Ciprofloxacin for Treatment of Severe TF in Children

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  Vol. 37, No. 5 NTIMICROBIAL AGENTS  ND CHEMOTHERAPY, May 1993, p. 1197-11990066-4804/93/051197-03 02.00/0 Ciprofloxacin for Treatment of Severe Typhoid Fever in Children P. DUTI'A,l* R. RASAILY, M. R. SAHA, U. MITRA, S. K. BHATTACHARYA,l M. K. BHATTACHARYA,l  ND M. LAHIRI2 National Institute of Cholera and EntericDiseases, P-33, C.L T. Road, Scheme-XM, Calcutta   700 010,1 and Dr. B. C. Roy Memorial Hospitalfor Children, Calcutta-700 054,2 India Received 30 October 1992/Accepted 24 February 1993 Eighteen children with bacteriologically confirmed severe typhoid fever were initially treated intravenously with ciprofloxacin  10 mg/kg of body weight per day). Clinical cure with eradication of multiresistant SalmoneUla typhi infection was observed in 17 patients (94.4 ; 95 confidence interval [CI], 84 to 100 ). Childrenregained normal consciousnesswithin an average of2days (95 CI, 1.8 to 2.2 days). The temperatures of the children returned to normal within 3.3 days (95 CI, 3.1 to 3.5 days). Complications were not observedduring the hospital stay ora 3-month follow-up period. Relapse and carrier state were also not encountered during the follow-up period. Typhoid fever continues to be a major health problem, especially in developing countries  9). It has been estimated that thecase fatalityrate from typhoid fever has reduced dramatically to less than 2 because oftheintroductionof chloramphenicol  21). However, the case fatality rate is still high among patients suffering from severetyphoid fever  8, 14). Intravenous administration of chloramphenicol with supportive measures is considered idealfor the prevention death in severely ill patients withtyphoid fever  10). Several workershave also recommended the useof corticosteroid alongwith chloramphenicol infusion to reduce themortality from severe typhoid fever  12, 18). The prevalence ofsevere typhoid fever caused by multi-drug-resistant strains of Sal- monella typhi has recently increased in Calcutta  2 . These circulating strains of S. typhi are highly susceptible to ciprofloxacin  19), a new synthetic fluoroquinolone with a broad spectrum of bactericidal activity and effectivetissue penetration  7 . Ciprofloxacin has also been used success- fully in the treatment of typhoid fever in children  20), despite controversyover its use in individuals in this age group  1 .   report hereour experience of treating life- threatening typhoid fever in children with intravenous cip-rofloxacin. Five hundredninety-two febrile patients with clinically suggestive typhoid fever who were admitted to the Dr.B.C. Roy Memorial Hospital for Children in Calcutta between February 1990 and January 1992 were screened for S. typhi. Typhoid fever was suspected in patients who had a sustained fever (>39°C) for 10 days or more but who did not have signs and symptoms suggesting other infections. Among the 592 patients, 33 had an abnormal state of consciousness or shock and were considered to have severe typhoid fever. Of these 33 patients with clinically suggestive severe typhoid fever, only 18 were positive for S. typhi by blood culture, and these18 patients met the entry criteria for inclusion into the study. An abnormal state of consciousness in patients with severe typhoid fever was defined asa condition in which the patient had one or more of the signs like delirium, obtundation, stupor, coma, or shock  12). Delirium was defined by mark- * Corresponding author. edly confused thinking or speech. An obtunded patient was one who appeared unconscious but when stimulated re- sponded appropriately to questions and commands. Stupor- ous patients were those who didnot respond verbally to any stimuli but who responded only to painful stimuli. Comatose patients were those who did not respond to any noxious cutaneous stimuli. Shock was considered to be present if the patient had a systolic blood pressureof <80 mm Hg and cold clammy skin with altered consciousness.   blood sample  5 ml) was collected aseptically from each patient and was inoculated intotryptic soybroth at the bedside of the patient for isolation of S. typhi by standardtechniques  22). Two milliliters of blood was also collected in a test tube for the Widal test, and sera were tested by the conventional agglutination method  6) with commercially available antigen (Entero test; Stangen Immunodiagnostic,Hydrabad, India). Antimicrobial susceptibilitytesting of the isolatedstrains of S. typhi was done by the Kirby Bauer disk diffusion method  3 . The MICs for the isolated strains of S. typhi were tested by the agar plate dilution method  13). Blood samples were also collected from these patients for other laboratory tests, including routine blood counts andbloodbiochemistry  e.g., sugar, urea, creatinine, serum sodium, potassium, chloride, and total bicarbonate). In- creased intracranial pressure was estimated by lumbar punc- ture and manometry. Funduscopic examination was also done to look for papilloedema.Cerebrospinal fluid was also tested for routineinvestigation. Patients who were clinically suspected of having severe typhoid fever  having an abnormal state of consciousness) were included in the study. All these patients had received two or more conventional drugs, either singly or in combi- nation, for treatment of their typhoid feverbefore inclusion into the study. Informed verbal consent and a complete history were obtained from the patients parents. Patients were weighed to the nearest 100 g.   thorough physical examination was performed, and treatment was initiated. Patients were followed up three times daily for the assess- ment of general condition, state of consciousness, and remissionof their fever to 37.5°C  axillary). Patients were also carefully observed for possible complications like gas- trointestinal bleeding, anemia requiring blood transfusion, 1197  ANTIMICROB. AGENTSCHEMOTHER. pneumonia  on thebasis of clinical examination), and intes- tinal perforation.Patients who had remission offever and whose state of consciousness became normal within 8 days of drug therapy and also who did not develop complications were discharged from thehospital on day 15. Remission of fever was considered when the maximum body temperature  axillary) was <37.5°C for 48h or more. Drug efficacy was judged primarily by the reduction in mortalityof the severely ill patients and secondarily by the patients clinical re- sponses, with particularattention given to the number of days of treatment required to make thepatients afebrile. At the time of discharge from the hospital, blood and stool sampleswere collected for isolation of S. typhi. Bacterio- logic cure was considered if blood and stool cultures were negative for S. typhi at the time of discharge. Parents were advised to bring their children to the hospital for follow-up every 15 days for 3 consecutivemonths. They were also advised to contact the investigators immediately if their children develop fever or anycomplication after discharge. At the time ofthe follow-upexaminations, blood and stool sampleswere also collected to screen for S. typhi. Routine blood counts, blood biochemistry, and examination of cere- brospinal fluid, including the estimation of increased intra- cranial pressure, were done at the time of discharge from the study. Routineblood counts and blood biochemistry were repeated at the time of the last follow-up examination. Lumbar puncture and manometry were done if patients had clinical evidence of increased intracranial pressure. We regarded relapse as the occurrence of fever and other symptoms of typhoid fever after an initial response to therapyand theisolation of S. typhi on blood culture. Patients who werefound to be excreting S. typhi during the follow-up period, after the completion oftherapy, were labelled as carriers. Allthe patients received ciprofloxacin at a dose of10 mg/kg of body weight per day in two divideddoses by intravenous infusion over 10min. When thepatients were able to take substances orally, therapy was switched to ciprofloxacin in tablet form at the same dosageregimen. Ciprofloxacin intravenously and orally) was given for a period of 14 or 7 days after the patient became afebrile. Intravenous fluid was administeredaccording to thepa- tient s body weight temperature,hydration status, clinical condition, and urinary output. Five percent glucose saline or Ringer's lactate were used. Sponging with tepid water and fanning wereneeded in children with a hightemperature(240°C).Convulsions were controlled with intravenous di- azepam. Oxygen was given by nasal catheter to dyspneic and cyanotic patients. Shock was treated only with intrave- nous fluid and/or blood transfusion. Eighteen children suffering from severetyphoid fever were treated intravenously with ciprofloxacin. They were positive for S. typhi by blood culture andhad a positive Widal test  antibody titer against S. typhi 0 antigen, 1:320or greater). All S. typhi strains isolated from the patients were susceptible to nalidixicacid, norfloxacin, ciprofloxacin, gen- tamicin, amikacin, and furazolidone but were resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethox- azole, and amoxicillin. The MICs of ampicillin were 800 to 1,600 ,ug/ml, those of chloramphenicol were 200 to 400 ,ug/ml, thoseof trimethoprim-sulfamethoxazole were > 1,600 ,ug/ml, and thoseof amoxicillin were 400 to 800 p,g/ml. Of these 18 children, 5 had delirium, 7 had delirium and obtundation, 4 had stupor, and 2 had shock. Detailed clinical and laboratory findings for these patients at the time of inclusion in the study are shown in Table 1. All the patients TABLE 1. Clinical and laboratory findings of the patients with severe typhoid fever at the timeof inclusion in the study Parameter Observed value Range Age  yr)a 6.4 ± 2.0 1.5-9.5 Body weight  kg)a15.3 ± 3.4 11-18.2 Days of illness 22.7 ± 13.1 10-62before inclusiona Axillary temp  OC a 39.9 ± 0.5 38.9-40.2 Clinical condition  no. of patients) Delirium 5 Delirium and 7 obtundation Stupor 4 Shock 2Hematological findingsa Total leukocyte  2.8 + 0.8) x 109  2.0-4.2) x 109 count/literPlateletcount/liter (110 + 10.5) x 109  80-180) x 109 Hemoglobin 1.0 ± 0.3 0.98-1.4  mmol/liter) Cerebrospinal fluid findingsa No. of cells/liter  0.003 + 0.001) x 109  0.002-0.006) x 109 Protein  mg/liter) 125 ± 8.0 100-186 Sugar  mmol/liter) 2.8 ± 0.62.3-3.6 a Values are means ± standard deviations. were severely ill withanabnormal state of consciousness. The mean age was 6.4 ± 2.0 years(standard deviation [SD]). The mean body weight was 15.3 ± 3.4 kg (SD). They suffered for a period of 22.7 ± 13.1 days(SD) before administration of ciprofloxacin. Cure was achieved in 17 patients (94.4 ; 95 confidence interval [CI], 84 to 100 ). Childrenregained normal consciousness withinan average 2 days (95 CI, 1.8 to 2.2 days). Their temperatures returned to normal within 3.3 days (95 CI, 3.1 to 3.5 days). Data were analyzed by using the SPSS PC+ software package to determine thecorrelation between the durationof illness before inclusion and theduration of fever andabnormal mentation followingthe initiation oftherapy. No significant correlation between thedurationof illness and durationof fever  0.15) andabnormal mentation (-0.19) were observed. Only one patient died after 24 h of ciprofloxacin administra- tion. This child was severely malnourished(body weight, <50 of the Harvard standardweight for age) and suffered for a prolonged period  62days). He was in shock at the timeof ciprofloxacin administration. All 17 children who were included in the study and survivedattended the hospital for reevaluation every 15 days for 3 months after discharge. S. typhi could not be isolated from stool or bloodsamples from these patients at the time ofdischargeorduringfollow-up. None had a relapseoffeveror complications such as arthropathy, metabolic acidosis, and increased intracranial pressure. They were not observed either clinically, by biochemical tests, or by lumbar puncture and manometry. The results ofthepresent study indicate that intravenous use of ciprofloxacin is beneficial in patients with severe typhoid fever. The cure rate was as high as 94 in the 1198 NOTES  NOTES 1199 present study. Chloramphenicol was the first drug shown to be effective therapy for typhoid fever and remains the drug of choice in many parts of the world. Chloramphenicol has also been used intravenously in patients withseveretyphoid fever; however, the cure rate could never havebeen as high as that obtained in the present study  5, 11). Corticosteroids have also been recommended by several workers for reduc- ing mortality in severely ill patients. Case fatality rate reductionsof 10 were observed bysome workers after the use ofintravenous chloramphenicoland corticosteroid  12). However, a recent study conducted in Papua New Guinea showed that themortality rate from severetyphoid fever was as high as 44 after the use of intravenous chloramphenicol and hydrocortisone  18). Broad-spectrum cephalosporins have also been evaluated clinically for the treatment ofsevere typhoid fever; the mortality rate was 16 17). The emergence of chloramphenicol-resistant strains of S. typhi has necessitated the useofother antimicrobial agents  2, 19). Recently, ciprofloxacin has successfully been used to treat typhoid fever in adults and children  4, 16,20). It has been documented that ciprofloxacin penetrates tissue well and that therapeutic concentrations canbe achieved in cerebrospinal fluid, even when there is no inflammation of the meninges  15). These results instigated us to use this drug to treat patients with severe typhoid fever who were deliri- ous, obtunded, stuporous, and in shock. These patients had an extremely poor prognosis and were at high risk of development of shock, coma, or death  12). Ciprofloxacin not only reduced the case fatality rate but also shortened the courseof illnessto a great extent. Patients regained their normalconsciousness within 2 daysandhad remission offeverwithin 3 days. We did notencounter any relapse or carrier state in our study population during the 3-month follow-up period. Several side effects of ciprofloxacin, in- cluding development of metabolic acidosis, occurrence of intracranial hypertension and development of arthralgia, havebeen reportedpreviously  1 , but these were not observed among the children in our study. On the basis of the results of this noncomparative study,ciprofloxacin is one of the drugs that can be used to treat multiply resistant, severe typhoid infections in children. We acknowledge the superintendent and visiting physicians ofDr. B.C. Roy Memorial Hospital for Children,Calcutta, for allowing us to study patients admitted to the hospital. REFERENCES 1. Adam, D. 1989. Use of quinolones in pediatricpatients. Rev. Infect. Dis. 2 Suppl.):S1113-S1116. 2. Anand, A. C., V. K. Kataria, W. Singh, and S. K. Chatterjee. 1990. Epidemic multiresistant enteric fever in Eastern India. Lancet i:352.  Letter.) 3. Bauer, A. W., W. M.M. Kirby, J. C. Sherris, and M. Turclk 1966.Antibiotic susceptibilitytesting by stadarized single disc method. Am. 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Typhoid fever, p. 1587-1589. In J. B. Wyngaarden and I. H. Smith, Jr.  ed.), Cecil text book ofmedicine, 17th ed. The W. B. Saunders Co., Philadelphia. 11. Gulati, P. D., S. N.Saxena, P. S. Gupta, andH. K. Chutani. 1968. Changing patterns of typhoid fever. Am. J. Med. 45:544- 548. 12. Hoffman, S. I., N. H. Punjabi, S. Kumala, A.Moechtar, S. P. Pulingsih, A. R. Rivai, R. C. Rockhill, T. E. Woodward, and A. A.Loedin. 1984. Reduction in mortality in chloramphenicol treated severe typhoid fever by high dosedexamethasone. N. Engl. J. Med. 310:82-88. 13. Jones,R. N., A. L. Barry, T. L. Garvan, and J. Washington II. 1985.Susceptibility tests. Microdilution and macrodilution brothprocedures, p. 972-977.InE. H. Lennette, A. Balows, W. J. Hausler, Jr., and H. J. Shadomy  ed.), Manual of clinical microbiology, 4th ed. American Society of Microbiology, Wash- ington, D.C. 14. Johnson, A. 0. K., and W. I. Aderele. 1981. Entericfever in childhood. J. Trop. Med. Hyg. 84:29-34. 15. McLain, J. B., J. 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