Antimicrobial therapy of multidrug resistant typhoid fever in children: pediatricians' opinion.SB Bavdekar
Dept. of Paediatrics, Seth GS Medical College, Parel, Mumbai.
Keywords: Adult, Age Factors, Anti-Infective Agents, Quinolone, economics,therapeutic use,Cephalosporins, economics,therapeutic use,Child, Drug Costs, Drug Resistance, Multiple, Human, Patient Selection, Typhoid Fever, drug therapy,microbiology,
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 More Details 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 in-vitro 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 TMP-SMX. Therefore, from a clinical perspective the term MDRST should denote only those strains for which there is block resistance to all the three first-line antibiotics, namely, chloramphenicol, ampicillin and TMP-SMX.
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 first-line drugs were reported with increasing frequency. However until 1986 en-bloc 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 18-30%, 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 TMP-SMX could no longer be considered as the first-line 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 SMX-TMR 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 in-vitro against S. typhi strains by readily achievable serum concentrations. However the development of resistance to rifampicin being only a one-step 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 life-threatening 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 side-effects in children following ciprofloxacin use is not higher than that in adults, that side-effects 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 first-line drugs. Although there can be no firm guidelines, it may be considered prudent to start therapy for MDRTF (quinolones or third-generation 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. in-vitro 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 life-threatening infections It has been shown to be effective and without serious side-effects, though long-term 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.
[Table - 1]