The treatment of enteric fever

Enteric fever (typhoid and paratyphoid fevers) is caused by fecal oral transmission of Salmonella enterica serotypes Typhi or Paratyphi A. About 27 million people suffer from enteric fever each year, with about 200 000 deaths, almost exclusively in the developing world. ¹ The incidence of this neglected illness in some parts of South Asia is as high 1600 per 100 000 population. Because of the ready availability of over-the-counter antibiotics and subsequent resistance to these drugs in areas of endimicity, enteric fever is becoming harder to treat. ²

Fluroquinolone (ciprofloxacin and olfloxacin) have for some years been the drugs of choice for enteric fever, ³ but resistance to these drugs has become very common in South Asia and have sporadically been reported in sub-Saharan Africa. Strains resistant to ciprofloxacin are not detected by current disc susceptibility breakpoints but are usually nalidixic acid resistant. Nalidixic acid sensitivity has to be carried out in all enteric fever organisms isolated from South Asia, and if resistance is noted ciprofloxacin should not be used. Gatifloxacin (10 mg/kg), azithromycin (10 mg/kg) or ceftriaxone (1–2 g/day) would be optimal choices in the treatment of enteric fever. ³ Cefixime, an oral third generation cephalosporin recommended by the WHO ⁴ for treatment of enteric fever, is not only expensive but appears relatively ineffective in comparison to gatifloxacin, a new generation fluroquinolone, as shown by recent unpublished trials (personal correspondence, Jeremy Farrar, Vietnam).

Gatifloxacin, a relatively inexpensive fluroquinolone antibiotic with once a day oral administration, is a new broad spectrum synthetic 8-methoxyfluoroquinolone which has the lowest minimum inhibitory concentration (MIC) of any antibiotic against S. typhi from Nepal and Vietnam. ² It appears effective for the treatment of enteric fever in the developing world. The different binding motif of gatifloxacin ⁵ clearly enables it to retain activity against S. enterica serovars Typhi and Paratyphi A, even in the presence of marked reduction in sensitivity to the older fluoroquinolones. Dysglycaemia has been reported with the usage of gatifloxacine in an elderly population; ⁶ this drug therefore has to be used with caution, even if randomized trials currently being carried out show it to be effective against enteric fever. However, in the developing world enteric fever is usually a young persons’ disease, and dysglycaemia with gatifloxacin has not been noted in the younger population; further trials with glucose monitoring of enteric fever patients being treated with gatifloxacin are underway.

Azithromycin and gatifloxacin appear to be equally effective as oral agents, but olfloxacin even in higher doses (20 mg/kg) is now ineffective. ⁷ Ceftriaxone is useful as a parenteral agent, although in vitro resistance has been documented to S. enterica serovar Paratyphi A. ² Trying to determine resistance to azithromycin has been difficult, partly due to its marked intracellular concentration.

Gentamycin is ineffective against enteric fever, although S. enterica may appear to be sensitive in vitro. Anecdotally, isolates are reverting to susceptibility to older drugs like chloramphenicol, which news has been very welcome in parts of South Asia where chloramphenicol is inexpensive. On the basis of syndrome of fever for three or four days with constitutional symptoms and no known source of infection, antibiotic treatment of typhoid fever is often started empirically in areas of endemicity without blood cultures. Concurrent treatment with doxycycline to cover for typhus and leptospirosis may also be necessary in such a setting, and malaria may also need to be ruled out. The potential for new drugs for enteric fever is not encouraging, as there are very few potential targets in Salmonella ⁸ against which new drugs could be designed, and thus we need to use what we have as effectively as possible.

In the treatment of severe typhoid, the 1986 Jakarta study is often quoted. ⁹ It was shown that high-dose dexamethasone (3 mg/kg infused intravenously over half an hour, followed by eight doses of 1 mg/kg six-hourly) resulted in a 10% case fatality, compared to 55.6% in controls, in severe typhoid (defined as shock or confusion in addition to typhoid fever). This was a single study which now appears almost impossible to duplicate in a single center because of the fewer number of severe typhoid patients, probably due to ready availability of over-the-counter antibiotics.

Perforation of ileal ulcers occurs in less than 5% of typhoid patients and presents with restlessness, hypotension and tachycardia.^3,10 Treatment is fluid correction and prompt surgery, which results in almost 97% survival in some series, compared to only 30% in conservatively managed patients.

Relapse rates of 10% have been described in patients treated with chloramphenicol; these patients respond very well to the same therapy used in the initial episode. Reinfection can be distinguished from relapse by molecular typing of isolates. There are no recent studies of typhoid carriers, but among carriers detected by screening about 25% give no history of typhoid fever. Patients discharged after treatment with six negative stools, three negative urine samples and negative Vi serology are considered free of infection. Antibiotics for eradication of carriage may be indicated if patients continue to excrete the organism after three months.

Recent reports ² 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.

In Western countries, typhoid is mostly seen in returning travelers—usually from South Asia—who were visiting friends and relatives. ¹¹ Prevention is better than cure, so counselling about prevention of typhoid needs to be targeted to this latter group; however, travel medicine has evolved around the tourist industry and this vulnerable group is often missed. Even travellers who are staying for less than a week in areas of endemicity will benefit from the vaccine.

Finally although in areas of endemicity, clean water supply and adequate public health infrastructure with useful vaccine are what we need to aim for, the effective treatment of this neglected disease with available antibiotics is equally pivotal.