Trimethoprim-sulfamethoxazole in the treatment of gastrointestinal infections, including enteric fever and typhoid carriers AM.
Geddes, md
Summary: Forty-three patients suffering from typhoid fever, 11 from paratyphoid fever, six from bacillary dysentery caused by Shigella flexneri, and nine carriers of Salmonella typhi or S. paratyphi B, have been treated with trimethoprim-sulfamethoxazole compound. Fifty-one of the 54 patients who had typhoid fever or paratyphoid fever responded satisfactorily to treatment. Two patients with typhoid fever failed to respond and one died. In the patients with bacillary dysentery acute symptoms subsided rapidly within 24 hours of starting trimethoprim-sulfamethoxazole. Seven of the nine typhoid or paratyphoid carriers have been followed up after treatment and only one remains a fecal excretor of S. typhi. Five patients in the series developed a skin rash during therapy, one a macrocytic anemia and one reversible neutropenia. It is concluded that trimethoprim-sulfamethoxazole is an effective agent for the treatment of enteric fever, severe bacillary dysentery and typhoid carriers. Resume: Le trimethoprime-sulfamethoxazole dans le traitement des infections du tube digestif, dans la fidvre typho'fde et chez les porteurs d 'organismes typhoYdes Nous avons traite avec I'association trimethoprime-sulfamethoxazole (TMP-SMX) 43 malades souffrant de fievre typhoide, 11 de fievre paratyphoYde, 6 de dysenterie bacillaire relevant de Shigella flexneri et 9 porteurs de Salmonella typhi ou S. paratyphi B. Des 54 malades qui etaient atteints de fievre typhoTde ou paratyphoYde, 51 ont reagi au traitement de facon satisfaisante. Deux victimes de la fievre typhoTde n'ont pas reagi et un deux est decede. Dans les cas de dysenterie bacillaire aigue, les symptdmes ont disparu rapidement, dans les 24 heures qui ont suivi le debut du traitement au TMP-SMX. Apres le traitement nous avons suivi sept des neuf porteurs d'organismes typhoYdes ou paratyphoides; un seul continuait a excreter par les feces des souches de S. typhi. Dans I'ensemble de nos malades cinq ont presente une eruption cutanee pendant le traitement, un a souffert d'une anemie macrocytaire et un autre d'une neutropenie reversible. Nous pouvons done conclure que le TMP-SMX est un medicament efficace pour le traitement de la fidvre typhoide, de la dysenterie bacillaire severe et des porteurs de souches de S. typhi ou S. paratyphi B.
Reprint requests to: Dr. A.M. Geddes, Department of communicable and tropical diseases, East Birmingham Hospital, Birmingham, B9 5ST, England
The majority of uncomplicated gastrointestinal tract infections resolve spontaneously without chemotherapy.1 In certain infec¬ tions, such as cholera, antibiotics may reduce the duration of the acute illness, while in others, e.g. Salmonella infections, chemotherapy may merely prolong fecal carriage of the infect¬ ing organism.2 Bacillary dysentery in temperate climates is usually caused by Shigella sonnei and is a mild infection that does not normally require antibacterial therapy. Infections due to Sh. dysenteriae and Sh. flexneri, however, can be extremely incapacitating and may even terminate fatally, particularly in debilitated patients. Chemotherapy is therefore usually recom¬ mended for these infections. Noninvasive intestinal infections caused by Salmonella species respond to symptomatic measures but if there is associated septicemia, as in typhoid fever, chemotherapy is required. Persistent fecal or urinary excretors of S. typhi or paratyphi constitute a public health hazard, and chemotherapy is indicated in an attempt to eradicate the organism from stool or urine. The present paper records our experience with trimethoprimsulfamethoxazole (TMP-SMX) in the treatment of: (1) a small number of patients suffering from bacillary dysentery caused by Sh. flexneri; (2) a group of patients suffering from enteric fever; and (3) carriers of S. typhi and S. paratyphi B. Patients and methods
Bacillary dysentery Six patients suffering from bacillary dysentery caused by Sh. flexneri were selected for treatment with TMP-SMX. All were severely ill, toxic and dehydrated, requiring intravenous fluid replacement therapy. In one, a 6-year-old child, the infecting organism was cultured from blood and stool. TMP-SMX suspension was administered orally to four patients, but in two who were extremely ill, including the septicemic child, the agent was given intravenously for the first 48 hours. In all six patients treatment was continued for 5 days. Enteric fever Fifty-four patients suffering from enteric fever (43 with typhoid fever and 11 with paratyphoid fever) were selected for treatment with TMP-SMX. The diagnosis was confirmed by culture of S. typhi or S. paratyphi from venous blood. In eight patients who were either gravely ill or vomiting persistently (six with typhoid and two with paratyphoid fever), TMP-SMX was given for the first 48 to 72 hours by intravenous infusion and subsequently by mouth. The other 46 patients were treated throughout their illness with oral TMP-SMX, usually given in a dose of two tablets (each containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole) two or three times a day. All patients were treated for 14 days. After the termination of treatment the patients were observed CMA JOURNAL/JUNE 14, 1975/VOL. 112 35S
in hospital for at least 2 weeks, during which time six stool and urine specimens were collected for culture. After discharge from hospital all patients were followed up by members of the Public Health Service.
after discharge from hospital (Table I). To date, all remain well, with negative stool and urine cultures. Maculopapular rashes developed during treatment in 5 of the 54 patients; 1 had a reversible macrocytic anemia and 1 had transient neutropenia.
Carriers of S. typhi and S. paratyphi B Carriers There were nine patients in this group. Eight were persistent fecal excretors of S. typhi and one of S. paratyphi B. Six had radiologic evidence of gallbladder disease. TMP-SMX was given in a daily dose of four tablets. Four patients received the drug for 3 weeks, four for 4 weeks and one for 6 weeks. After the completion of therapy it proved possible to follow up seven of the nine carriers. Results Bacillary dysentery All six patients in this group, including the septicemic child, responded satisfactorily to trimethoprim-sulfamethoxazole therapy but three continued temporarily to excrete Sh. flexneri in stools for varying periods after treatment was discontinued. Fever and toxicity subsided within 24 hours of starting treatment in all patients but in four diarrhea persisted for a further 2 or 3 days. Enteric fever Two patients suffering from typhoid fever failed to respond to oral TMP-SMX and one died within 24 hours of starting treatment. One of the treatment failures had thoracic empyema and it is probable that the other, who could not speak English, either did not take the tablets or vomited them. The remaining 51 patients responded satisfactorily to therapy but three relapsed clinically within 21 days of stopping TMP-SMX and four others temporarily excreted S. typhi in stools after the discontinuation of treatment. Only one of the four, however, became a chronic fecal excretor. Twenty-nine patients with typhoid fever and six with paratyphoid fever were available for follow-up Table I-Duration of follow-up of 29 patients with typhoid fever and 6 with paratyphoid fever Number of patients Months
Typhoid fever
60 48 36 18 12 9 6 3 1
2 2 1 5 5 4 1 8 1
1 2 1
Total
29
6
Seven of the nine carriers have been followed up and only one continues to excrete S. typhi. Negative stools have been obtained from the other six patients, who have been observed for periods of 2, 5, 6, 24, 36 and 48 months respectively. Conclusions Trimethoprim-sulfamethoxazole is a valuable addition to the range of chemotherapeutic agents available for the treatment of certain gastrointestinal tract infections. Our study confirms the efficacy of this compound in severe bacillary dysentery, enteric fever and carriers of S. typhi and S. paratyphi B. The recent introduction of an intravenous preparation of TMP-SMX has considerably enhanced its usefulness in gastrointestinal tract infections in which oral therapy is often impractical. We consider that TMP-SMX is the drug of choice for bacillary dysentery caused by Sh. flexneri or Sh. dysenteriae. In infections caused by these organisms, as in cholera, chemotherapeutic agents may not immediately eradicate the infecting organism from the stool but do reduce the duration of the acute illness. TMP-SMX is probably as effective as chloramphenicol in typhoid and paratyphoid fever.3 Kamat,4 in 1970, claimed that it might be superior to chloramphenicol in typhoid fever but there is probably little difference between the two agents with regard to clinical response and relapse rates. In our study, however, only 1 of 54 patients became a persistent excretor of S. typhi, whereas up to 4% of patients suffering from typhoid fever who are treated with chloramphenicol become typhoid carriers. Chloramphenicol-resistant S. typhi strains are increasing in frequency5 and TMP-SMX appears to be effective in infections caused by these organisms.6 It is important to remember, however, that chloramphenicol-resistant Salmonella species are usually also resistant to sulfonamides. Our experience with trimethoprim-sulfamethoxazole in typhoid carriers, although limited, agrees with that of Pichler and his colleagues, who found the combination to be of considerable value in this condition.7
Paratyphoid fever
References 2
I. GEDDES AM: Enteric fever, salmonellosis and food poisoning. Br Med J 1:98, 1973 2. Effect of neomycin in non-invasive salmonella infections of the gastrointestinal tract. Joint project by members of the Association for the Study of Infectious Disease. Lance: 2:1159, 1970 3. GEDDES AM, GOODALL JAD: Chloramphenicol resistance in the typhoid bacillus. Br Med I 3:525, 1972 4. KAMAT SA: Evaluation of the therapeutic efficacy of trimethoprim-sulphamethoxazole in enteric fever. Br Med J 3: 320, 1970 5. ANDERSON ES, SMITH HR: Chloramphenicol resistance in the typhoid bacillus. Br Med 1 3: 329, 1972 6. LAMPE RM, MANSUWAN P. DUANGMANI C: Chloramphenicolresistant typhoid. Lancet 1: 623, 1974 7. PICHLER M, KNOTHE H, SPITZY KH, et al: Trimethoprim-Sul-
36S
CMA JOURNAL/JUNE 14, 1975/VOL. 112
famethoxazole, edited by FINLAND M, KASS EH, Chicago and London, U of Chicago Pr, 1973, p 311
Geddes, md
Summary: Forty-three patients suffering from typhoid fever, 11 from paratyphoid fever, six from bacillary dysentery caused by Shigella flexneri, and nine carriers of Salmonella typhi or S. paratyphi B, have been treated with trimethoprim-sulfamethoxazole compound. Fifty-one of the 54 patients who had typhoid fever or paratyphoid fever responded satisfactorily to treatment. Two patients with typhoid fever failed to respond and one died. In the patients with bacillary dysentery acute symptoms subsided rapidly within 24 hours of starting trimethoprim-sulfamethoxazole. Seven of the nine typhoid or paratyphoid carriers have been followed up after treatment and only one remains a fecal excretor of S. typhi. Five patients in the series developed a skin rash during therapy, one a macrocytic anemia and one reversible neutropenia. It is concluded that trimethoprim-sulfamethoxazole is an effective agent for the treatment of enteric fever, severe bacillary dysentery and typhoid carriers. Resume: Le trimethoprime-sulfamethoxazole dans le traitement des infections du tube digestif, dans la fidvre typho'fde et chez les porteurs d 'organismes typhoYdes Nous avons traite avec I'association trimethoprime-sulfamethoxazole (TMP-SMX) 43 malades souffrant de fievre typhoide, 11 de fievre paratyphoYde, 6 de dysenterie bacillaire relevant de Shigella flexneri et 9 porteurs de Salmonella typhi ou S. paratyphi B. Des 54 malades qui etaient atteints de fievre typhoTde ou paratyphoYde, 51 ont reagi au traitement de facon satisfaisante. Deux victimes de la fievre typhoTde n'ont pas reagi et un deux est decede. Dans les cas de dysenterie bacillaire aigue, les symptdmes ont disparu rapidement, dans les 24 heures qui ont suivi le debut du traitement au TMP-SMX. Apres le traitement nous avons suivi sept des neuf porteurs d'organismes typhoYdes ou paratyphoides; un seul continuait a excreter par les feces des souches de S. typhi. Dans I'ensemble de nos malades cinq ont presente une eruption cutanee pendant le traitement, un a souffert d'une anemie macrocytaire et un autre d'une neutropenie reversible. Nous pouvons done conclure que le TMP-SMX est un medicament efficace pour le traitement de la fidvre typhoide, de la dysenterie bacillaire severe et des porteurs de souches de S. typhi ou S. paratyphi B.
Reprint requests to: Dr. A.M. Geddes, Department of communicable and tropical diseases, East Birmingham Hospital, Birmingham, B9 5ST, England
The majority of uncomplicated gastrointestinal tract infections resolve spontaneously without chemotherapy.1 In certain infec¬ tions, such as cholera, antibiotics may reduce the duration of the acute illness, while in others, e.g. Salmonella infections, chemotherapy may merely prolong fecal carriage of the infect¬ ing organism.2 Bacillary dysentery in temperate climates is usually caused by Shigella sonnei and is a mild infection that does not normally require antibacterial therapy. Infections due to Sh. dysenteriae and Sh. flexneri, however, can be extremely incapacitating and may even terminate fatally, particularly in debilitated patients. Chemotherapy is therefore usually recom¬ mended for these infections. Noninvasive intestinal infections caused by Salmonella species respond to symptomatic measures but if there is associated septicemia, as in typhoid fever, chemotherapy is required. Persistent fecal or urinary excretors of S. typhi or paratyphi constitute a public health hazard, and chemotherapy is indicated in an attempt to eradicate the organism from stool or urine. The present paper records our experience with trimethoprimsulfamethoxazole (TMP-SMX) in the treatment of: (1) a small number of patients suffering from bacillary dysentery caused by Sh. flexneri; (2) a group of patients suffering from enteric fever; and (3) carriers of S. typhi and S. paratyphi B. Patients and methods
Bacillary dysentery Six patients suffering from bacillary dysentery caused by Sh. flexneri were selected for treatment with TMP-SMX. All were severely ill, toxic and dehydrated, requiring intravenous fluid replacement therapy. In one, a 6-year-old child, the infecting organism was cultured from blood and stool. TMP-SMX suspension was administered orally to four patients, but in two who were extremely ill, including the septicemic child, the agent was given intravenously for the first 48 hours. In all six patients treatment was continued for 5 days. Enteric fever Fifty-four patients suffering from enteric fever (43 with typhoid fever and 11 with paratyphoid fever) were selected for treatment with TMP-SMX. The diagnosis was confirmed by culture of S. typhi or S. paratyphi from venous blood. In eight patients who were either gravely ill or vomiting persistently (six with typhoid and two with paratyphoid fever), TMP-SMX was given for the first 48 to 72 hours by intravenous infusion and subsequently by mouth. The other 46 patients were treated throughout their illness with oral TMP-SMX, usually given in a dose of two tablets (each containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole) two or three times a day. All patients were treated for 14 days. After the termination of treatment the patients were observed CMA JOURNAL/JUNE 14, 1975/VOL. 112 35S
in hospital for at least 2 weeks, during which time six stool and urine specimens were collected for culture. After discharge from hospital all patients were followed up by members of the Public Health Service.
after discharge from hospital (Table I). To date, all remain well, with negative stool and urine cultures. Maculopapular rashes developed during treatment in 5 of the 54 patients; 1 had a reversible macrocytic anemia and 1 had transient neutropenia.
Carriers of S. typhi and S. paratyphi B Carriers There were nine patients in this group. Eight were persistent fecal excretors of S. typhi and one of S. paratyphi B. Six had radiologic evidence of gallbladder disease. TMP-SMX was given in a daily dose of four tablets. Four patients received the drug for 3 weeks, four for 4 weeks and one for 6 weeks. After the completion of therapy it proved possible to follow up seven of the nine carriers. Results Bacillary dysentery All six patients in this group, including the septicemic child, responded satisfactorily to trimethoprim-sulfamethoxazole therapy but three continued temporarily to excrete Sh. flexneri in stools for varying periods after treatment was discontinued. Fever and toxicity subsided within 24 hours of starting treatment in all patients but in four diarrhea persisted for a further 2 or 3 days. Enteric fever Two patients suffering from typhoid fever failed to respond to oral TMP-SMX and one died within 24 hours of starting treatment. One of the treatment failures had thoracic empyema and it is probable that the other, who could not speak English, either did not take the tablets or vomited them. The remaining 51 patients responded satisfactorily to therapy but three relapsed clinically within 21 days of stopping TMP-SMX and four others temporarily excreted S. typhi in stools after the discontinuation of treatment. Only one of the four, however, became a chronic fecal excretor. Twenty-nine patients with typhoid fever and six with paratyphoid fever were available for follow-up Table I-Duration of follow-up of 29 patients with typhoid fever and 6 with paratyphoid fever Number of patients Months
Typhoid fever
60 48 36 18 12 9 6 3 1
2 2 1 5 5 4 1 8 1
1 2 1
Total
29
6
Seven of the nine carriers have been followed up and only one continues to excrete S. typhi. Negative stools have been obtained from the other six patients, who have been observed for periods of 2, 5, 6, 24, 36 and 48 months respectively. Conclusions Trimethoprim-sulfamethoxazole is a valuable addition to the range of chemotherapeutic agents available for the treatment of certain gastrointestinal tract infections. Our study confirms the efficacy of this compound in severe bacillary dysentery, enteric fever and carriers of S. typhi and S. paratyphi B. The recent introduction of an intravenous preparation of TMP-SMX has considerably enhanced its usefulness in gastrointestinal tract infections in which oral therapy is often impractical. We consider that TMP-SMX is the drug of choice for bacillary dysentery caused by Sh. flexneri or Sh. dysenteriae. In infections caused by these organisms, as in cholera, chemotherapeutic agents may not immediately eradicate the infecting organism from the stool but do reduce the duration of the acute illness. TMP-SMX is probably as effective as chloramphenicol in typhoid and paratyphoid fever.3 Kamat,4 in 1970, claimed that it might be superior to chloramphenicol in typhoid fever but there is probably little difference between the two agents with regard to clinical response and relapse rates. In our study, however, only 1 of 54 patients became a persistent excretor of S. typhi, whereas up to 4% of patients suffering from typhoid fever who are treated with chloramphenicol become typhoid carriers. Chloramphenicol-resistant S. typhi strains are increasing in frequency5 and TMP-SMX appears to be effective in infections caused by these organisms.6 It is important to remember, however, that chloramphenicol-resistant Salmonella species are usually also resistant to sulfonamides. Our experience with trimethoprim-sulfamethoxazole in typhoid carriers, although limited, agrees with that of Pichler and his colleagues, who found the combination to be of considerable value in this condition.7
Paratyphoid fever
References 2
I. GEDDES AM: Enteric fever, salmonellosis and food poisoning. Br Med J 1:98, 1973 2. Effect of neomycin in non-invasive salmonella infections of the gastrointestinal tract. Joint project by members of the Association for the Study of Infectious Disease. Lance: 2:1159, 1970 3. GEDDES AM, GOODALL JAD: Chloramphenicol resistance in the typhoid bacillus. Br Med I 3:525, 1972 4. KAMAT SA: Evaluation of the therapeutic efficacy of trimethoprim-sulphamethoxazole in enteric fever. Br Med J 3: 320, 1970 5. ANDERSON ES, SMITH HR: Chloramphenicol resistance in the typhoid bacillus. Br Med 1 3: 329, 1972 6. LAMPE RM, MANSUWAN P. DUANGMANI C: Chloramphenicolresistant typhoid. Lancet 1: 623, 1974 7. PICHLER M, KNOTHE H, SPITZY KH, et al: Trimethoprim-Sul-
36S
CMA JOURNAL/JUNE 14, 1975/VOL. 112
famethoxazole, edited by FINLAND M, KASS EH, Chicago and London, U of Chicago Pr, 1973, p 311
