Treatment of enteric fever
Rahman M¹

Enteric fever (typhoid and paratyphoid), caused by Salmonella enterica serovar Typhi (S. Typhi) or serovar Paratyphi A, B, C, represents a major burden of disease in the communities, due to lack of pure water and adequate sanitation. More than 27 million cases of enteric fever occur worldwide in each year, with 216000 deaths.¹ The incidence is highest (100cases/100,000 population per year) in South-central and Southeast Asia, medium in the rest of Asia, Africa, Latin America and some parts of Oceania and low in the rest of the world. It is more common among young children and adolescents (2-15 years) and in urban than rural areas. S. Typhi represents the commonest cause of bacteraemia in this age group, and annual typhoid rates (confirmed by blood culture) in recent studies from Bangladesh, India, Pakistan, and Indonesia range from 149 to as high as 573 cases per 100000 children.² In developed countries, returning travellers or those visiting friends and relatives in their family’s country of origin are at risk.^1,2,3 In endemic areas, most patients are treated with oral antibiotics as outpatients, but only those who are severely diseased need hospital admission. Relapse may complicate the illness, and faecal carriage in 1-5% of patients can become chronic and lead to further transmission in the community.

Typhoid fever is the most common febrile illnesses encountered by the physicians in Bangladesh. Proper and timely administration of appropriate antimicrobial therapy prevents complications of enteric fever and reduces cast fatality rate to <1%. The choice of empirical antimicrobial therapy depends on the susceptibility of S. Typhi and S. Paratyphi strains present in the area of residence or travel. Until the 1987, two to three weeks of Chloramphenicol or Amoxicillin or Trimethoprim-sulphamethoxazole was the treatment of choice for enteric fever.⁴ Diagnosis and treatment lately became a challenge due to emergence of MDR S. Typhi (resistant to Amoxicillin, Chloramphenicol and Trimethoprim-sulphmethoxazole) in 1990 in Bangladesh as an expansion of MDR S. Typhi strains from China, Pakistan, India and Nepal.^5,6 In 1989 all S. Typhi isolates were susceptible to all first-line antibiotics in Bangladesh. MDR strains emerged in 1990 in Bangladesh and increased to 44% in 1994 from 8% in 1990 and declined to 22% in 1996 and increased again to 42% in 20026 and 61% in June, 2009. Fluoroquinolones (Ciprofloxacin and Ofloxacin) became the treatment of choice for typhoid fever with 98% cure rate and <2% faecal carriage, and were simultaneously sold widely over the counter to treat fever of various aetiologies in developing countries including Bangladesh. The extensive pressure of quinolones leads to the selection of single point mutations in the gyr A gene of S. typhi, causing resistance to first-generation 4-quinolones Nalidixic acid (NART strains, MIC ≥32 µg/ml) and decreased Ciprofloxacin or Ofloxacin susceptibility [(DCS strains, MIC = 0.125-1µg/ml) (but formally these isolates are still within the Clinical Laboratory Standard Institute (CLSI) breakpoints for susceptibility] in 8% of S. Typhi strains in 2000 in Bangladesh that increased to 71% in 20025 90% in June, 2009. This resulted in a poor clinical response (prolonged recovery time, therapeutic and microbiologic failures, more relapses and prolonged faecal bacterial shedding period) to treatment with the Ofloxacin or Ciprofloxacin even with increased doses (1-2 g/day). With increase use of Fluoroquinolones such as Ciprofloxacin, Naldixic acid-resistant (MIC ≥32 µg/ml) S. Typhi (NART) isolates with decreased Ciprofloxacin susceptibility (MIC = 0.125-1µg/ml) appeared, have reached high levels in Central, South, and South East Asia.^2,3,6,7 Under this circumstances, the World Health Organisation recommends the Fluoroquinolones or Cefixime for the treatment of MDR typhoid fever and Azithromycin, the third-generation cephalosporins, or a 10–14 day course of high-dose older generation Fluoroquinolones (e.g. Ofloxacin or Ciprofloxacin) for the treatment of Nalidixic acid resistant typhoid fever.⁷ Recently, nearly ~4% of S. Typhi isolates developed complete Ciprofolaxin or Ofloxacin resistance (MIC ≥ 4 µg/ml) in Bangladesh due to additional mutations in gyrA and parC genes which has also been reported from India, Nepal and Kuwait making these drugs less optimum for empirical therapy in spite of recommendation by WHO. Ciprofloxacin is no more a drug for empirical therapy of enteric fever in almost all the countries of the world unless complete Ciprofloxacin susceptibility is proved by very low MIC values (MIC <0.125 µg/ml). Patients infected with NART strains should be treated with Gatifloxacin, Azithromycin or Ceftriaxone. High doses of ciprofloxacin are usually associated with delayed resolution time, complications, treatment failures and prolonged faecal carriage. The laboratory detection of DCS strains is problematic because they are still classified as susceptible by CLSI guidelines. Isolates with DCS are usually resistant to the first generation quinolone, Nalidixic acid, and this is a useful, but not 100% reliable, surrogate laboratory marker for resistance. In some areas of Asia such as India, Nepal, Bangladesh and Kuwait, S. Typhi isolates that are fully resistant to ciprofloxacin (MIC ≥ 4 µg/ml) have emerged at the same time as the proportion of MDR infections has remained unchanged or declined. The emergence of fully Ciprofloxacin-resistant S. Typhi strains is a worrying development that further limits treatment options. Ceftriaxone, Cefotaxime and oral Cefixime are effective for the treatment of MDR, NART and Ciprofloxacin-resistant S. Typhi strains. It is likely that there will be more reports of fully resistant strains in the future from regions of the world where typhoid fever is endemic. Treatment of chronic carrier with antibiotics for 4-6 weeks is effective and surgery is required in failure cases. Dexamethasone (2 days course, 3mg/kg first dose followed by 1mg/kg 6 hourly for 8 doses) with chloramphenicol reduced mortality rate in patients with severe disease with shock and obtundation.

For enteric fever acquired in Bangladesh and many other countries of Asia, more than 90% of isolates have DCS so Ciprofloxacin and Ofloxacin should be avoided. Azithromycin, Gatifloxacin, or Ceftriaxone can be used as empirical therapy depending on the severity of illnesses. Resistance to Ceftriaxone and Azithromycin is rarely reported, but isolates that are fully resistant to Ciprofloxacin are now being detected and Ceftriaxone is effective for these infections. Combinations of drugs are being used, but evidence for the effectiveness of this strategy is inadequate.

High quality & adequately powered multicentre clinical trials are needed to compare treatment options for enteric fever. Trials should include children, ambulatory patients and severe cases and be completed quickly to encounter rapidly changing resistance patterns. MDR S. Paratyphi A is emerging rapidly in India and other Asian countries to add a new health problem and one should keep it in mind when treating enteric fever.² Finally, prevention of enteric fever should not be forgotten, nor should the potential use of vaccination in areas where the disease burden is high and drug resistance is common.