Treatment of enteric feverBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1159 (Published 03 June 2009) Cite this as: BMJ 2009;338:b1159
All rapid responses
Resistence to infection to gut organisms depends upon antigen
presentation, the secretion of IgA, and T cell competence. All are
impaired when there is a chronic energy deficit for they are highly energy
dependent. Inf Crohn's disease, for example, "lazy" T cells are implicated
it the pathogenesis. A chronic energy defict is accompanied by alterations
in the gaseous milieu in the lumen of the gut, a potentially important
variable in the case of microaerophilic and anaerobic organisms such as H
pylori and C difficile (1).
The energy deficit could be due to mucosal ischaemia induced, for
example, by dehydration in an hot climate. It could also be due to a
nutritional deficit particularly in regard to those nutrients necessary
for the de novo resynthesis of ATP. Prolonged carriage may, therefore, be
partially or wholly the product of a mucosal energy deficit.
1. Richard G Fiddian-Green. Chronic intestinal ischaemia and
Hirschsprung’s disease. Archives of Disease in Childhood 2007;92:185.
2. Virchow's cell theory in action?
Richard G Fiddian-Green (23 March 2009) rapid response re: Jo C
Dumville, Gill Worthy, J Martin Bland, Nicky Cullum, Christopher Dowson,
Cynthia Iglesias, Joanne L Mitchell, E Andrea Nelson, Marta O Soares,
David J Torgerson on behalf of the VenUS II team. Larval therapy for leg
ulcers (VenUS II): randomised controlled trial. BMJ 2009; 338: b773
Competing interests: No competing interests
We read with interest the editorial entitled ‘Treatment of enteric
fever’ by Drs Parry and Beeching1. We agree that ’fluoroquinolones remain
the first option in areas where resistance is uncommon’. The authors
rightly highlight the need to understand the factors that determine the
emergence of isolates with decreased susceptibility to ciprofloxacin (DSC)
in many parts of Asia. They query whether this may be because
ciprofloxacin dose is too low, the duration of treatment is too short, or
because ciprofloxacin is used indiscriminately in all patients with fever.
There is no doubt that any of these or all of them may contribute to the
selection of resistant mutants, however the question remains what factor
determines the emergence of resistant mutants in the first place. We
suggest that the understanding the carrier state of the typhoidal
Salmonellae may offer an explanation.
A number of facts can substantiate the crucial role of the faecal
carriage of typhoidal Salmonellae in the emergence of DSC.
First, typhoidal Salmonellae are well adapted human parasites with
the ability to invade, persist .and in some individuals establish a
chronic carrier state with persistent excretion of the organism for months
Second, although the intensity of excretion by carriers may vary
widely, figures as high as 450x106 organisms per gram of faeces in a
paratyphoid carrier have been quoted, and between 1x106 and 10000x106 for
typhoid carriers3. We would suggest that such high microbial gut
concentration guarantees increased spontaneous mutation leading to
polyclonality and antibiotic resistance in typhoid and paratyphoid
carriers, in a similar manner as it occurs in the critically ill with gut
overgrowth of potentially pathogenic organisms4,5.
Third, it has also been reported that high level quinolone resistance
was induced through the long carrier state of S.paratyphi A under
selective pressure of frequent quinolone administration6.
Fourth, the emergence of isolates with DSC occurs in parts of Asia
with a high level of carriage in endemic areas7.
Fifth, most chronic carriers are asymptomatic and a quarter may have
had no history of typhoid fever8, a fact which further contributes to
transmission of DSC mutants.
Sixth, although clonal spread of particular quinolone resistant
strains was reported in some areas9, the evidence that resistance has
emerged de novo in different strains is also published10.
Seventh, resistance to ciprofloxacin has been described in cases of
gut overgrowth of other gram-negative organisms, such as Acinetobacter, by
similar mutation mechanism as in Salmonella11.
Eighth, and finally, one of the authors of the editorial in the
discussion (CMP) concludes together with Threlfall9 in their extensive
review on the same subject that ‘patterns of resistance in Salmonella are
However finding and treating chronic carriers will remain a daunting
We believe that surveillance of the abnormal carrier state for
resistant bacteria will become an essential part of managing typhoid fever
in the future era of antimicrobial resistance9. The addition of enteral
antimicrobials polymyxin/tobramycin to eradicate abnormal carriage may be
part of that management of resistance against fluoroquinolones and/or
HKF van Saene
1. Parry CM, Beeching NJ. Treatment of enteric fever. BMJ 2009; 338:
2. Wain J, Hien TT, Connerton P, Ali T, Parry CM, Chinh NT, Vinh H, Phuong
CX, Ho VA, Diep TS, Farrar JJ, White NJ, Dougan G. Molecular typing of
multiple-antibiotic-resistant Salmonella enterica serovar typhi from
Vietnam: application to acute and relapse cases of typhoid fever. J Clin
Microbiol 1999; 37: 2466-2472.
3. Christie AB. Typhoid and paratyphoid fevers. In Infectious Diseases:
Epidemiology and Clinical Practice. Eds AB Christie Churchill Livingstone
New York, 1987; pp 100-164.
4. van Saene HK, Taylor N, Damjanovic V, Sarginson RE. Microbial gut
overgrowth guarantees increased spontaneous mutation leading to
polyclonality and antibiotic resistance in the critically ill. Curr Drug
Targets 2008; 9: 419-421.
5. Damjanovic V, Taylor N, van Saene HK. Origin of epidemic clones of
Acinetobacter in the critically ill. J Hosp Infect 2009; 73: 285-286.
6. Adachi T, Sagara H, Hirose K, Watanabe H. Fluoroquinolone-resistant
Salmonella paratyphi A. Emerg Infect Dis 2005; 11: 172-174.
7. Roumagnac P, Weill FX, Dolecek C, Baker S, Brisse S, Chinh NT, Le TA,
Acosta CJ, Farrar J, Dougan G, Achtman M. Evolutionary history of
Salmonella typhi. Science 2006; 314: 1301-1304.
8. Bhan MK, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet
2005; 366: 749-762.
9. Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and
nontyphoidal salmonellae. Curr Opin Infect Dis 2008; 21: 531-538.
10. Hasan R, Cooke FJ, Nair S, Harish BN, Wain J. Typhoid and paratyphoid
fever. Lancet 2005; 366: 1603-1604.
11. Riley TV, Webb SA, Cadwallader H, Briggs BD, Christiansen L, Bowman
RA. Outbreak of gentamicin-resistant Acinetobacter baumanii in an
intensive care unit: clinical, epidemiological and microbiological
features. Pathology 1996; 28: 359-363.
12. Taylor N, van Saene HK, Abella A, Silvestri L, Vucic M, Peric M.
Selective digestive decontamination. Why don't we apply the evidence in
the clinical practice? Med Intensiva 2007; 31: 136-145.
Competing interests: No competing interests
The recent editorial by Parry and Beeching is indeed timely (1).
Clinicians at all levels are finding it difficult to decide the optimal
treatment and management of this now mostly travel associated disease in
the UK and other developed countries. However many questions remain
A first interesting point is should Paratyphoid fever be treated in
the same fashion as Typhoid fever? Most research on ‘Enteric fevers’
focuses on the treatment of Typhoid fever leaving one to assume the same
goes for Paratyphoid fever.
In the past Paratyphoid fever has been regarded as a ‘less severe’
infection than Typhoid fever but this view has more recently been
This question has never been more relevant as in England and Wales from
2000-2008 laboratory identified cases of Salmonella paratyphi A
outnumbered those of Salmonella typhi in the years 2001, 2002, 2004 and
2006 (3). More time needs to be spent looking specifically at Paratyphoid
Secondly how should those with uncomplicated Enteric fevers be
treated initially? WHO guidelines exist but are non-specific and becoming
out of date (4).
In endemic countries uncomplicated Enteric fever is treated on an out
patient basis with oral antibiotics. Should all those suspected of having
uncomplicated Enteric fever be admitted to hospital for antibiotics in the
UK? Initial treatment must cover for drug resistant strains as many
cases diagnosed in the UK are acquired from areas with known high rates of
drug resistance. For example London travellers visiting relatives or
friends on the Indian sub-continent account for 40% of enteric fevers in
England, Wales and Northern Ireland (5).
If ceftriaxone were the initial antibiotic of choice patients would have
to be admitted for treatment. Following this and once sensitivities of
cultured organisms become known should patients be discharged on a
suitable oral antibiotic and if so after how many days of intravenous
therapy? Or, could all uncomplicated enteric fevers be treated from the
start on an out patient basis with azithromycin for example which would
cover for any drug resistant organisms? Further complicating the matter
is the fact that the organism is often never isolated in Enteric fevers
and therefore sensitivities are unknown. This once again raises the
question of which antibiotic to use, where to treat patients initially and
for the remainder of their antibiotic course in uncomplicated enteric
The answers to these questions have big implications regarding resource
allocation especially in hospitals where Enteric fevers are commonly
diagnosed and for patients who may be inappropriately admitted to hospital
for extended periods of time.
2.Bradley A Connor, Eli Schwartz. Typhoid and paratyphoid fever.
Lancet Infect Dis 2005;5:623-28
3.Health Protection Agency. Salmonella Typhi and Salmonella
Paratyphi Laboratory reports (cases only).
4.World Health Organization Department of Vaccines and Biologicals.
Background document: the diagnosis, prevention and treatment of typhoid
fever. Geneva: WHO, 2003:19-
Competing interests: No competing interests