Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of typhoid in South Asia; a randomised controlled trial

Typhoid fever is characterized by fever and abdominal symptoms. It affects more than 14 million children and adults globally each year. Between one and two million of these patients may progress to severe and life-threatening complications including intestinal bleeding, intestinal puncture (perforation) with surrounding inflammation (peritonitis) and a syndrome of somnolence and coma (encephalopathy). Up to 1% of patients who get typhoid may die of the disease. A typhoid illness can be followed by a relapse 2-3 weeks later and lead to a prolonged period of ill health and catastrophic financial cost to the family with a resulting burden on the health system and society. In South Asia, which is the largest typhoid hub in the world, the annual burden of disease is estimated at seven million.

Effective antimicrobial treatment leads to a resolution of the patient illness in 4 to 6 days and reduces risk of progression to life-threatening complications. If started early in the disease a 7 to 10-day course of treatment with a single oral antimicrobial treatment can be given in an out-patient setting without the need for expensive hospitalization. In the last 20 years fluoroquinolones, such as ciprofloxacin, have been successfully used. However antimicrobial resistance in the bacteria that cause typhoid fever has now become common in Asia and sub-Saharan Africa. In South Asia resistance to ciprofloxacin in typhoid is widespread. Resistance limits the choice of effective antimicrobials and increases the risk of patients developing severe disease. Because of these concerns Salmonella has been recently listed in the 'Priority 2: HIGH on the WHO Priority Pathogens List.

A number of experts have called for the use of antimicrobial combinations in typhoid fever to improve the efficacy of treatment and mitigate the problems of resistance. This suggestion is not backed up by good quality evidence. A current standard regimen, recommended by the World Health Organization, is a 7-day course of the oral antimicrobial azithromycin. Emerging evidence from small studies suggests that a combination of azithromycin and cefixime may achieve a better cure than azithromycin alone. The ACT-South Asia study aims to answer the question whether a combination of azithromycin and cefixime is more effective than azithromycin alone in the outpatient treatment of uncomplicated typhoid fever. In this trial we will recruit 1500 patients across four sites in typhoid-endemic areas of Bangladesh, India, Nepal and Pakistan. We will use a placebo (sugar pill) instead of cefixime in the single drug arm so that neither the patient nor the study team know which patient is receiving which treatment. Our aim is to assess whether treatment outcomes are better with the combination regime at completion of the one week of treatment and again at follow-up one and three months after treatment was started. Both of these antimicrobials are widely used and have an excellent safety profiles, but we will carefully monitor for side effects. We will additionally investigate the financial implications for families and the health system.

The recent emergence and spread of a particularly resistant typhoid strain in Pakistan adds urgency to this question. If the combination treatment is better than the single antibiotic treatment, the involvement of four countries in the study will allow generalization of the results across South Asia and other typhoid endemic areas. Considering the high burden of typhoid fever in this region even small improvements in the treatment success will translate into a benefit for many individuals and families and the health system as a whole. For example, a reduction in treatment failures in the 7 million patients with typhoid fever in South Asia from 15 % (with azithromycin alone) to 10 % using the antimicrobial combination, will mean at least 350,000 patients will experience a faster cure, fewer hospital admissions with less financial impact.

More than 14 million children and adults develop typhoid fever each year with 10-15% at risk of the severe forms of disease and 140,000 deaths. Fluoroquinolones, such as ciprofloxacin, have been successfully used in this role for the last 20 years but in South Asia resistance to ciprofloxacin in typhoid is now widespread. In the face of fluoroquinolone resistance, a seven-day course of oral azithromycin is commonly recommended.

In areas of Pakistan affected by the current outbreak of XDR typhoid with strains resistant to all commonly used antimicrobials including the ciprofloxacin, cefixime and ceftriaxone, azithromycin is the only oral option. It has been suggested that antimicrobial combinations may improve the efficacy of treatment and mitigate the problems of resistance in typhoid fever, but no good quality evidence exists. Small studies suggest a combination of azithromycin and cefixime gives a better outcome than azithromycin alone.

The ACT-South Asia trial is designed to test this suggestion in a 3-year phase IV, double-blinded, randomized, controlled trial. The randomization (1:1) will be a superiority blinded design to evaluate whether a 7-day combined regimen of azithromycin and cefixime is superior to a 7-day regimen of azithromycin alone in the out-patient treatment of uncomplicated typhoid fever in 1500 children and adults in Bangladesh, India, Nepal and Pakistan. The primary endpoint is treatment success at the end of one week of treatment and an absence of relapse at one month. The trial will also address the duration of faecal shedding of S.Typhi and S.Paratyphi A, the safety of the drugs, the cost-effectiveness and acceptability of each regimen, the effect of the intervention on the patients clinically suspected of typhoid who are blood culture negative and the effect of the regimens on resistance in the patient's normal flora.

This trial will benefit:
- Adults and children with clinically suspected and confirmed typhoid fever, and their families
- Trial sites in South Asia
- Ministries of Health, health care services and National Professional Societies
- International policymakers

How might they benefit from the research?

Adults and children with suspected and confirmed typhoid fever and their families:
Typhoid fever is associated with significant morbidity and mortality. There is also a financial cost to families, health care services and society. If the proposed study intervention leads to improved outcomes, this could improve health and have a positive impact on quality of life for a large number of affected adults and children worldwide. This international collaboration across South Asia mean the results will be generalizable across the sub-continent and potentially further afield.

Trial sites in South Asia:
Scientists and medical professionals at each site will gain research experience and this will help to build the research expertise in each country and contribute scientific knowledge applicable to local populations. The formation of a regional collaborative clinical trial network with investigators and sites working to international standards will be a benefit for the development of future trial proposal to address important regional and global questions.

Ministries of Health, health care services and National Professional Societies:
If the study finds that the combination regimen is significantly better than the current recommended treatment with patients recovering quicker and fewer developing sever and complicated disease this could lead to long-term economic impact for both families and the healthcare system if the overall cost of illness is less.

International policymakers:
This trial examines the questions identified as priority research gaps by WHO. The current guidance is based on limited evidence and is outdated. Our trial may potentially provide solid evidence for the appropriate clinical management of typhoid fever. Should the study results demonstrate that a combination of azithromycin and cefixime is superior to azithromycin alone, combined with a favourable health economic and acceptability evaluation, then we would anticipate rapid transfer of this interventions to WHO and national health policy guidance in the countries of the region and subsequently into clinical practice. In addition, a positive result could provide a scientific rationale for the development of fixed dose combination tablets with appropriate doses of each antimicrobial.