Multidrug - resistant typhoid fever
http://www.100md.com
《美国医学杂志》
1 Department of Pediatrics, Batra Hospital & Medical Research Centre, New Delhi, India
2 Department of Pharmacology, Maulana Azad Medical College, New Delhi, India
Objective. To study the epidemiological pattern, clinical picture, the recent trends of multidrug-resistant typhoid fever (MDRTF), and therapeutic response of ofloxacin and ceftriaxone in MDRTF. Methods. The present prospective randomized controlled parallel study was conducted on 93 blood culture-proven Salmonella typhi children. All MDRTF cases were randomized to treatment with ofloxacin or ceftriaxone. Results. Of 93 children, 62(66.6%) were MDRTF. 24 cases were below 5 years, 26 between 5-10 years and 12 were above 10 years. Male to female ratio was 1.85: 1. Majority of cases came from lower middle socio-economic classes with poor personal hygiene. Fever was the main presenting symptom. Hepatomegaly and splenomegaly was present in 88% and 46% cases respectively. 19(30.6%) cases developed complications. Mean defervescence time with ceftriaxone and ofloxacin was 4.258 and 4.968 days respectively. Conclusion. MDRTF is still emerging as serious public and therapeutic challenge. Ceftriaxone is well-tolerated and effective drug but expensive whereas ofloxacin is safe, cost-effective and therapeutic alternative in treatment of MDRTF in children with comparable efficacy to ceftriaxone.
Keywords: Multidrug-resistant; Typhoid fever; Salmonella typhi; Ceftriaxone and Ofloxacin
Typhoid fever is a distinctive acute multi-systemic febrile disease caused primarily by Salmonella More Details typhi . It is recognized as a major cause of morbidity globally with over 21.6 million cases annually worldwide, and an estimated 216500 deaths.[1] Almost 80% of cases and deaths are in Asia. The attack rate as high as 1100 cases per 100000 populations have been documented in developing countries.[2] It remains a serious publichealth in developing countries.
The recent explosive emergence and spread of MDRTF with resistance to the conventionally used antibiotics for the treatment of typhoid fever, namely chloramphenicol, ampicillin and co-trimoxazole has caused significant therapeutic and public health problem. The problem is also compounded by the fact that a large number of cases of MDRTF occur in childhood with significantly higher morbidity and mortality.
MDRTF in childhood is frequently associated with a more severe clinical illness and higher rates of toxicity, hepatomegaly, hypotensive shock, and death.[3] There is an urgent need to keep the possible emergence of untreatable strains to a minimum, by prudent use of existing drugs and by resting the temptation to use yet more antibiotics. We undertook this study with the aim of documenting the clinical picture, complications, and sensitivity patterns of S. typhi isolates, epidemiological pattern, recent trends of MDRTF, and therapeutic response to ofloxacin and ceftriaxone.
Materials and Methods
The present prospective randomized controlled parallel study was conducted on 93 children up to 12 years admitted in our hospital between May 2002 and April 2004 with clinical presentation of typhoid fever without any localizing signs, and a positive blood culture for S. typhi .
All those children were excluded who had a history of an effective antibiotic therapy within one week prior to admission in the hospital, a known allergy to penicillin, chloramphenicol, quinolones or cephalosporins, and a history of immunization with typhoid vaccine. The informed written consent was obtained from the parents of the children prior to the inclusion of the children in this study.
A detailed epidemiological and clinical history, a thorough clinical examination and laboratory investigations at the time of admission and during the course of hospital stay were performed in all cases and the findings were recorded in the pre-made proforma.
Epidemiological and clinical history : In addition to patients name, age, sex, address, socio-economic status, hygiene and sanitation, some epidemiological information like education, occupation, family income, number of family members, level of personal hygiene (practice of hand washing with soap by family members after defecation and before eating and preparing food), source of drinking and portable water supply, and habit of defecation (use of sanitary latrine, open pit latrine) by family members were also obtained from parents. Socio-economic status of the parents was estimated by Kuppuswamy's classification. On admission, a detailed clinical history was taken in each case.
Clinical examination : A detailed general and systemic examination was done in all cases. In general examination, authors took note of general condition, toxic look, level of consciousness, temperature, pulse rate, pulse character, respiratory rate, blood pressure, pallor, jaundice, icterus, rash, petechiae and lymphadenopathy.
In systemic examination, children were thoroughly examined for throat congestion, altered sensorium, rhonchi, meningismus, abdominal distension, abdominal tenderness, hepatomegaly and splenomegaly. All associated findings and complications were noted in all children.
Laboratory investigations : A blood sample for complete hemogram, serum bilirubin, liver enzymes, serum urea, serum creatinine, serum sodium, serum potassium, Widal test and blood culture was obtained in all children on admission and thereafter if the children's condition warranted it. Stool and urine samples were also sent for culture examination. The chest and abdominal X-rays were done in children where it was indicated.
Treatment : The patients with a presumptive clinical diagnosis of typhoid fever were initially treated with chloramphenicol (75 mg/Kg/day) by oral or intravenous route. The mid-course modification of therapy was done after the availability of blood culture and sensitivity report. All MDRTF cases were randomized to treatment with ofloxacin (20 mg/Kg/day) or ceftriaxone (100 mg/Kg/day). The clinical course was closely monitored and the period of defervescence was recorded. The time to defervescence is defined as the time interval from starting an appropriate antimicrobial chemotherapy until the documentation of normal body temperature. The clinical response to therapy was considered inadequate if there was deterioration or no clinical improvement within 7-10 days of starting specific therapy. The drug efficacy was judged primarily by the patient's clinical response with particular attention being given to the number of days of treatment required make the patient afebrile.
The patients were carefully observed for possible complications. The children were followed up for three months to detect relapse or complications.
Data Analysis : The epidemiological, clinical, laboratory and therapeutic data were collected from each patient and recorded on a specially designed proforma. The various tests of significance e.g. Chi-square, Standard error of difference between means and p-value where applied to assess the probability and significance of the data. The statistical computing was performed and the data were analyzed statistically by using Epi Info Version 6.04d (Centers for Disease Control and Prevention, USA).
Results
Of 93 blood culture-proven S. typhi cases, 62(66.6%) were MDRTF. The incidence was highest (30.6%) seen in the age group of 2 - 5 years. The second peak (25.8%) was observed among age group of 7 - 10 years. It was seen only in a one infant. 22(35.5%) cases were females and 40(64.5%) cases were males. Therefore, male: female ratio was 1.85: 1.
MDRTF cases were seen throughout the year but the rate of both hospitalization of cases and isolation of S. typhi were relatively low during the months of October and December. The majority of children belonged to lower middle socio-economic classes with poor personal hygiene. A history of travel away from the community was not observed in any of the children. Most of the affected families consumed either municipal supplied water or water from tube wells. Majority (88.7%) of the families and their children used sanitary latrines.
Fever was the main presenting symptom in all the cases. High-grade fever was observed in 75.8% cases. The duration of fever was of more than seven days in the majority (72.6%) of cases at the time of admission. The pattern of fever was intermittent in majority (71%) of cases. Only 6 (9.6%) cases had fever with chills and rigors. Headache was associated with fever in 34(54.8%) cases. Other features seen were diarrhea (74.2%), abdominal pain (62.9), vomiting (61.2%), malaise (48.3%), anorexia (33.8%), nausea (32.2%), cough (32.2%), constipation (14.5%) and GIT bleeding (12.9%).
46(74.1%) cases were toxic at time of presentation. Relative bradycardia and coated tongue were seen in 7(11.2%) and 22(35.4%) cases respectively. Hypotension was noted in 4 (6.4%) cases, one patient was unconscious and two patients had loose motions and vomiting at the time of admission. Clinically pallor and icterus was present in 26(41.9%) and 18(29%) cases respectively. Hepatomegaly and splenomegaly was present in 88% and 46% cases respectively.
Laboratory examination of blood revealed that anemia (hemoglobin < 10.0 gm/dl) was noted in 16(25.8%) cases and leucopenia (< 4000/cmm) in 3% cases. Transient thrombocytopenia was documented in 3(4.8%) cases. Raised level of serum bilirubin was seen in 13 (20.9%) cases. About 13% cases had raised SGPT level above 100 U/L. The sensitivity, specificity, positive predictive value and negative predictive value of Widal test were 68.57%, 37.08%, 43.11 and 62.92 respectively. The antimicrobial susceptibility patterns to commonly used antibiotics are shown in [Table - 1].
19(30.6%) of children developed complications. The main complications observed by us were hepatitis (14.5%), intestinal bleeding (4.8%) and pleural effusion (1.6%). Intestinal perforation occurred in one child during the second week of illness and he required surgery plus antibiotic and metronidazole therapy. The mean defervescence time was 4.258 days in case of ceftriaxone and 4.968 days in case of ofloxacin. The difference in mean defervescence time between ceftriaxone and ofloxacin was statistically significant. (P-value< 0.05) All patients recovered completely and none had clinical relapse of fever or complications within the follow period of three months after discharge from the hospital.
Discussion
In this study, 66.6% of the isolated strains of S. typhi were MDRTF. We observed maximum MDRTF cases in the age group of 2 - 5 years (30.6%) which was similar to other studies.[4],[5] The incidence of MDRTF among children below one year of age is very rare. It is evident that children between 2 - 5 years of age are most susceptible age group and thereby are the highest risk group against MDRTF. The maximum number of cases was found from April to August in both the years, thus highlighting the seasonal variation in the incidence of MDRTF cases.
Fever was the commonest presentation in all the cases. Fever was observed in 100% of cases in most of the studies by other authors.[3],[6],[7] The classical continuous stepladder rise of temperature was not seen in any of the cases and the majority (75.8%) of the cases had high grade fever. Bhutta et al reported high-grade fever in 90% cases.[8]
There was a significant difference in the incidence of gastrointestinal complaints - abdominal pain (62.9% versus 30% Agarwal et al[3]); diarrhea (74.2% versus 47.1% Rasaily et al[9] versus 3% Koul et al[10]); GIT bleeding (12.9% versus 7% Koul et al[10]). All these differences simply reflect the protean manifestations of MDRTF and may well reflect the regional differences. Encephalopathy (8%) was the commonest CNS manifestation noted in our study, continuing the observation of others.[2],[11]
Hepatomegaly was seen in 88% cases in this study similar to that reported by Chandra et al[12]. Bhutta et al[8] and Koul et al[10] reported hepatomegaly in 33% of cases. Splenomegaly was seen in 46% of cases in our study which was similar to that reported by Kabra et al[6]. Though higher incidence of splenomegaly have been reported by other authors.[11], [12]
Most of the patients in this study had normal leukocyte count although leucopenia is said to be the common hematological finding in typhoid fever.[13] Leucopenia was seen in 3% cases, continuing the observation of others.[8],[10],[13] The total culture positivity rate was 41%, continuing the observation of others.[14]
The commonest complications are GIT bleeding, intestinal perforation and typhoid encephalopathy. Earlier reports suggest a complication rate of 10-40% in MDRTF.[9],[10] Intestinal perforation, a well known complication of typhoid fever in adults is less frequent in children and its presence in only one child suggests that it is very rare in children.
Osler first reported hepatic complications of typhoid fever in 1899.[15] Since then, several reports of typhoid hepatitis have been described in adults. However, very few reports detailing the spectrum of hepatic injury in typhoid fever exist in the pediatric literature. The reported incidence of typhoid hepatitis varies from 0.4% - 6%. Several patient series have previously reported biochemical evidence of hepatic dysfunction in 23% - 60% of cases.[16]
We observed pneumonia in 3.2% cases. Similar results have been reported by others.[8],[12] Pleural effusion was seen in only one case whereas Biswal et al[17] reported more frequent incidence of pleural effusion in MDRTF. Other complications reported in literature include parotitis, paralytic ileus, arthritis, chorea and cerebellar ataxia,[8],[10] splenic abscess, subphrenic abscess and pancreatitis, rose spots, cutaneous ulcers and subcutaneous abscesses[18] were not observed by us.
The patients treated with ceftriaxone had a slightly shorter time to defervescence than did those treated with ofloxacin. The difference of mean was significant and both results were within time frames reported in previous clinical trials for treatment of MDRTF.[19]
The effectiveness of ceftriaxone in the treatment of typhoid fever in children is a particularly important finding because ofloxacin, which constitute the other group of drugs being used as alternative treatment for MDRTF. Ofloxacin is not recommended in children due to arthropathic toxicity in growing animals. The examination of available clinical data to date provides no absolute evidence that ofloxacin induces significant arthropathy in children, in contrast to data reported in some animal species. However, literature does say that ofloxacin should be used with caution in children below 12 years of age. Ofloxacin has been used with good clinical response without significant side effects in typhoid fever[20] and cystic fibrosis[21].
Conclusion
MDRTF is still emerging as serious public and therapeutic challenge. Ceftriaxone is well-tolerated and effective drug for MDRTF in children but expensive. Ofloxacin is safe, cost-effective and therapeutic alternative in treatment of MDRTF with comparable efficacy to ceftriaxone. However, further studies in a larger group of patients are needed to validate our findings. The rapid spread of MDRTF over a large geographic area presents multiple challenges, especially in developing countries where access to newer and more expensive antimicrobial agents may be limited. Therefore, research efforts must be continued to focus on oral agents with chances of high cure rate.
References
1.Wasfy MO, Oyofo BA, David JC et al. Isolations and antibiotic susceptibility of Salmonella , Shigella , and Campylobacter from acute enteric infections in Egypt. J Health Popul Nutr 2000; 18: 33-38.
2.Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bull World Health Organ 1994; 72 : 957-971. [PUBMED]
3.Agarwal K S, Singh S K, Kumar N et al. A study of current trends in enteric fever. J Commun Dis 1998; 30(3): 171-174.
4.Sood S, Kapil A, Das B, Jain Y, Kabra SK. Re-emergence of chloramphenicol-sensitive Salmonella typhi . Lancet 1999; 353 : 1241-1242.
5.Sinha A, Sazawal S, Kumar R et al. Typhoid fever in children aged less than 5 years. Lancet 1999; 354 : 734-737.
6.Kabra S K, Kabra M, Talati A, Soni N, Patel S, Modi R R. Multidrug-resistant typhoid fever. Trop Doct 2000; 30: 195-197.
7.Wongsawat J, Pancharoen C, Thisyakorn U. Typhoid fever in children: Experience in King Chulalongkorn Memorial Hospital. J Med Assoc Thai 2002; 85: 1247-1250. [PUBMED]
8.Bhutta ZA, Naqvi SH, Razzaq ZA et al. Mutidrug-resistant typhoid in children: Presentation and Clinical features. Rev Infect Dis 1991; 13: 832-836.
9.Rasaily R, Dutta P, Saha MR, Mitra U et al. Multidrug-resistant typhoid fever in hospitalized children: clinical, bacteriological and epidemiological profiles. Eur J Epidemiol 1994; 10: 41-46.
10.Koul P B, Murali M V, Sharma P P, Ghai O P, et al. Multidrug-resistant Salmonella typhi infection: clinical profile and therapy. Indian Pediatr 1991; 28: 352-356.
11.Garg K, Mangal N, Mathur HC. Clinical profile of multidrug-resistant typhoid fever in Jaipur city. Indian Pediatr 1994; 31: 191-193. [PUBMED]
12.Chandra R, Srinivasan S, Nalini P, Rao RS. Multidrug-resistant enteric fever. J Trop Med Hyg 1992; 95: 284-287. [PUBMED]
13.Johnson AOK, Aderele WI. Enteric fever in childhood. J Trop Med Hyg 1981; 84: 29-35.
14.Vallenas C, Hernandez H, Kay B et al. Efficacy of bone marrow, blood, stool and duodenal contents culture for bacteriologic confirmation of typhoid fever in children. Pediatr Infect Dis 1985; 4 : 496-498.
15.Osler W. Hepatic complication of typhoid fever. Johns Hopkins Hosp Rep 1899; 8 : 373-387.
16.Ramchandaran S, Godfrey JJ, Perera MVF. Typhoid hepatitis. J Am Med Assoc 1974; 230: 236-240.
17.Biswal N, Mathai B, Bhatia B D, Srinivasan S et al. Enteric fever: A changing perspective. Indian Pediatr 1994; 31: 813-819.
18.Burnett J W. Uncommon bacterial infections of skin. Arch Dermat 1962; 86 : 597-607.
19.Smith MD, Duong NM, Hoa NT et al. Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever. Antimicrob Agents Chemother 1994; 38: 1716-1720.
20.Asperilla MO, Smego RAJr, Scott LK. Quinolone antibiotics in the treatment of Salmonella infections. Rev Infec Dis 1990; 12: 873-879.
21.Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Eng J Med 1996; 335: 179-188. [PUBMED] [FULLTEXT](Kumar Rajiv, Gupta Nomeeta, Shalini)
2 Department of Pharmacology, Maulana Azad Medical College, New Delhi, India
Objective. To study the epidemiological pattern, clinical picture, the recent trends of multidrug-resistant typhoid fever (MDRTF), and therapeutic response of ofloxacin and ceftriaxone in MDRTF. Methods. The present prospective randomized controlled parallel study was conducted on 93 blood culture-proven Salmonella typhi children. All MDRTF cases were randomized to treatment with ofloxacin or ceftriaxone. Results. Of 93 children, 62(66.6%) were MDRTF. 24 cases were below 5 years, 26 between 5-10 years and 12 were above 10 years. Male to female ratio was 1.85: 1. Majority of cases came from lower middle socio-economic classes with poor personal hygiene. Fever was the main presenting symptom. Hepatomegaly and splenomegaly was present in 88% and 46% cases respectively. 19(30.6%) cases developed complications. Mean defervescence time with ceftriaxone and ofloxacin was 4.258 and 4.968 days respectively. Conclusion. MDRTF is still emerging as serious public and therapeutic challenge. Ceftriaxone is well-tolerated and effective drug but expensive whereas ofloxacin is safe, cost-effective and therapeutic alternative in treatment of MDRTF in children with comparable efficacy to ceftriaxone.
Keywords: Multidrug-resistant; Typhoid fever; Salmonella typhi; Ceftriaxone and Ofloxacin
Typhoid fever is a distinctive acute multi-systemic febrile disease caused primarily by Salmonella More Details typhi . It is recognized as a major cause of morbidity globally with over 21.6 million cases annually worldwide, and an estimated 216500 deaths.[1] Almost 80% of cases and deaths are in Asia. The attack rate as high as 1100 cases per 100000 populations have been documented in developing countries.[2] It remains a serious publichealth in developing countries.
The recent explosive emergence and spread of MDRTF with resistance to the conventionally used antibiotics for the treatment of typhoid fever, namely chloramphenicol, ampicillin and co-trimoxazole has caused significant therapeutic and public health problem. The problem is also compounded by the fact that a large number of cases of MDRTF occur in childhood with significantly higher morbidity and mortality.
MDRTF in childhood is frequently associated with a more severe clinical illness and higher rates of toxicity, hepatomegaly, hypotensive shock, and death.[3] There is an urgent need to keep the possible emergence of untreatable strains to a minimum, by prudent use of existing drugs and by resting the temptation to use yet more antibiotics. We undertook this study with the aim of documenting the clinical picture, complications, and sensitivity patterns of S. typhi isolates, epidemiological pattern, recent trends of MDRTF, and therapeutic response to ofloxacin and ceftriaxone.
Materials and Methods
The present prospective randomized controlled parallel study was conducted on 93 children up to 12 years admitted in our hospital between May 2002 and April 2004 with clinical presentation of typhoid fever without any localizing signs, and a positive blood culture for S. typhi .
All those children were excluded who had a history of an effective antibiotic therapy within one week prior to admission in the hospital, a known allergy to penicillin, chloramphenicol, quinolones or cephalosporins, and a history of immunization with typhoid vaccine. The informed written consent was obtained from the parents of the children prior to the inclusion of the children in this study.
A detailed epidemiological and clinical history, a thorough clinical examination and laboratory investigations at the time of admission and during the course of hospital stay were performed in all cases and the findings were recorded in the pre-made proforma.
Epidemiological and clinical history : In addition to patients name, age, sex, address, socio-economic status, hygiene and sanitation, some epidemiological information like education, occupation, family income, number of family members, level of personal hygiene (practice of hand washing with soap by family members after defecation and before eating and preparing food), source of drinking and portable water supply, and habit of defecation (use of sanitary latrine, open pit latrine) by family members were also obtained from parents. Socio-economic status of the parents was estimated by Kuppuswamy's classification. On admission, a detailed clinical history was taken in each case.
Clinical examination : A detailed general and systemic examination was done in all cases. In general examination, authors took note of general condition, toxic look, level of consciousness, temperature, pulse rate, pulse character, respiratory rate, blood pressure, pallor, jaundice, icterus, rash, petechiae and lymphadenopathy.
In systemic examination, children were thoroughly examined for throat congestion, altered sensorium, rhonchi, meningismus, abdominal distension, abdominal tenderness, hepatomegaly and splenomegaly. All associated findings and complications were noted in all children.
Laboratory investigations : A blood sample for complete hemogram, serum bilirubin, liver enzymes, serum urea, serum creatinine, serum sodium, serum potassium, Widal test and blood culture was obtained in all children on admission and thereafter if the children's condition warranted it. Stool and urine samples were also sent for culture examination. The chest and abdominal X-rays were done in children where it was indicated.
Treatment : The patients with a presumptive clinical diagnosis of typhoid fever were initially treated with chloramphenicol (75 mg/Kg/day) by oral or intravenous route. The mid-course modification of therapy was done after the availability of blood culture and sensitivity report. All MDRTF cases were randomized to treatment with ofloxacin (20 mg/Kg/day) or ceftriaxone (100 mg/Kg/day). The clinical course was closely monitored and the period of defervescence was recorded. The time to defervescence is defined as the time interval from starting an appropriate antimicrobial chemotherapy until the documentation of normal body temperature. The clinical response to therapy was considered inadequate if there was deterioration or no clinical improvement within 7-10 days of starting specific therapy. The drug efficacy was judged primarily by the patient's clinical response with particular attention being given to the number of days of treatment required make the patient afebrile.
The patients were carefully observed for possible complications. The children were followed up for three months to detect relapse or complications.
Data Analysis : The epidemiological, clinical, laboratory and therapeutic data were collected from each patient and recorded on a specially designed proforma. The various tests of significance e.g. Chi-square, Standard error of difference between means and p-value where applied to assess the probability and significance of the data. The statistical computing was performed and the data were analyzed statistically by using Epi Info Version 6.04d (Centers for Disease Control and Prevention, USA).
Results
Of 93 blood culture-proven S. typhi cases, 62(66.6%) were MDRTF. The incidence was highest (30.6%) seen in the age group of 2 - 5 years. The second peak (25.8%) was observed among age group of 7 - 10 years. It was seen only in a one infant. 22(35.5%) cases were females and 40(64.5%) cases were males. Therefore, male: female ratio was 1.85: 1.
MDRTF cases were seen throughout the year but the rate of both hospitalization of cases and isolation of S. typhi were relatively low during the months of October and December. The majority of children belonged to lower middle socio-economic classes with poor personal hygiene. A history of travel away from the community was not observed in any of the children. Most of the affected families consumed either municipal supplied water or water from tube wells. Majority (88.7%) of the families and their children used sanitary latrines.
Fever was the main presenting symptom in all the cases. High-grade fever was observed in 75.8% cases. The duration of fever was of more than seven days in the majority (72.6%) of cases at the time of admission. The pattern of fever was intermittent in majority (71%) of cases. Only 6 (9.6%) cases had fever with chills and rigors. Headache was associated with fever in 34(54.8%) cases. Other features seen were diarrhea (74.2%), abdominal pain (62.9), vomiting (61.2%), malaise (48.3%), anorexia (33.8%), nausea (32.2%), cough (32.2%), constipation (14.5%) and GIT bleeding (12.9%).
46(74.1%) cases were toxic at time of presentation. Relative bradycardia and coated tongue were seen in 7(11.2%) and 22(35.4%) cases respectively. Hypotension was noted in 4 (6.4%) cases, one patient was unconscious and two patients had loose motions and vomiting at the time of admission. Clinically pallor and icterus was present in 26(41.9%) and 18(29%) cases respectively. Hepatomegaly and splenomegaly was present in 88% and 46% cases respectively.
Laboratory examination of blood revealed that anemia (hemoglobin < 10.0 gm/dl) was noted in 16(25.8%) cases and leucopenia (< 4000/cmm) in 3% cases. Transient thrombocytopenia was documented in 3(4.8%) cases. Raised level of serum bilirubin was seen in 13 (20.9%) cases. About 13% cases had raised SGPT level above 100 U/L. The sensitivity, specificity, positive predictive value and negative predictive value of Widal test were 68.57%, 37.08%, 43.11 and 62.92 respectively. The antimicrobial susceptibility patterns to commonly used antibiotics are shown in [Table - 1].
19(30.6%) of children developed complications. The main complications observed by us were hepatitis (14.5%), intestinal bleeding (4.8%) and pleural effusion (1.6%). Intestinal perforation occurred in one child during the second week of illness and he required surgery plus antibiotic and metronidazole therapy. The mean defervescence time was 4.258 days in case of ceftriaxone and 4.968 days in case of ofloxacin. The difference in mean defervescence time between ceftriaxone and ofloxacin was statistically significant. (P-value< 0.05) All patients recovered completely and none had clinical relapse of fever or complications within the follow period of three months after discharge from the hospital.
Discussion
In this study, 66.6% of the isolated strains of S. typhi were MDRTF. We observed maximum MDRTF cases in the age group of 2 - 5 years (30.6%) which was similar to other studies.[4],[5] The incidence of MDRTF among children below one year of age is very rare. It is evident that children between 2 - 5 years of age are most susceptible age group and thereby are the highest risk group against MDRTF. The maximum number of cases was found from April to August in both the years, thus highlighting the seasonal variation in the incidence of MDRTF cases.
Fever was the commonest presentation in all the cases. Fever was observed in 100% of cases in most of the studies by other authors.[3],[6],[7] The classical continuous stepladder rise of temperature was not seen in any of the cases and the majority (75.8%) of the cases had high grade fever. Bhutta et al reported high-grade fever in 90% cases.[8]
There was a significant difference in the incidence of gastrointestinal complaints - abdominal pain (62.9% versus 30% Agarwal et al[3]); diarrhea (74.2% versus 47.1% Rasaily et al[9] versus 3% Koul et al[10]); GIT bleeding (12.9% versus 7% Koul et al[10]). All these differences simply reflect the protean manifestations of MDRTF and may well reflect the regional differences. Encephalopathy (8%) was the commonest CNS manifestation noted in our study, continuing the observation of others.[2],[11]
Hepatomegaly was seen in 88% cases in this study similar to that reported by Chandra et al[12]. Bhutta et al[8] and Koul et al[10] reported hepatomegaly in 33% of cases. Splenomegaly was seen in 46% of cases in our study which was similar to that reported by Kabra et al[6]. Though higher incidence of splenomegaly have been reported by other authors.[11], [12]
Most of the patients in this study had normal leukocyte count although leucopenia is said to be the common hematological finding in typhoid fever.[13] Leucopenia was seen in 3% cases, continuing the observation of others.[8],[10],[13] The total culture positivity rate was 41%, continuing the observation of others.[14]
The commonest complications are GIT bleeding, intestinal perforation and typhoid encephalopathy. Earlier reports suggest a complication rate of 10-40% in MDRTF.[9],[10] Intestinal perforation, a well known complication of typhoid fever in adults is less frequent in children and its presence in only one child suggests that it is very rare in children.
Osler first reported hepatic complications of typhoid fever in 1899.[15] Since then, several reports of typhoid hepatitis have been described in adults. However, very few reports detailing the spectrum of hepatic injury in typhoid fever exist in the pediatric literature. The reported incidence of typhoid hepatitis varies from 0.4% - 6%. Several patient series have previously reported biochemical evidence of hepatic dysfunction in 23% - 60% of cases.[16]
We observed pneumonia in 3.2% cases. Similar results have been reported by others.[8],[12] Pleural effusion was seen in only one case whereas Biswal et al[17] reported more frequent incidence of pleural effusion in MDRTF. Other complications reported in literature include parotitis, paralytic ileus, arthritis, chorea and cerebellar ataxia,[8],[10] splenic abscess, subphrenic abscess and pancreatitis, rose spots, cutaneous ulcers and subcutaneous abscesses[18] were not observed by us.
The patients treated with ceftriaxone had a slightly shorter time to defervescence than did those treated with ofloxacin. The difference of mean was significant and both results were within time frames reported in previous clinical trials for treatment of MDRTF.[19]
The effectiveness of ceftriaxone in the treatment of typhoid fever in children is a particularly important finding because ofloxacin, which constitute the other group of drugs being used as alternative treatment for MDRTF. Ofloxacin is not recommended in children due to arthropathic toxicity in growing animals. The examination of available clinical data to date provides no absolute evidence that ofloxacin induces significant arthropathy in children, in contrast to data reported in some animal species. However, literature does say that ofloxacin should be used with caution in children below 12 years of age. Ofloxacin has been used with good clinical response without significant side effects in typhoid fever[20] and cystic fibrosis[21].
Conclusion
MDRTF is still emerging as serious public and therapeutic challenge. Ceftriaxone is well-tolerated and effective drug for MDRTF in children but expensive. Ofloxacin is safe, cost-effective and therapeutic alternative in treatment of MDRTF with comparable efficacy to ceftriaxone. However, further studies in a larger group of patients are needed to validate our findings. The rapid spread of MDRTF over a large geographic area presents multiple challenges, especially in developing countries where access to newer and more expensive antimicrobial agents may be limited. Therefore, research efforts must be continued to focus on oral agents with chances of high cure rate.
References
1.Wasfy MO, Oyofo BA, David JC et al. Isolations and antibiotic susceptibility of Salmonella , Shigella , and Campylobacter from acute enteric infections in Egypt. J Health Popul Nutr 2000; 18: 33-38.
2.Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bull World Health Organ 1994; 72 : 957-971. [PUBMED]
3.Agarwal K S, Singh S K, Kumar N et al. A study of current trends in enteric fever. J Commun Dis 1998; 30(3): 171-174.
4.Sood S, Kapil A, Das B, Jain Y, Kabra SK. Re-emergence of chloramphenicol-sensitive Salmonella typhi . Lancet 1999; 353 : 1241-1242.
5.Sinha A, Sazawal S, Kumar R et al. Typhoid fever in children aged less than 5 years. Lancet 1999; 354 : 734-737.
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