Antimicrobial therapy of multidrug resistant typhoid fever in children: pediatricians' opinion.
Dept. of Paediatrics, Seth GS Medical College, Parel, Mumbai.
S B Bavdekar
Dept. of Paediatrics, Seth GS Medical College, Parel, Mumbai.
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Bavdekar S B. Antimicrobial therapy of multidrug resistant typhoid fever in children: pediatricians' opinion. J Postgrad Med 1996;42:65-7
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Bavdekar S B. Antimicrobial therapy of multidrug resistant typhoid fever in children: pediatricians' opinion. J Postgrad Med [serial online] 1996 [cited 2021 May 13 ];42:65-7
Available from: https://www.jpgmonline.com/text.asp?1996/42/3/65/437
Typhoid fever continues to be a major health problem due to poor hygienic and sanitary conditions prevalent in developing countries. India reported more than 354.000 cases of enteric fever in 1991 resulting in 1448 deaths. The emergence of Salmonella typhi strains resistant to multiple antibiotics have been causing enormous childhood morbidity and increasing the cost of therapy. This article reviews and examines the therapeutic alternatives available to treat multi-drug resistant typhoid fever (MDRTF) in children.
Chloramphenicol (Cm) was primarily responsible for decreasing the mortality due to typhoid. Ampicillin (Am) and trimethoprim - sulfamethoxazole (TMPSMX) were other drugs used with great degree of efficacy in the treatment of typhoid fever. Their invitro efficacy also closely correlated with in-vitro pattern of susceptibility and together they formed the first line of anti-microbial agents against typhoid. Clinical laboratories in addition, test for susceptibility of S. typhi to amino-glycosides, tetracyclines, furazolidone, Nalidixic acid, first generation cephalosporins and erythromycin. However, these drugs are hardly ever used in the treatment of typhoid fever. Epidemiological studies tended to define MDRST as strains resistant to two or more antibiotics in vitro. However, this is of no clinical relevance as a strain resistant to gentamicin, furazolidone and cephalothin would be designated as MDRST though it was susceptible to chloramphenicol, ampicillin and/or TMPSMX. Therefore, from a clinical perspective the term MDRST should denote only those strains for which there is block resistance to all the three firstline antibiotics, namely, chloramphenicol, ampicillin and TMPSMX.
Cm resistance in S. typhi was first reported in 1950. But extensive epidemics caused by Cm resistant S typhi were first witnessed in India and Mexico in 1972 and were subsequently reported from other countries. Later strains of S. typhi resistant to two of the three firstline drugs were reported with increasing frequency. However until 1986 enbloc resistance involving all three first line drugs was limited to anecdotal case reports. Epidemio-logically important strains of MDRST started emerging in the late 1980s. Southeast Asia, Africa, Latin America and parts of China and Indian subcontinent began to constitute an endemic zone for MDRST. The 1990s witnessed a surge in the incidence of MDRTF, which accounted for 1830%, of typhoid cases. Studies in Indian children have reported that upto 69% of typhoid cases may be caused by MDRST strains. Because of the high incidence of MDRTF, Cm. Am and TMPSMX could no longer be considered as the firstline drugs in typhoid fever.
Effective antimicrobial therapy is required to control morbidity and prevent death from typhoid fever. With the emergence of MDRTF doctors were forced to look for options other than Cm, Am and SMXTMR As laboratories routinely tested sensitivity of S. typhi against a variety, of anti-microbial agents. pediatricians turned to these drugs. However agents like furazolidone, gentamicin and cephalexin when used alone or in combination, failed to show consistently good results,,,,,. Rifampicin has been shown to be effective invitro against S. typhi strains by readily achievable serum concentrations. However the development of resistance to rifampicin being only a onestep mutation, its usefulness in the treatment of MDRTF as the sole agent is unlikely. Some workers have tried aztreonam. But this newer drug has also not given superior results consistently. The options have, therefore, narrowed down to third generation cephalosporins and fluoroquinolones.
Third generation cephalosporins
Cefotaxime and ceftriaxone are the main third generation cephalosporins used in pediatric trials for the treatment of MDRTF Excellent results have been obtained with ceftriaxone in children,. Cefotaxime is comparatively less efficacious, requires a longer time for defervescence of symptoms, is associated with a higher relapse rate and may have to be administered for a longer period. The duration of treatment with third generation cephalosporins is controversial. It has been suggested that in adults, ceftriaxone may be required to be given for only 3 days, Most studies in paediatric patients, however, recommend treatment for 7 to 10 days or for at least 3 days after defervescencel,. Third generation cephalosporins are very safe for paediatric use but are required to be administered parenterally and are extremely costly.
Quinolones were the other group of drugs tried in adults with MDRTF, with excellent results. Paediatricians however, were less fortunate. This group of drugs was considered to be contraindicated in individuals below the age of 18 years for the fear of toxicity to growing cartilage. But, faced with the spectre of a lifethreatening infection like MDRTF, paediatricians started using them in resistant infections. Of the various quinolones, the maximum clinical experience in paediatric practice has been with ciprofloxacin. Its efficacy in treating MDRTF has been unequivocal,,. It has certain advantages over third generation cephalosporins. An oral preparation is available the duration of therapy is shorter, cure rates are closer to 100% and is comparatively cheaper [Table:1].
A few studies have shown good results with ofloxacin, but sufficient paediatric experience is lacking. Some doubt still lingers in the minds of paediatricians as regards to the safety of the drug. It is, therefore, necessary to see its usage in MDRST infection in a proper perspective.
As stated earlier, the major worry regarding the use of quinolones in children has been its potential for causing arthropathy, Animal studies have shown that, this potential is species specific, drug specific and dosage dependent. It is to be remembered that nalidixic acid which is known to cause the greatest arthropathogenicity in lower animals has been used in children for about 20 years. Clinical data collected over many years has shown that the frequency of sideeffects in children following ciprofloxacin use is not higher than that in adults, that sideeffects seldom require discontinuation of the drug, that joint swellings when they occur can be reversed by stopping the drug and that reintroduction of ciprofloxacin does not necessarily lead to reappearance of joint Symptoms,,,. Magnetic resonance imaging (MRI) has been a sensitive tool in detecting early and discrete inflammatory, degenerative or traumatic lesions of articular cartilage under both clinical and experimental conditions. Schaad et al conducted clinical laboratory, radiological and MRI investigations on children and adolescents receiving 3 month courses of ciprofloxacin but did not find any evidence of cartilage damage even 22 months after the course. Thus, from available studies it appears medically and ethically justified to use ciprofloxacin in life threatening infections such as MDRTF.
MDRTF however, does not have any pathognomonic clinical features though it seems to have dominant hepatomegaly, is more likely to present with toxicity, is more prone to complications and of course is associated with higher rates of mortality,,,. Paediatricians are faced with the dilemma of either using a costly regimen (third generation cephalosporins) or a drug whose use is not beyond question (ciprofloxacin) without knowing whether the infection is resistant to firstline drugs. Although there can be no firm guidelines, it may be considered prudent to start therapy for MDRTF (quinolones or thirdgeneration cephalosporins) if:
1. a child presents with a life threatening complication.
2. there is clinical deterioration or development of complication during conventional antibiotic therapy.
3. there is an epidemic of MDRTF.
4. invitro sensitivity suggests infection with MDRST
5. there is failure to respond to an adequate trial of conventional antibiotics,,,.
Typhoid fever continues to be a major public health problem in developing countries. It is unlikely to reduce in the near future as vast improvements in sanitary conditions are unlikely to occur in the short term. Till MDRTF emerged, antimicrobial therapy of typhoid fever was limited to using one of the three first line drugs depending upon clinical response and sensitivity pattern. Physicians caring for adults use ciprofloxacin or third generation cephalosporins for treating such infections. Ceftriaxone is a good drug for MDRST infections in children as it is safe and efficacious. For years, ciprofloxacin has been considered unsuitable for individuals younger than 18 years due to its potential for arthropathogenicity. Data available from clinical studies wherein it has been used on compassionate grounds indicates that ciprofloxacin may have to be used in lifethreatening infections It has been shown to be effective and without serious sideeffects, though longterm follow-up studies will be required to ultimately define its ability to cause cartilage damage in humans. The fact that it is much cheaper than ceftriaxone is an additional factor to be considered in developing countries. One should be reluctant to use the drug for trivial infections in children, but there is enough data to support its use in children with a potentially lethal infection like MDRTF.
The author thanks the Dean, Seth GS Medical College & King Edward Memorial Hospital, Mumbai for permission to publish this article.
Park K. Typhoid Fever. In: Park (ed) Park's Textbook of Preventive and Social Medicine, Jabalpur: M/s Banarsidas Bhanot Publishers; 1995, pp 1614.|
|2||Ryder RW, Blake PA, Murlin AL. Increase in antibiotic resistance among isolates of Salmonella in the United States 196775. J Infect Dis 1980; 142:485491.|
|3||Smith SM, Palumbo PE, Edelson PJ. Salmonella strains resistant to multiple antibiotics: therapeutic implications. Paediatr Infect Dis 1984; 3:455460.|
|4||Panikar CKJ, Vimala KN. Transferable chloramphenicol resistance in Salmonella typhi. Nature 1972; 239:109110.|
|5||Olarte J, Galind DE. Salmonella typhi resistant to chloramphenicol. ampicillin and other antimicrobial agents: Strains isolated during an extensive typhoid fever epidemic in Mexico. Antimicrob Agents Chemother 1973; 4:597601.|
|6||Gupta A. Multidrug resistant typhoid fever in children: epidemiology and therapeutic approach. Paediatr Infect Dis J 1994; 13:134140.|
|7||Rawe B, Ward LR, Threlfall EJ. Spread of multi resistant Salmonella typhi. Lancet 1990; 336:1065.|
|8||Buch NA, Hassan MU, Kakroo DK. Enteric Fever: A changing sensitivity pattern, clinical profile and outcome. Indian Pediatr 1994; 31:981985.|
|9||Arora RK, Gupta A, Joshi NM, Kataria VK, Lail P, Anand AC. Multi drug resistant typhoid fever: study of an outbreak in Calcutta. Indian Pediatr 1992; 29:6166.|
|10||Biswal N, Mathai B, Bhatia BD, Srinivasan S, Nalini P. Enteric fever: changing perspective Indian Pediatr 1994; 31:813819.|
|11||Mishra S, Patwari AK, Anand VK, Pillai PK. Multi drug resistant typhoid fever: therapeutic considerations. Indian Pediatr, 1992; 29:443448.|
|12||Santosh Kumar A, Legori M, Sathy N, Mathaw R. Furazoli done in Typhoid Fever correlation of clinical efficacy with serum bactericidal activity. Indian Pediatr 1995; 32:533538.|
|13||Hayani KC, Pickering LK. Salmonella Infections In: Feigin RD, Cherry. JD, editorsw. Textbook of Paediatric Infectious Diseases, Philadelphia: WB Sunders Co; 1992, pp 620636.|
|14||Thakkar VP, Kumar R, Khurana S, Thakkar R. Comparison of ciprofloxacin versus cephalexin and gentamicin in the treatment of multi drugs Resistant Typhoid Fever Indian Pediatr 1994; 31:200201.|
|15||Gotuzzo E, Echeyarria J, Carrillo C, Sanchez J. Ran domized comparison of aztreonam and chloramphenicol in treatment of typhoid fever. Antimicrob Agents Chemother 1994; 38:558562.|
|16||Mishra S, Niranjan S, Kumar H, Sharma D. Ceftriaxone: Use in Multi drug resistant typhoid fever. Indian Pediatr 1993; 30:67-70.|
|17||Gulati S, Marwaha RK, Singhis S, Ayyagari A, Kumar L. Third generation cephalosporins in multi drug Resistant Typhoid fever. Indian Paediatr 1992; 29:513516.|
|18||Keusch GT. Salmonellosis. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Faud AS, Kasper PL, editors. Harrison's Principles of Internal Medicine. New York: McGraw Hill Inc; 1994, pp 671676.|
|19||Bavdekar A, Chaudhari M, Bhave S, Pandit A. Ciprofloxacin in Typhoid Fever. Indian Paediatr 1991; 58:335339.|
|20||Sen S, Goyal RS, Dev R. Ciprofloxacin in the management of multi drug resistant typhoid fever. Indian Pediatr 1991; 28:417-419.|
|21||Wang FU, Gu XJ, Zhand MF. Treatment of typhoid fever with ofloxacin. J Antimicrob Chemother 1989; 23:785788.|
|22||Schaad UB. Use of Quinolones in Paediatrics. Drugs 1993; 45(Suppp B):3741.|
|23||Chysky V, Kapila K, Hulimann IR, Arciari G, Schacht P, Echols R. Quinolones in clinical use. Safety of ciprofloxacin in children world wise clinical experience based on compassionate use. Emphasis on joint evaluation. Infection 1991; 4:289296.|
|24||Black A, Redmond AB, Steen HJ, Oborska IT. Tolerance and safety of ciprofloxacin in paediatric patients. J Antimicrob Chemother 1990; 26(Suppl):259.|
|25||Karande SC, Kshirsagar NA. Adverse drug reaction monitoring of Ciprofloxacin in paediatric practice. Indian Pediatr 1992; 29:1818.|
|26||Desmyttere S, Dab I, Malfoor A, Pierard D, Deprachins B. Ciprofloxacin use in children with cystic fibrosis. Third Inter-national Symposium of new quinolones, Vancouver. Canada: Book of abstracts; 1990, pp 2.|
|27||Schaad UB, Stoupis C, Wedgwood J, Tschappeler H, Vock P. Clinical radio-logic and magnetic resonance monitoring for skeletal toxicity in paediatric patients with cystic fibrosis receiving a 3 month course of ciprofloxacin. Paediatric Infect Dis J 1991; 10:723729.|
|28||Sharma A, Gathwala G. Clinical profile and outcome in Enteric fever. Indian Pediatr 1993; 30:4750.|
|29||Raghuraman TS, Krishnamurthy L, Menon PK, Singh D, Jayaprakash DG. Clinical profile and therapy in Enteric Fever. Indian Paediatr 1994; 31:196199.|
|30||Mandal BK. Treatment of multiresistant typhoid fever. Lancet 1990; 336383.