Typhoid fever:, treatment failure and multiple relapses with trimethoprim- sulfamethoxazole and chioramphenicol therapy D. PORTNOY, MD; S. SEAH, MD, FRCP[C] Chioramphenicol, ampicillin and tri- could not be excluded. The antibiotic methoprim-sulfamethoxazole are the was discontinued and treatment with antibiotics most frequently used in chloroquine initiated. the treatment of typhoid fever. AlTwo days later the patient had a though treatment failure and relapse sudden episode of shaking chills that can occur with all three antibiotics, lasted 1 hour and fever (temperature multiple relapses are uncommon. We 400C). On her own she began taking report a case of typhoid fever that the trimethoprim-sulfamethoxazole relapsed after inadequate therapy again, in the same dosage, but in with trimethoprim-sulfamethoxazole, spite of 8 days of therapy her tempefailed to respond to treatment with rature continued to spike daily to the same antibiotic and then relapsed 400C. She was therefore admitted to after treatment with chloramphenicol, hospital. even though the organism remained At the time of admission the pasensitive in vitro to both drugs. Al- tient complained of fatigue and myalthough relapses commonly occur gia but was in no acute distress. Her within 2 weeks after treatment, in temperature was 38 0C, her blood our patient there was a 6-week inter- pressure 110/70 mm Hg, her pulse rate I 08/mm and her respiratory val between relapses. rate 28/mm. Results of the physical Case report examination were unremarkable. The One week after returning from a chest roentgenogram was normal, the trip to India a 31-year-old previously hemoglobin concentration 10.6 g/dl, healthy woman experienced a sudden the hematocrit 29.7%, th. leukocyte episode of shaking chills lasting 30 count 6.0 x 1 O'/l and the differential minutes and a headache that persisted count normal. The serum lactate defor 3 days. She was asymptomatic for hydrogenase concentration was 333 the next 3 days and subsequently had mIU/ml (normal range 'of values daily episodes of fever (temperature 100 to 125 mIU/ml) and the serum 400C), chills, headache, myalgia and glutamic oxaloacetic transaminase fatigue. She saw her doctor 10 days concentration was 95 mIU/ml (norafter the onset of the illness and re- mal range of values 8 to 40 mIU/ml). ceived a prescription for trimethoAlthough she had taken her mornprim (160 mg)-sulfamethoxazole ing dose of trimethoprim-sulfame(800 mg), to be taken orally twice a thoxazole five sets of blood cultures day. Three days later she was afeb- and a stool culture from samples obrile. tained that day grew Salmonella When the myalgia and fatigue per- typhi. The organism was found to be sisted despite 6 days of antibiotic sensitive to trimethoprim-sulfameththerapy she consulted another phy- oxazole, chloramphenicol and ampisician. Cultures of blood and stool cillin by disc sensitivity testing. The obtained that day and three blood Widal test was positive for Salmonella smears for malaria were negative, but group D at a dilution of 1:640. The since the patient was taking trime- identity of the organism was conthoprim-sulfamethoxazole her physi- firmed by the Laboratoire d'enterocian felt that a diagnosis of malaria bact.riologie, minist.re des Affaires sociales de Quebec at Ste-Anne-deFrom the department of microbiology Bellevue. Stool samples obtained and infectious diseases, Montreal General from members of the patient's family Hospital were negative on culture. Reprint requests to: Dr. D. Portnoy, Therapy with chloramphenicol, Department of microbiology and infectious diseases, Montreal General 500 mg taken orally every 6 hours, Hospital, 1650 Cedar Ave., Montreal, was started and the patient was afebPQ H3G 1A4 1264 CMA JOURNAL/MAY 19, 1979/VOL. 120
rile 5 days later. She completed a 14day course of chloramphenicol therapy, and subsequent blood and stool cultures were negative. Six weeks after the completion of therapy with chloramphenicol the patient's temperature spiked to 390C. Blood and stool cultures were positive for S. typhi; the organism was sensitive to trimethoprim-sulfamethoxazole, chloramphenicol and ampicillin. The patient was readmitted to hospital. Results of the physical examination and laboratory investigations, including oral cholecystography, were normal. The patient was retreated with chloramphenicol, 500 mg taken orally every 6 hours, and 5 days later she was afebrile. A 14-day course of chloramphenicol therapy was completed and the patient was sent home. She had remained well when last seen, 4 months after discharge.
Discussion The rate of relapse of untreated typhoid fever is between 5% and 20% .'.' Although antibiotic therapy has decreased the mortality of typhoid fever from 12% to 4%3 it has failed to decrease the relapse rate. Treatment failure and relapse occur more frequently with trimethoprimsulfamethoxazole than with chloramphenicol therapy.4" Our patient's initial response to trimethoprim-sulfamethoxazole therapy was rapid: she was afebrile 3 days after it was started, and cultures of blood and stool obtained on the sixth day of therapy were negative. Relapse occurred 2 days after this therapy was discontinued. Reinstitution of trimethoprim-sulfamethoxazole therapy was ineffective, although the duration of therapy was inadequate; the blood and stool cultures were still positive after 8 days of therapy in an adequate dosage,4 and the organism remained sensitive to the antibiotic. Scragg and Rubidge' noted that in 19 of 80 patients with typhoid fever receiving trimethoprim-sulfamethoxa-
zole the blood cultures remained positive for up to 19 days despite adequate therapy. Most of the organisms isolated from these cultures were sensitive to the antibiotic. Positive blood cultures persisted for the first 4 days in only I of 34 patients receiving chloramphenicol. Snyder and colleagues0 noted that in seven patients with typhoid fever that did not respond to trimethoprim-sulfamethoxazole the serum concentrations of the drug were adequate and failed to account for the lack of response to treatment, and that the correlation between disc and tube dilution methods of determining in vitro sensitivity of the organism was excellent. The interval between the end of the primary attack and relapse in patients with typhoid fever has varied from 1 to 70 days, with a peak of 8 to 10 days after completion of therapy,2 usually at a time of maximum antibody response.7 In our patient there was a 6-week interval between the first and the second relapse. A number of antibiotics, such as
tetracycline, cephalosporins, sulfonamides and aminoglycosides, may inhibit S. typhi in vitro but yield poor results or be ineffective in the management of patients with typhoid fever.1 Chioramphenicol, ampidillin and trimethoprim-sulfamethoxazole are the antibiotics most frequently used to treat typhoid fever, but treatment failure and relapse can occur with the use of these agents in spite of in vitro demonstration of the organism's sensitivity. Our report serves to emphasize that although sensitivity testing is helpful in choosing an appropriate antibiotic it does not guarantee a cure. The failure of response to trimethoprim-sulfamethoxazole therapy and the subsequent cure with chloramphenicol in our case support the findings by others4"'8 that chloramphenicol is the preferred drug for the treatment of typhoid fever. Since relapse may occur several weeks after "successful" treatment, one should consider extending the follow-up period to at least 2 months after the completion of therapy.
References 1. HORNICK P: Typhoid fever, in Infectious Diseases, 2nd ed, HOEPRICH PD (ed), Har-Row, New York, 1977,
p 562 2. CHIUsTIE AB: Typhoid and Paratyphoid Fevers. Infectious Diseases: Epidemiology and Clinical Practice, Livingstone, Edinburgh, 1969 3. WOODWARD TE, SMADEL JE: Management of typhoid fever and its complications. Ann intern Med 60: 144, 1964 4. SNYDER MJ, GONZALEZ 0, PALOMINO
C, et al: Comparative efficacy of chioramphenicol, ampicillin and cotrimoxazole in the treatment of typhoid fever. Lancet 2: 1155, 1976 5. SCRAGG JN, RUBIDGE CJ: Trimethoprim and sulfamethoxazole in typhoid fever in children. Br Med J 3: 738, 1971 6. SNYDER MJ, PERRONI J, GONZALEZ 0,
et al: Trimethoprim-sulfamethoxazole in the treatment of typhoid and paratyphoid fevers. J Infect Dis 128 (suppi): S734, 1973 7. WATSON KG: The relapse state in typhoid fever treated with chloramphenicol. Am J Trop Med 6: 72, 1957 8. PILLAY N, ADAMS EB, NORTHCOOMBES D: Comparative trials of amoxycillin and chloramphenicol in treatment of typhoid fever in adults. Lancet 2: 333, 1975
.QAE4*
(dL. LA BOURSE D'ETUDES OSLER 1980 Le Comit. de selection de Ia Bourse d'.tudes Osler offre une bourse annuelle pour Ia poursuite d'.tudes en vue d'am.liorer 'enseignement de Ia m6decine clinique. Date limite des demandes: le 31 octobre 1979. L'attributlon Un fonds est garde en fiducie par 'Association m.dicaIe canadienne, qui utilise un montant de $2000 en int6r.t pour attribuer une bourse chaque ann.e. Le candidat La bourse est accessible . tous les dipI6m.s des facult.s de m6decine r.cemment nomm.s . Un poste . Ia facuIt. de m.decine d'une universit. canadienne et d.sireux de pousser leurs .tudes par une p.riode de perfectionnement portant sur l'enseignement de Ia m6decine clinique. Pour de plus amples renseignements s'adresser au: Coordonnateur Consell do I'.ducation m6dlcaIe L'ASSOCIATION M.DICALE CANADIENNE C.P. 8650 Ottawa, Ontario, Canada KI G 0G8 CMA JOURNAL/MAY 19, 1979/VOL. 120 1265
rile 5 days later. She completed a 14day course of chloramphenicol therapy, and subsequent blood and stool cultures were negative. Six weeks after the completion of therapy with chloramphenicol the patient's temperature spiked to 390C. Blood and stool cultures were positive for S. typhi; the organism was sensitive to trimethoprim-sulfamethoxazole, chloramphenicol and ampicillin. The patient was readmitted to hospital. Results of the physical examination and laboratory investigations, including oral cholecystography, were normal. The patient was retreated with chloramphenicol, 500 mg taken orally every 6 hours, and 5 days later she was afebrile. A 14-day course of chloramphenicol therapy was completed and the patient was sent home. She had remained well when last seen, 4 months after discharge.
Discussion The rate of relapse of untreated typhoid fever is between 5% and 20% .'.' Although antibiotic therapy has decreased the mortality of typhoid fever from 12% to 4%3 it has failed to decrease the relapse rate. Treatment failure and relapse occur more frequently with trimethoprimsulfamethoxazole than with chloramphenicol therapy.4" Our patient's initial response to trimethoprim-sulfamethoxazole therapy was rapid: she was afebrile 3 days after it was started, and cultures of blood and stool obtained on the sixth day of therapy were negative. Relapse occurred 2 days after this therapy was discontinued. Reinstitution of trimethoprim-sulfamethoxazole therapy was ineffective, although the duration of therapy was inadequate; the blood and stool cultures were still positive after 8 days of therapy in an adequate dosage,4 and the organism remained sensitive to the antibiotic. Scragg and Rubidge' noted that in 19 of 80 patients with typhoid fever receiving trimethoprim-sulfamethoxa-
zole the blood cultures remained positive for up to 19 days despite adequate therapy. Most of the organisms isolated from these cultures were sensitive to the antibiotic. Positive blood cultures persisted for the first 4 days in only I of 34 patients receiving chloramphenicol. Snyder and colleagues0 noted that in seven patients with typhoid fever that did not respond to trimethoprim-sulfamethoxazole the serum concentrations of the drug were adequate and failed to account for the lack of response to treatment, and that the correlation between disc and tube dilution methods of determining in vitro sensitivity of the organism was excellent. The interval between the end of the primary attack and relapse in patients with typhoid fever has varied from 1 to 70 days, with a peak of 8 to 10 days after completion of therapy,2 usually at a time of maximum antibody response.7 In our patient there was a 6-week interval between the first and the second relapse. A number of antibiotics, such as
tetracycline, cephalosporins, sulfonamides and aminoglycosides, may inhibit S. typhi in vitro but yield poor results or be ineffective in the management of patients with typhoid fever.1 Chioramphenicol, ampidillin and trimethoprim-sulfamethoxazole are the antibiotics most frequently used to treat typhoid fever, but treatment failure and relapse can occur with the use of these agents in spite of in vitro demonstration of the organism's sensitivity. Our report serves to emphasize that although sensitivity testing is helpful in choosing an appropriate antibiotic it does not guarantee a cure. The failure of response to trimethoprim-sulfamethoxazole therapy and the subsequent cure with chloramphenicol in our case support the findings by others4"'8 that chloramphenicol is the preferred drug for the treatment of typhoid fever. Since relapse may occur several weeks after "successful" treatment, one should consider extending the follow-up period to at least 2 months after the completion of therapy.
References 1. HORNICK P: Typhoid fever, in Infectious Diseases, 2nd ed, HOEPRICH PD (ed), Har-Row, New York, 1977,
p 562 2. CHIUsTIE AB: Typhoid and Paratyphoid Fevers. Infectious Diseases: Epidemiology and Clinical Practice, Livingstone, Edinburgh, 1969 3. WOODWARD TE, SMADEL JE: Management of typhoid fever and its complications. Ann intern Med 60: 144, 1964 4. SNYDER MJ, GONZALEZ 0, PALOMINO
C, et al: Comparative efficacy of chioramphenicol, ampicillin and cotrimoxazole in the treatment of typhoid fever. Lancet 2: 1155, 1976 5. SCRAGG JN, RUBIDGE CJ: Trimethoprim and sulfamethoxazole in typhoid fever in children. Br Med J 3: 738, 1971 6. SNYDER MJ, PERRONI J, GONZALEZ 0,
et al: Trimethoprim-sulfamethoxazole in the treatment of typhoid and paratyphoid fevers. J Infect Dis 128 (suppi): S734, 1973 7. WATSON KG: The relapse state in typhoid fever treated with chloramphenicol. Am J Trop Med 6: 72, 1957 8. PILLAY N, ADAMS EB, NORTHCOOMBES D: Comparative trials of amoxycillin and chloramphenicol in treatment of typhoid fever in adults. Lancet 2: 333, 1975
.QAE4*
(dL. LA BOURSE D'ETUDES OSLER 1980 Le Comit. de selection de Ia Bourse d'.tudes Osler offre une bourse annuelle pour Ia poursuite d'.tudes en vue d'am.liorer 'enseignement de Ia m6decine clinique. Date limite des demandes: le 31 octobre 1979. L'attributlon Un fonds est garde en fiducie par 'Association m.dicaIe canadienne, qui utilise un montant de $2000 en int6r.t pour attribuer une bourse chaque ann.e. Le candidat La bourse est accessible . tous les dipI6m.s des facult.s de m6decine r.cemment nomm.s . Un poste . Ia facuIt. de m.decine d'une universit. canadienne et d.sireux de pousser leurs .tudes par une p.riode de perfectionnement portant sur l'enseignement de Ia m6decine clinique. Pour de plus amples renseignements s'adresser au: Coordonnateur Consell do I'.ducation m6dlcaIe L'ASSOCIATION M.DICALE CANADIENNE C.P. 8650 Ottawa, Ontario, Canada KI G 0G8 CMA JOURNAL/MAY 19, 1979/VOL. 120 1265
