and stool cultures were performed prior to initiation of antibiotic therapy. Blood was also obtained for hematologic measurements and serum biochemistry determination. During period of hospitalization, clinical examination of the patient was performed daily, based on a structured form. The vital parameters (including body temperature) were measured 6 hourly. One month after discharge, all the patients were called for review to the hospital for a final examination. However, they were instructed to return immediately if they became sick before the scheduled follow-up visit.

The patients/guardians were administered a structured questionnaire regarding any major changes in the symptoms or development of any adverse events. On 3^rd and 7^th day, and 30 days after the treatment was started, blood was obtained for culture, hematologic measurements, and serum biochemistry determination. The stool for culture was collected on day 3 and day 7 after the start of treatment and also 1 month after completion of therapy. The patients were asked to return 30 days after the completion of treatment for a final clinical examination and laboratory investigations.

Specimen processing: The blood and stool specimens were cultured using standard clinical methods. All the blood cultures were blindly sub cultured after^[1],[7] 14 days of incubation. They were also cultured when the broth appeared cloudy. MacConkey agar and Salmonella Shigella agar were used for plating stool specimens. Any bacterial colony in blood, stool or urine cultures which were suggestive of Salmonella species, were further tested using standard methods to confirm their identification.^[3] Kirby-Bauer or disc diffusion antibiotic sensitivity testing method was used for testing the susceptibility of S. Typhi to nalidixic acid, chloramphenicol, ciprofloxacin, ofloxacin, trimethoprim-sulfamethoxazole, and ampicillin. The Etest strips (bioMerieux) were used for testing susceptibility to both azithromycin and ceftriaxone.^[4]CLSI (Clinical and Laboratory Standards Institute) Guidelines were used to assign susceptibility and resistance breakpoints for each antibiotic tested.^[5]

Statistical analysis of data: The statistical analysis was performed using Epi Info version 7 (Centers for Disease Control, Atlanta, GA.) and SPSS for Windows version 7.5 (SPSS, Inc., Chicago, Il.). The fever clearance time and duration of admission after the start of treatment, were compared using survival analysis and the log rank test. The Fisher exact test and relative risk with a 95% confidence interval (CI) was used for the outcome variables. Normally distributed data was compared using the Student t test, and non-normally distributed data was compared using the Mann-Whitney U test. Proportions were compared with the chi-square test with Yates’ correction or the Fisher exact test.

Ethics compliance: The study was performed with the ethical permission of the Institutional Review Board of our hospital.

Out of 124 consecutive children with suspected typhoid who were admitted in our hospital in North India, 58 got an alternative diagnosis within 48 hours of admission. After the entry to the study, two patients were found to have taken a fluoroquinolone before admission to the hospital. 64 patients (28 males, 36 females) ranging in age from 3 to 18 years were enrolled in the study and randomly assigned to one of the two treatment groups. These 64 children (30 receiving azithromycin, 34 receiving ceftriaxone) had blood cultures or stool cultures from which S. typhi was isolated. 6 of our patients grew S.typhi from both stool and blood samples and 64 patients had the bacteria isolated only from the blood.

The epidemiological, clinical, and laboratory features of patients with culture-confirmed typhoid fever under the treatment group are shown in [Table 1].There were no significant statistical differences between these groups. Both antibiotic therapies were highly effective in the patients as shown in [Table 2]. The patients responded quickly to therapy; the mean time for defervescence ± SD was 5.5 ± 1.9days and 4.5±1.6days for azithromycin recipients and ceftriaxone recipients, respectively (p value was not significant).

The clinical cure was achieved in 28 (93.3%) of 30 patients treated with azithromycin and in 33 (97%) of 34 patients treated with ceftriaxone by day 7 of treatment [Table 3]. In the azithromycin group, 2 had clinical failure as a result of slow resolution of fever. Both the clinical failures in this group were due to mild gastrointestinal symptoms that were resolved 7 days after treatment was started and did not require any additional treatment. Persistent fever caused one treatment failure at the end of 8 days of treatment in the ceftriaxone group. However, the fever resolved without additional therapy in this patient later.

By day 7, bacteriological cure was achieved in every patient treated with azithromycin and in 33 (97%) of 34 patients treated with ceftriaxone. One patient who did not respond to therapy in the ceftriaxone therapy was clinically healthy. The child was continued with ceftriaxone and thereafter achieved a complete cure. This included blood culture turning sterile. After discharge from the hospital, 60 patients of the study group (28 of 30 azithromycin recipients and 32 of 34 ceftriaxone recipients) returned for post treatment follow-up evaluation. Four patients were lost to follow up. 5 of the 34 patients treated with ceftriaxone returned, before the scheduled 1-month follow-up evaluation, because of recurrence of typhoid-related symptoms. S. typhi was isolated from blood specimens from 3 of these patients. All the 5 patients were treated with a second course of antibiotics (ofloxacin) that resulted in resolution of their symptoms. No relapses occurred in the group treated with azithromycin. With the exception of the 5 patients described above, all patients were clinically well when they returned for evaluation 1 month after completion of therapy.

No patient had any serious adverse effect. The gastrointestinal symptoms were commonly reported by both groups. Vomiting occurred more frequently among patients treated with azithromycin (6 patients) than among those treated with ceftriaxone (5 patients), but the difference between the groups was not significant. However, this symptom was mild and transient and resolved in most cases within 3 day of initiation of treatment. In no case was the symptom severe enough to require treatment or alteration of antibiotic therapy.

Diarrhoea was the most common adverse effect in patients treated with ceftriaxone, occurring in 12 patients, compared with 8 in the azithromycin group. Diarrhoea also did not require treatment or alteration of the antibiotic therapy regimen.

In countries like India, where typhoid fever is highly endemic but have limited resources, the cost and compliance of treatment as well as safety and efficacy of the regime play an important role. In our study, the two drugs compared were both effective and gave clinical cure to all patients within 10 days. Both treatment groups were successful without occurrence of complications during or after the treatment.

Our study has shown that a 7-day course of azithromycin is an effective treatment for uncomplicated typhoid fever in children. These patients had a clinical and microbiological cure rate approaching 100%.^[6] The average defervescence time of 5.5 ± 1.9 days with azithromycin was longer than ceftriaxone [4.5 ± 1.6 days]. However, this was neither statistically significant nor clinically relevant. In addition, the durations of fever in both treatment groups were within the time frames [3 – 8 days] as reported in previous trials on the treatment of typhoid fever.^[7],[8],[9]

Both the study drugs were effective in eradicating faecal carriage of S. Typhi. After antibiotic therapy was initiated, the culture of stool specimens from all children was completely sterile. The study found that three days after starting treatment, 4 (13.3%) of 30 patients treated with azithromycin remained bacteraemic, and 1 patient (2.9%) out of 34 of the ceftriaxone group was bacteraemic. Almost similar results were seen in previous studies.^[6]

In a previous study,^[10] ceftriaxone showed a better bacterial clearance as compared to other drugs like chloramphenicol. This may be due to rapid sterilization of the blood after treatment with ceftriaxone, as high serum levels are achieved with dose of 75-mg/kg intravenous dose as compared to the serum levels achieved after drugs administered orally. However, in the ceftriaxone group, 5 patients (14.7%) had a clinical relapse about a month later despite clinical and bacteriological cure. Most importantly, there were no relapses in the azithromycin group. One patient treated with azithromycin was a clinical failure initially but responded completely thereafter.

There are a few studies on efficacy of azithromycin in typhoid fever in adults but not many in children. In a study in Bahrain, three of four adults failed to respond when azithromycin was given as a 1gram dose on day 1 followed by 500 mg given each day for the next 6 days.^[11]The three failures had clinically deteriorated by day 4 or 5 of the therapy.

Azithromycin is known to achieve high intracellular concentrations^[11] and activity.^[12] The discordance between in vitro susceptibility and in vivo effectiveness is probably explained by the predominant intracellular location of Salmonella Typhi bacteria.^[13] However, approximately one-third of Salmonella Typhi organisms in the blood of patients with typhoid are extracellular.^[14] As a consequence, the organisms may be exposed to inadequate concentrations of azithromycin which may be resulting in slow clearance of bacteraemia.

In our study, there was 93.3% clinical cure by day 7 in the azithromycin group and 97% clinical cure in the ceftriaxone group. Both groups had achieved 100% clinical cure by day 10 of treatment. In a similar comparative study in India, azithromycin at 500 mg per day for 7 days was 88% clinically successful and 100% microbiologically successful by day 8 in 42 adults, with blood culture-positive typhoid fever. These were compared with 86% and 94% success rates in 35 adults treated with chloramphenicol at 2 to 3 gram per day for 14 days.^[15]

Even though bacteraemia persisted longer, no patient of azithromycin group had either a clinical or microbiologically confirmed relapse of typhoid fever. On day 30, when the patients reported for scheduled review visit, 5 (14.7%) of 34 patients who received ceftriaxone therapy had suspected relapses. Out of these 5 patients, 4 patients had a microbiologically confirmed relapse. These findings are similar to earlier reports in the literature of relapse rates of 5%-15% of ceftriaxone treated patients.^{[7],[16],[17]}

The absence of relapse in the azithromycin group is similar to other studies.^[6],[7],[8] The high intracellular concentrations of azithromycin along with the long half-life of the drug may be the reason of relapse not occurring when treating a intracellular infection like typhoid fever.^{[18],[19],[20]} The absence of relapse in the azithromycin group is similar to other studies.^[21],[22]

Our study showed no significant difference between the clinical responses of the two groups. The limitation of our study was the small size of sample. Further studies will be required to confirm that resistance, relapse and long-term carriage will not be a problem with azithromycin. Some patients with typhoid fever are unable to swallow oral preparations or have vomiting either due to the medication or illness. This may also limit its use as an OPD treatment.

Azithromycin is much less expensive than the third-generation cephalosporins and seems to be an effective alternative. The once-daily dose of azithromycin along with the short duration of therapy is convenient and would improve patient compliance. Thus, ease of treatment of typhoid fever would remain the greatest advantage.

The recovery for typhoid fever starts within two to three days when patients are treated with appropriate antibiotic therapy on time thereby reducing deaths. However, if patients do not get treatment then mortality may be as high as 20 per cent due to complications of typhoid. The use of antibiotics like azithromycin for short duration, which requires single daily dose and can be administered orally improves the patient compliance in treatment of typhoid fever. This will reduce the economic burden on the developing countries with resource crunch by decreasing both morbidity and mortality.

Acknowledgement

We are highly grateful to the Department of Microbiology for all the laboratory support rendered and the Department of Bio Statistics in helping us with the statistical analysis of the study.

Financial support and sponsorship

Nil

Conflict of interest

There are no conflicts of interest.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.205534

[Table 1], [Table 2], [Table 3]