An analysis of children with typhoid fever admitted in 1991.CT Deshmukh, UB Nadkarni, SC Karande
Dept. of Pediatrics, KEM Hospital, Parel, Bombay, Maharashtra.
In 28 children, with bacteriologically and/or serologically diagnosed typhoid fever treated at KEM Hospital, Bombay in 1991, initially one of the three recommended drugs (viz. chloramphenicol, amoxycillin or co-trimoxazole) was given for 7 days for defervescence to occur. In those who failed to respond, a second trial of therapy with one of the other two drugs was initiated, after omitting the first drug. A second failure of therapy was taken as an indication to use ciprofloxacin singly. Eventually, 18 (64.3%) cases responded to chloramphenicol or amoxycillin or co-trimoxazole. Ciprofloxacin was used in 19(35.7%) cases. the failure rate of treatment with chloramphenicol was 50%, with amoxycillin 71.4%, with co-trimoxazole 75% and 0% with ciprofloxacin. An analysis of the 28 cases revealed that apart from fever (in 100%), splenomegaly (in 82.1%) was the most important clinical pointer to diagnosis, along with absolute eosinopenia (in 71.4%). There were no major complications, except 2 cases with typhoid hepatitis who responded to choramphenicol and co-trimoxazole, respectively. Blood culture grew Salmonella typhi in 7 cases, of which 5 (72%) were multidrug resistant S. typhi. There were no characteristic clinical features to identify multi-drug resistant typhoid fever.
Keywords: Amoxicillin, therapeutic use,Anti-Infective Agents, therapeutic use,Anti-Infective Agents, Fluoroquinolone, therapeutic use,Child, Ciprofloxacin, therapeutic use,Human, Penicillins, therapeutic use,Splenomegaly, Trimethoprim-Sulfamethoxazole Combination, therapeutic use,Typhoid Fever, diagnosis,drug therapy,
Typhoid fever is a major endemic health problem among children in India. To add to this, since 1990 there has been an emergence of multi-drug resistant typhoid fever in various parts of India,,,.
In this article, we have compared the clinical features and laboratory findings in children with typhoid fever who responded to treatment with one of the three recommended drugs viz. chloramphenicol, amoxycillin or cotrimoxazole, with those who eventually needed ciprofloxacin for a cure.
In 1991, 124 children with a clinical diagnosis of typhoid fever were admitted to three different units with multiple physicians treating them. The clinical diagnosis of typhoid lever based on the progressive development of listlessness and a persistent fever, lasting longer than 4 days was confirmed by, (i) isolation of S typhi by blood culture, or (ii) Widal agglutination titres of 1:160 or greater for S. typhi O antigen, or (iii) a positive countercurrent immunoelectrophoresis test to detect serum S typhi antigen whenever Widal's test was not being done in the laboratory. The diagnosis was bacteriologically and/or serologically confirmed in only 48. Of these 48 proven cases, 20 had received either an irrational and haphazard treatment before admission, such as using ciprofloxacin or norfloxacin or a combination of two recommended drugs without any laboratory evidence of typhoid fever or had received inadequate dosages of one of the recommended drug or it was changed hastily to another drug without even 5 days trial.
Excluding these patients, data of only 28 patients who were initially treated with either chloramphenicol or amoxycillin or co-trimoxazole in recommended dosages for a minimum period of 5 to 7 days, awaiting both defervescence and the antibiotic sensitivity report were analysed. Sensitivity of antibiotic discs was tested by the Kirby-Bauer disk diffusion technique. In the 7 bacteriologically proven patients this report was used as a guideline for deciding the drug to be used. In the remaining 21 patients whose diagnosis was confirmed by only serological methods, if defervescence, reduction in lever peak and decrease in spleen and liver size did not occur within 7 days the drug was omitted. The child was now treated with one of the other two recommended drugs, for another 7 days. A second failure of therapy led to omitting the drug, and was taken as an indication for using ciprofloxacin. Ciprofloxacin was given initially intravenously (5-10 mg/kg/day in b.d. doses), and once defervescence occurred, orally (7.5 - 15 mg/kg/day in b.d. doses), for a total 10 day period.
A complete hemogram and serum transaminases were done in all the patients, and were interpreted as per age related values. Chest radiograph, ECG and CSF examination were done when indicated.
Statistical comparison between the two groups viz. those who responded to a recommended drug (Group A) and those who required ciprofloxacin (Group B) was performed using student's ‘t’ test (p < 0.05 was considered significant) and X2 test (X2 value representing 95% confidence level was considered significant).
Of the 28 patients, 18 (Group A) responded to either chloramphenicol, amoxycillin or co-trimoxazole, and 10 (Group B) to ciprofloxacin. There were no clinical features to differentiate these 2 groups [Table - 1], [Table - 2].
Leucopenia was a highly significant finding in Group B [Table - 3]. As the first line drug, chloramphenicol was successful in 12/21 (57.1%) cases, amoxycillin in 1/4 (25%) and co-trimoxazole in 0/2 (0%). As the second line drug, chloramphenicol was successful in 2/3 (66.7%) cases, amoxycillin in 1/2 (33.3%), and co-trimoxazole in 2/5 (40%). The overall success rate of treatment with chloramphenicol was 50%, with amoxycillin 28.6% with co-trimoxazole 25%.
All the 10 patients eventually treated with ciprofloxacin responded well. In 4, ciprofloxacin was used after first line treatment (with chloramphenicol in 3 and co-trimoxazole in 1) failed, with worsening of the toxic look of the child. Only in 1 of these 4 cases, antibiotic sensitivity report confirmed multi-drug resistant S typhi. In another 6 cases ciprofloxacin was used as the third line drug. Even though antibiotic sensitivity report in 4 of these 6 cases confirmed multi-drug resistant S typhi, the clinical status of the child did not discourage a second trial with another recommended drug. But eventually in all the 4 patients, need for ciprofloxacin became evident.
Two patients had hepatitis and they responded to chloramphenicol and co-trimoxazole, respectively. No other complications were seen.
Early diagnosis of multi-drug resistant S typhi is a therapeutic challenge. Blood cultures were positive in only about 40% of children during the initial stage of typhoid fever. Also, prior treatment with antibiotics is known to inhibit growth on blood cultures and depress Widal titres. Although a clinical diagnosis of typhoid fever was made in 124 children admitted in 1991 only 48 (38.7%) were bacteriologically and/or serologically confirmed 'Recent reports',,, suggest a high percentage (64 to 82%) of multi-drug resistant typhoid fever cases. In our cases, only in 5 (17.8%) of 28 patients multi-drug resistant S. typhi were isolated. However, clinically multidrug resistance was found in 11 (39.3%) of 28 patients treated with various drugs. Ciprofloxacin was used in 10 (35.7%) patients, and in 6 of them two trials with a recommended drug had failed to initiate defervescence. A third trial with another recommended drug was not considered practical in a child with fever of more than 2 weeks duration.
We did not find any clinical feature to identify multi-drug resistant typhoid fever [Table - 1], [Table - 2] nor any increased incidence of complications. Arora, et al have also found no increased incidence of complications. Others,, have reported increased incidence of complications in their multidrug resistant cases such as encephalopathy, shock, gastrointestinal haemorrhage, meningitis, myocarditis and hepatitis. In our study, 2 patients of typhoid hepatitis, Group II (severe) according to the clinicobiochemical classification, responded to chloramphenicol and co-trimoxazole, respectively.
One interesting observation was in a 7-year-old girl with history of fever for 60 days and positive Widal test on admission. Fever continued for a further 12 day period, during treatment with co-trimoxazole and later chloramphenicol. Use of ciprofloxacin led to defervescence within 4 days. Anand, et al have reported 12 cases with multidrug resistant typhoid fever with history of fever for 6 to 7 weeks, till use of ciprofloxacin led to defervescence. It seems that unlike in routine typhoid fever cases, natural defervescence does not occur after 3 to 4 weeks in multi-drug resistant cases.
Eosinopenia, as seen in 71.4% patients in our study, may be useful pointer towards diagnosis of typhoid fever in children with prolonged fever and hepatosplenomegaly.
Ciprofloxacin is not recommended for use in children because of its possible adverse effect on growing cartilage. Though a long-term follow-up is needed to detect such a complication we did not encounter any other complications with ciprofloxacin use. A survey done in 1990 from our hospital, revealed that 147 paediatricians in Maharashtra over a 2 month period had prescribed ciprofloxacin in 2792 children with typhoid fever. There seems to be a hasty tendency to directly use ciprofloxacin or jump to using it without a fair trial with at least 2 of the recommended drugs used singly. Also, limited facilities for culture and antibiotic sensitivity testing adds to the problem. Since ceftriaxone a recommended drug for multi drug resistant typhoid fever is expensive, alternative drugs have been tried with moderate success viz. cephalexin,, gentamicin, cefotaxime and cephalexin with furazolidine. Arora et al have reported total failure with gentamicin and furazolidine.
Injudicious use of chloramphenicol. amoxycillin and co-trimoxazole for trivial infections like gastroenteritis and common cold has led to the emergence of multidrug resistant S typhi strains. Proper sanitation measures, use of clean drinking water, widespread vaccination against typhoid fever, and a rational drug therapy will help tide over this problem. Ciprofloxacin has now been officially listed as an essential reserve drug for strains of S typhi resistant to chloramphenicol, amoxycillin and co-trimoxazole. We recommend that ciprofloxacin should be used after at least one trial with the standard antibiotic therapy has failed.
[Table - 1], [Table - 2], [Table - 3]