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Editorial

Indian Pediatrics 1999; 36:129-131 

The Challenge of Multidrug Resistant Typhoid in Childhood: Current Status and Prospects for the Future


Despite considerable advances in the understanding of the pathogenesis and micro- biology of typhoid fever, the disorder still accounts for over 16 million cases annually globally, with an estimated 600,000 deaths( I). While accurate population-based figures of the burden of typhoid fever in developing countries are unavailable, conservative estimates indicate varying incidence rates ranging from 150 per 100,000 population in South America to over 1000 cases per 100,000 population in some Asian countries(1). A recent survey with active surveillance of typhoid in a slum population of Delhi reveals an overall incidence of 9.9 per 1000 person days, with an almost three folds higher incidence in children under -5 years of age(2).

A major problem in recent years has been the emergence of drug-resistance in strains of Salmonella typhi causing. infections. Although outbreaks of chloramphenicol-resistant typhoid fever were reported from the. early 1970s, the real problem began with the emergence of multidrug-resistant (MDR) strains of Salmonella typhi in the mid eighties from the subcontinent(3,4). These strains rapidly assumed epidemic proportions, accounting for almost 60-90% of all cases of typhoid in certain reports(5,6). It was also recognized that MDR typhoid was frequently associated with increased morbidity and toxicity among children(7), a fact reaffirmed by the significantly increased mortality with such infections, at times exceeding 10%(8). While the increased morbidity with MDR typhoid could be due to delay in presentation and institution of appropriate therapy, it is conceivable that the toxicity is also reflective of greater virulence of infecting strains of MDR Salmonella typhi. This is also supported by recent observations of significantly higher rates of quantitative bacteremia among patients with MDR typhoid in Vietnam(9) and the association of specific pulse-field. gel electrophoresis patterns with increased. morbidity and mortality among patients with typhoid fever(10).

Apart from the need to establish a diagnosis rapidly, successful therapy ofMDR typhoid is critically dependent upon prompt institution of appropriate antibiotic therapy. A number of therapeutic strategies have been employed in the management of MDR typhoid infections in childhood ranging from administration of quinolones(11),' third generation cephalosporins(12) and mono- bactams(13). Despite concerns about possible toxicity, the oral quinolones have found wide- spread use because of the ease of administration and their relatively low cost. However, the natural consequence of such ready avail- ability and indiscriminate use of quinolones is the emergence of resistance, and despite claims to the contrary, there are several reports of increasing resistance to quinolones among Salmonella typhi strains(14). This is not only a problem limited to isolated cases(15), but has also led to epidemics of infection with such isolates in Central Asia(16) . arid endemic quinolone resistant typhoid in Vietnam(17). Contrary to initial views that quinolone resistance in Salmonella typhi primarily involved molecular mutations in the gyr A gene( 18), thus limiting the propensity to transfer resistance, the recent demonstration of plasmid-mediated quinolone resistance in Gram negative bacteria is. most alarming(19) as the potential for spread of resistance is considerably greater.

It is therefore imperative; that management strategies for typhoid. include appropriate antimicrobial prescribing as an important objective. This is particularly true for south Asia, where some recent observations indicate that both MDR and sensitive strains of Salmonella typhi may exist concurrenly(20). Clearly in such a situation, recommending a single blanket antibiotic as the first-line treatment of typhoid may not be appropriate. It is therefore essential that suitable guidelines be developed for the prompt recognition and appropriate therapy of typhoid fever in the community. The development of an algorithm based on clinical and simple laboratory criteria for the rapid diagnosis of typhoid and subsequent triage to appropriate first or second-line therapy, would go a long way to- wards rational management of this disorder, and also reduce the risk of. emergence. of further drug resistance.

It is important to underscore the point that the most effective strategies for the control of typhoid are public health measures: These should consist of recognition and prevention of high-risk behaviors(21) and general improvement in standards of gygiene, water supply and sewage disposal. Given the global economic downturn, these important objectives may now appear rather distant for many countries in the developing world. It is thus important to also focus on vaccination strategies as important preventive measures in endemic areas. In this regards the relatively high. burden of illness and severity of typhoid among young children in South Asia (2,7,22) is of considerable importance. While others have suggested that typhoid fever is both un-common(23) and mild(24) in young children, such differences in epidemiological patterns may represent regional differences in strains of Salmonella typhi. Although two relatively newer vaccines (Vi vaccine and an oral typhoid vaccine based on the attenuated Ty21 strain) are available, a recent systematic analysis indicates that the classic heat-inactivated whole cell vaccine may be more effective(25). Given their basic lipopolysaccharide content none of these available vaccines are effective in young infants. The need therefore for a suitable, relatively inexpensive Vi conjugate vaccine, which could be incorporated within existing EPI programs, is pressing. Other novel preventive strategies could also include measures geared towards increasing local mucosal immunity thus reducing invasion by virulent strains of Salmonella typhi. The recent elucidation of the mechanism of invasion of Salmonella typhi into intestinal mucosalcells(26) also offers the vision of. exciting future strategies to reduce the likelihood of invasive Salmonella typhi infection in developing countries.


Zulfiqar Ahmed Bhutta,
Professor of Pediatrics and Child Health,
The Aga Khan University Medical Center,
 Karachi 74800,
 Pakistan.

E-mail: zulfiqar;[email protected].
 

References

1. Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: Present status. Bull WHO 1994; 72: 957-971.

2. Dutta AK, Kanwal SK. Typhoid fever: An Asian perspective. In: Proceedings on the APPSGAN workshop on Pediatric Gastroenterology and Nutrition, Galle, Sri-Lanka, October 1998, pp 71-78.

3. Bhutta ZA, Naqvi SH, Razzaq RA, Farooqui BJ. Multidrug resistant typhoid in children: . Prevention and clinical features. Rev Infect Dis 1992; 12: 832-836.

4. Rao PS, Rajashekar V, Varghese GK, Shivananda G. Emergence of multidrug resistant salmonella typhi in rural Southern India. Am 1 Trop Med Hyg 1993; 48: 108-111.

5. Rowe B, Ward LR, Threlfall EJ. Multidrug resistant Salmonella typhi: A worldwide epidemic: Clin Infect Dis 1997; 24: S106-S109.

6. Rasaily R, Dutta P, Saha MR, Mitra U, Lahiri M, Pal SC. Multidrug resistant typhoid fever in hospitalized children. Eur J Epidemiol 1994; 10: 4146.

7. Bhutta ZA. Typhoid fever: Impact of age and drug resistance on mortality. Arch Dis Child 1996;75:214-217.

8. Gupta A. Multidrug-resistant typhoid fever in children: Epidemiology and therapeutic approach. Pediatr Infect Dis 11994; 13: 134-140.

9. Wain 1, Diep TS, Ho V A, Walsh AM, Hoa NT, Parry CM, et al. Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility and antibiotic resistance. 1 Clin Microbiol1998; 36: 1683-1687.

10. Thong KL, Megan Passey M, Clegg A, Combs BG, Yassin RM, Pang T. Molecular analysis of isolates of Salmonella typhi obtained from patients with fatal and nonfatal typhoid fever. 1 Clin Microbiol1996; 34: 1029-1033.

11. Takkar VP, Kumar R, Khurana S, Takkar R. Comparison of ciprofloxacin versus cephalexin in the treatment of multi drug resistant typhoid fever. Indian Pediatr 1994; 31: 200-201.

12. Bhutta ZA, Khan lA, Molla AM. Therapy of .multidrug resistant typhoid fever with oral cefixime vs intravenous ceftriaxone. Pediatr Infect Dis 1 1994; 13: 990-994.

13. Girgis NI, Sultan Y, Hammad 0, Farid Z. .Comparison of the efficacy, safety and cost of cefixime, .ceftriaxone and aztreonam in the treatment of multi drug resistant Salmonella typhi septicemia in children. Pediatr Infect Dis 11995; 14: 603-605.

14. Rowe B, Threlfall EJ, Ward LR. Ciprofloxacin-resistant Salmonella typhi in the UK. Lancet 1995; 346: 1065.

15. Bhutta ZA. Quinolone-resistant Salmonella paratyphi B meningitis in the newborn. 1 Infec- tion 1997; 35: 308-310.

16. Murdoch DA, Banatvala NA, Bone A, Shoismatulloev BI. Epidemic ciprofloxacin-resistant Salmonella typhi in Tajikistan. Lancet 1998; 351: 339.

17. Parry C, Wain 1, Chinh NT, Vinh H, Farrar II.. Quinolone-resistant Salmonella typhoid in Vietnam. Lancet 1998; 351: 1289.

18. Shanahan PMA, lesudason MV, Thomson Cl, Amyes SGB. Molecular analysis of and identification of antibiotic resistance genes in clinical isolates to Salmonella typhi from India. 1 Gin Microbiol1998; p. 1595-1600.

19. Martinez LM, Pascual A, lacoby GA. Quinolone resistance from a transferable plasmid. Lancet 1998; 351: 797-799.

20. Jesudason MV, lohn R, lohn TJ. The concurrent prevalence of chloramphenicol-sensitive and' multidrug resistant Salmonella typhi in Vellore, S. India: Epidemiol Infect 1996: 116: 225-227.

21. Luby SP, Faizan MK, Fisher-Hoch SP, Syed A, Mintz: ED, Bhutta ZA, et al. Risk factors for typhoid fever in an endemic setting, Karachi, Pakistan. Epidemiol Infect 1998; 120: 129- 138.

22. Pandey KK, Srinavasan S. Typhoid fever below five years. Indian Pediatr 1990; 27: 153- 156.

23. William T, Mahle MD. Salmonella typhi infection in children younger than five years of age. Pediatr Infect Dis 1 1993; 12: 627-631.

24. Topley 1M. Mid typhoid fever. Arch Dis Child. f986; 61:164-167.

25. Engels EA, Falagas ME, Lau M, Bennish ML. Typhoid Tever vaccines: A meta-analysis pf studies on efficacy and toxicity. BMI 1998; .516: 110-116. .

26. Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn 55, Banting G, et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998; 393: 79-82.
 

 

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