J Int Med Res (1979) 7, 247
Comparative Clinical Trial of Amoxycillin and Chloramphenicol in the Treatment of Typhoid in Adults C U Abengowe, MA, FRCP, FWACP, DCH, Consultant Physician, Department ofMedicine, Ahmadu Bello University Hospital, Kaduna, Nigeria A randomized clinical trial in sixty-two adult patients sufferingfrom typhoid fever, proved by blood and marrow culture, showed that amoxycillin in a dosage schedule of 1 g 8-hourly orally for fourteen days was better than chloramphenicol with regard to clinical and temperature response and in respect ofcarriers and relapse rates. One patient developed a hypersensitivity reaction to amoxycillin which cleared on withdrawal of the drug. Success was achieved in 90% of cases. These findings lend very strong support to the value of amoxycillin as a superior alternative to chloramphenicol in the treatment oftyphoidfever.
Introduction
Typhoid fever is one of the commonest causes of illness presenting as pyrexia of unknown origin (PUO) in the Ahmadu Bello University Teaching Hospital (ABUTH), Kaduna in Nigeria. Chloramphenicol has for a long time been regarded as the drug par excellence for the treatment of typhoid fever and paratyphi A infections and has reduced the mortality of typhoid fever from 10% to less than 1%, complications being less severe and less frequent (Manriques et al 1965). Therapeutic failure with chloramphenicol in typhoid is rare, but there is evidence that resistant strains of Salmonella typhi are beginning to appear in certain parts of the world, particularly Central America (Calderon 1974) and Vietnam (Butler et aI1973). Although chloramphenicol has the slight disadvantage that it may cause bone marrow aplasia, ironically its clinical effectiveness, reliable absorption orally and comparatively low cost make it particularly suitable for widespread and often
indiscriminate use in developing countries. In these countries febrile, gastro-intestinal and respiratory infections are common and the poverty and lack of adequate health facilities encourage the greater and unsupervised use of low-cost drugs, thus favouring the emergence of resistant bacterial strains. Many authors have reported a high rate of relapse in patients treated with chloramphenicol (Christie 1974, Watson 1957) and in South Africa the response of patients to chloramphenicol has been found to be not as good as formerly by Scragg (1976). It has also been suggested that a considerable number of chloramphenicol-treated patients may become temporary or permanent carriers of S.typhi (Jersild et al 1969). Trimethoprimsulphamethoxazole has generally been shown to be a good alternative to chloramphenicol (Uwaydah, Batossian & Balabanian 1975) although in one paediatric study it was bacteriologically inferior (Scragg & Rubidge 1971). Also, possible haematological
0300-0605/79/030247-06 $02·00
© Cambridge Medical Publications Limited
248
The Journal ofInternational Medical Research
idiosyncracies must be considered. All these factors emphasize the need for an alternative drug for the treatment of typhoid fever. Amoxycillin is a semi-synthetic penicillin with a chemical structure similar to that of ampicillin but with greatly enhanced oral absorption and a more rapid bactericidal action (Rolinson, MacDonald & Wilson 1977). Scragg compared amoxycillin and chloramphenicol in a randomized trial in 200 children with typhoid and found amoxycillin therapeutically superior to chloramphenicol (Scragg 1976), and comparable results to chloramphenicol have been reported in adult patients (Pillay, Adams & North-Coombes 1975, Afifi, Adnan & Garf 1976). In spite of the encouraging reports already mentioned of success in treating typhoid fever with amoxycillin it was felt that there was a need for a clinical trial to be undertaken comparing the effectiveness of this drug with chloramphenicol in typhoid in West Africa.
found to have blood and/or marrow cultures positive for S.typhi were entered into the trial. Altogether sixty-two culture-positive patients entered the trial (Table 1), thirty being treated with amoxycillin 1 g every 8 hours and thirtytwo with chloramphenicol 750 mg every 6 hours, both drugs being given by mouth for fourteen days.
Patients and Methods Patients Seventy-three African patients of both sexes were initially admitted to the medical wards of ABUTH for the study on a clinical diagnosis of typhoid fever and were then randomly assigned to treatment with either amoxycillin or chloramphenicol. On admission and before specific therapy was started (often within 24 hours of admission) blood, marrow, urine and stool samples were obtained from all patients for culture and those patients subsequently
Investigations Blood, stool and urine cultures were obtained on admission and after five, ten and fifteen days; marrow cultures were done at the beginning and end of treatment only. Blood was also taken for haemoglobin, platelets and white cell count and differential before treatment and after five, ten and fifteen days. Haemoglobin genotype, blood group and blood for malaria parasites were examined on admission, and G-6- P-D enzyme estimation at admission and after fifteen days. Serum electrolytes, blood urea, liver function tests (alkaline phosphatase, transaminases, serum bilirubin and serum cholesterol) and Widal agglutination testing were also carried out. Patients had chest X-ray and ECG on admission, and follow-up stools and urine cultures were taken for up to three months or longer if indicated. All organisms were assessed for sensitivity by antibiotic discs c o n t a i n i n g either amoxycillin or chloramphenicol. A rectal snip for histological examination was also taken in cases where stool examination was negative for S.mansoni or S.haematobium. Any side-effects from drug therapy were inquired for daily and noted.
Table 1 Age, sex and duration of illness in typhoid patients studied beforeadmission Duration ofillness before admission Sex
No. of patients
M
F
Age range (in years)
Mean age (in years)
Range (days)
Mean (days)
Amoxycillin
30
13
17
16-56
20·6
1-29
9·3
Chloramphenicol
32
14
18
16-65
22·3
I-3D
9·3
249
C U Abengowe
Results
Clinical response as judged by general welIbeing, relief of toxaemia and return of appetite was good and preceded temperature response by 2-3 days. The majority of patients (fortyone out of sixty-two) showed a remarkable improvement over 72-96 hours. There was a satisfactory response within five days in twenty-seven patients (90%) of the amoxycillin group and in twenty-four patients (75%) of the chloramphenicol group, the difference being statisticaIly significant (p < 0·001). Clinical response could not be correlated with the severity of illness nor with the length of history before admission. Temperature response is shown in Table 2. Sixty per cent of patients in each group had an initial high fever (39°C). The number of days taken for the temperature to return to normal was significantly longer in the chloramphenicol group than in the amoxyciIIin-treated group (p < 0·00 I). Interestingly, in the three patients
with S.mansoni in their stools, temperature returned to normal by crisis. Three patients treated with amoxycillin and nine patients treated with chloramphenicol had persistent fever throughout the course of treatment. These twelve patients (19·4%) accounted for the cases with complications in the trial and are summarized together with the one relapse and convalescent carrier occurring in the chloramphenicol-treated group in Table 3. Laboratory findings Blood culture was negative by the fifteenth day in twenty-eight (93·3%) of the amoxyciIIin group and twenty-two (68·7%) of the chloramphenicol group showing a significant difference (p < 0·001). S.typhi was recovered from one patient in the chloramphenicoltreated group at 7 and 21 days and treatment was changed to amoxyciIIin with a good response. There were four convalescent
Table 2 Response to treatment with amoxycillin and chloramphenicol of the two groups of patients with typhoid in terms of temperature response
Time taken for return to normal temperature (37 to 37·5°C) Treatment
Range (days)
Mean (days)
No return offever
Amoxycillin
2-14
6·9
27 patients (90·0%)
Chloramphenicol
3-15
8·0
24 patients (75·0%)
Table 3 Complications
Complications
Amoxycillin
Chloramphenicol
Fulminating toxaemia (shock) Relapse Convalescent carrier Peritonitis and GI haemorrhage Meningitis (acute) Lobar pneumonia Psychosis Deaths
None None None 1 I 1 I None
1 I 4 3 None 1 2 None
250
The Journal ofInternational Medical Research
carriers (patients excreting S. typhi) in the chloramphenicol group; all four were successfully treated with amoxycillin 1 g 8hourly for fourteen days. S.typhi isolated from all patients on admission, from the relapsed case and from the four carriers, were sensitive to both antibiotics. Schistosome ova were seen at microscopy in stool or rectal snip samples in three patients on amoxycillin and in four patients on chloramphenicol. Ova were still present in six patients at Day 15. These patients were treated with niridazole immediately after typhoid treatment. Agglutination tests (Widal) were significantly raised (> 1/350) on admission, or became rapidly so shortly afterwards in fortythree patients (70%) and also positive for paratyphi A in seven patients (11%). On admission, anaemia of less than 10 g/IOO ml was present in 1% of patients in each group. The haemoglobin did not drop more than 2 g/100 ml and tended to fall more in the chloramphenicol group. Leucocyte counts ranged from 2300-3600/mm 3 with a mean of 2500/mm 3 in both groups. An interesting feature was the presence of a disproportionate eosinopenia in 70% which disappeared as the patient recovered (Africans often have a raised eosinophil count because of chronic parasitization since childhood). Moderate thrombocytopenia was present in three patients of each group and severe thrombocytopenia in one patient of each group. Five patients were jaundiced before treatment and had slightly raised serum unconjugated bilirubin and transaminase levels. Reticulocyte counts were raised indicating haemolysis and all five patients had G-6-P-D deficiency (three in the amoxycillin and two in the chloramphenicol group). Raised transaminases were seen in 66% of both groups, all returning to normal with treatment. Raised blood ureas were seen in twenty patients but all normalized. with rehydration. Urine analysis was non-contributory.
addition but after six days of treatment he was still febrile and was changed to amoxycillin, following which, defervescence occurred within 48 hours. One patient treated with amoxycillin and three treated with chloramphenicol remained ill and febrile, developing definite abdominal signs compatible with peritonitis and/or intestinal haemorrhage on the 7th-10th day of treatment. All had laparotomy - three treated with chloramphenicol had perforation with a leak and one treated with amoxycillin had intestinal haemorrhage. Two patients had lobar pneumonia (one in each treatment goup) and one patient in the amoxycillin group had meningitis. Psychosis (typhoid madness) occurred in one patient receiving amoxycillin 24 hours after admission (Day 2). Two patients receiving chloramphenicol became confused three and four days respectively after treatment had been started, one becoming so bad after seven days that his treatment was changed to amoxycillin with considerable improvement. One patient treated with chloramphenicol relapsed with reisolation of S.typhi from blood cultures on the 21st day of treatment. He responded well to amoxycillin 1 g 8-hourly for fourteen days. Four patients became convalescent carriers; all had been treated with chloramphenicol. Post-treatment stools were positive for S.typhi in two patients, urine culture positive in one and both urine and stool cultures positive in one. These patients were similarly successfully treated with a full course of amoxycillin.
Complications Altogether sixteen patients had complications (Table 3). One patient in the chloramphenicol group was admitted in a state of shock with high fever and fulminating toxaemia. Parenteral hydrocortisone was given in
Discussion The treatment groups in this study were comparable with regard to age, sex and length of history before admission. All patients in the study had either positive blood or marrow cultures.
Adverse reactions One patient developed a maculoerythematous rash on her body after eight days of amoxycillin therapy and although not distressed by it was changed to chloramphenicol with consequent improvement. Two patients developed transient diarrhoea during the first week of amoxycillin treatment, and four patients complained of a bad taste in the mouth and noisy abdomen during chloramphenicol therapy.
C U Abengowe
The finding of a negative blood culture is a frequent occurrence since the patient may have had antibiotics already prescribed by the referring doctor or may have given himself antibiotics before admission, since antibiotic abuse in Nigeria, as in many developing countries, is a common problem. Bone marrow cultures were always taken in this study as in our experience proven cases of typhoid invariably have a positive marrow culture when the initial blood culture is negative. Patients presenting with complications were not excluded from the trial because it was felt that the effectiveness of the trial drug in a developing country should be assessed in complicated as well as uncomplicated cases in order that its full worth might be evaluated. Clinical and temperature responses were found to be significantly better with amoxycillin than with chloramphenicol. The trial revealed a high cure rate of 90% following amoxycillin, compared with 75% in the chloramphenicol group. There were no relapses or carriers in the amoxycillin-treated group whereas there was one relapse in the chloramphenicol group, four convalescent carriers, one psychotic and one fulminating toxaemic patient, all of whom failed to recover with chloramphenicol but did well when re-treated with amoxycillin. The complications observed developed early in the course of treatment (2-3 days) in the chloramphenicol group and so it would appear that chloramphenicol was slower in controlling the infection than amoxycillin in the early days of the illness, thus complications occurred somewhat more frequently in the chloramphenicol group. The differences however were small and not enough to cause a significant bias in the results. All Styphi isolated during the trial were sensitive to both amoxycillin and chloramphenicol. Despite the comparatively high dose schedule of amoxycillin it was well tolerated and there were no serious side-effects. This high dose probably contributed greatly to the rapid clinical response, high cure rate, lack of relapse and absence of early carrier cases obtained in this study. The essentially bacteriostatic mode of action of chloramphenicol possibly did not help the drug much in a comparative trial with a good bactericidal competitor.
251 Successful treatment of typhoid carriers has previously been reported with both amoxycillin (Kosmidis et at 1972, Miinnich et at 1974) and trimethoprim-sulphamethoxazole (Geddes, Pugh & Nye 1975), and comparative trials between amoxycillin and trimethoprimsulphamethoxazole in the therapy of typhoid fever have shown both drugs to be effective and of comparable value in the treatment of chloramphenicol-resistant infections (Gilman et at 1975). In view of the greater efficacy of amoxycillin compared to chloramphenicol found in this trial, it is considered fair comment to suggest that amoxycillin may well become the drug of choice in the treatment of typhoid fever, especially in patients with haematological idiosyncrasies due to chloramphenicol or sulphonamides. However, in developing countries where money is scarce, amoxycillin should be reserved for the treatment of fulminating cases or those with severe complications. Acknowledgement I am grateful to my clinical and laboratory colleagues for their co-operation and to the Medical Department of Beecham International Division for supplies of Amoxil and advice on the conduct of the study.
REFERENCES Afifi A M, Adnan M & EI Garf A A (1976) Amoxycillin in treatment of typhoid fever in patients with haematological contraindications to chloramphenicol. British Medical Journal 2, 1033 Butler T, Linh N N, Arnold K & Pollack M (1973) Chloramphenicol-resistant typhoid fever in Vietnam associated with R factor. Lancet 2, 983 Calderon E (1974) Amoxycillin in the treatment of typhoid fever due to chloramphenicol resistant Salmonella typhi. The Journal ofInfectious Diseases 129, Suppl. 219 Christie A B (1974) Infectious Diseases: Epidemiology & Clinical Practice. Churchill Livingstone, London Geddes A M, Pugh N R & Nye F J (1975) Treatment and follow-up studies with cotrimoxazole in enteric fever and in typhoid carriers. Journal ofAntimicrobial Chemotherapy 1,51 GDman R H, Tenninel M, Levine M M, HemandezMendoza P & Hornick R B (1975) Comparison of trimethoprim-sulphamethoxazole and amoxycillin in therapy of chloramphenicol-resistant and chloramphenicol-sensitive typhoid fever. Journal of Infectious Diseases 132,630
252
The Journal of International Medical Research
JerslJd T, Neukirch E, Raun J, Riverts Eriksen K & TuUnuis S (1969) Antibiotic Medicine 6,292 Kosmldis J, Williams J D, Andrews J & Goodall J A D (1972) Amoxycillin - Pharmacology, bacteriology and clinical studies. British Journal of Clinical Practice 26, 341 Manrlques L, Salcedo M, Borgono J M, Marzullo E, Kraijevic R, Parades L & Valdivieso R (1965) Clinical trials with ampicillin in typhoid fever and paratyphoid A. British Medical Journal 2, 152 Miinnicb D, Bekesi S, Lakatos M & Bardovlcs E (1974) Treatment of typhoid carriers with amoxycillin and in combination with probenecid. Chemotherapy 20, 29 Pillay N, Adams E B & North-Coombes D (1975) Comparative trial of amoxycillin and chloramphenicol in treatment of typhoid fever in adults. Lancet 2,333
Rolinson G N, MacDonald A D & Wilson A A (1977) Bactericidal action of fJ-lactamase antibiotics on Escheria coil with particular reference to ampicillin and amoxycillin. Journal of Antimicrobial Chemotherapy 3, 541 Scragg J N & Rubidge C J (1971) Trimethoprim and sulphamethoxazole in typhoid in children. British Medical Journal 3, 738 ScraggJ N (1976) Further experience with amoxycillin in typhoid fever in children. British Medical Journal 2, 1031 Uwaydah M, Batossian R & Balabanian M (1975) Co-trimoxazole compared to chloramphenicol in the treatment of enteric fever. Scandinavian Journal of Infectious Disease 7,123 Watson K C (1957) The relapse state in typhoid fever treated with chloramphenicol. American Journal of Medicine and Hygiene 6, 72
Comparative Clinical Trial of Amoxycillin and Chloramphenicol in the Treatment of Typhoid in Adults C U Abengowe, MA, FRCP, FWACP, DCH, Consultant Physician, Department ofMedicine, Ahmadu Bello University Hospital, Kaduna, Nigeria A randomized clinical trial in sixty-two adult patients sufferingfrom typhoid fever, proved by blood and marrow culture, showed that amoxycillin in a dosage schedule of 1 g 8-hourly orally for fourteen days was better than chloramphenicol with regard to clinical and temperature response and in respect ofcarriers and relapse rates. One patient developed a hypersensitivity reaction to amoxycillin which cleared on withdrawal of the drug. Success was achieved in 90% of cases. These findings lend very strong support to the value of amoxycillin as a superior alternative to chloramphenicol in the treatment oftyphoidfever.
Introduction
Typhoid fever is one of the commonest causes of illness presenting as pyrexia of unknown origin (PUO) in the Ahmadu Bello University Teaching Hospital (ABUTH), Kaduna in Nigeria. Chloramphenicol has for a long time been regarded as the drug par excellence for the treatment of typhoid fever and paratyphi A infections and has reduced the mortality of typhoid fever from 10% to less than 1%, complications being less severe and less frequent (Manriques et al 1965). Therapeutic failure with chloramphenicol in typhoid is rare, but there is evidence that resistant strains of Salmonella typhi are beginning to appear in certain parts of the world, particularly Central America (Calderon 1974) and Vietnam (Butler et aI1973). Although chloramphenicol has the slight disadvantage that it may cause bone marrow aplasia, ironically its clinical effectiveness, reliable absorption orally and comparatively low cost make it particularly suitable for widespread and often
indiscriminate use in developing countries. In these countries febrile, gastro-intestinal and respiratory infections are common and the poverty and lack of adequate health facilities encourage the greater and unsupervised use of low-cost drugs, thus favouring the emergence of resistant bacterial strains. Many authors have reported a high rate of relapse in patients treated with chloramphenicol (Christie 1974, Watson 1957) and in South Africa the response of patients to chloramphenicol has been found to be not as good as formerly by Scragg (1976). It has also been suggested that a considerable number of chloramphenicol-treated patients may become temporary or permanent carriers of S.typhi (Jersild et al 1969). Trimethoprimsulphamethoxazole has generally been shown to be a good alternative to chloramphenicol (Uwaydah, Batossian & Balabanian 1975) although in one paediatric study it was bacteriologically inferior (Scragg & Rubidge 1971). Also, possible haematological
0300-0605/79/030247-06 $02·00
© Cambridge Medical Publications Limited
248
The Journal ofInternational Medical Research
idiosyncracies must be considered. All these factors emphasize the need for an alternative drug for the treatment of typhoid fever. Amoxycillin is a semi-synthetic penicillin with a chemical structure similar to that of ampicillin but with greatly enhanced oral absorption and a more rapid bactericidal action (Rolinson, MacDonald & Wilson 1977). Scragg compared amoxycillin and chloramphenicol in a randomized trial in 200 children with typhoid and found amoxycillin therapeutically superior to chloramphenicol (Scragg 1976), and comparable results to chloramphenicol have been reported in adult patients (Pillay, Adams & North-Coombes 1975, Afifi, Adnan & Garf 1976). In spite of the encouraging reports already mentioned of success in treating typhoid fever with amoxycillin it was felt that there was a need for a clinical trial to be undertaken comparing the effectiveness of this drug with chloramphenicol in typhoid in West Africa.
found to have blood and/or marrow cultures positive for S.typhi were entered into the trial. Altogether sixty-two culture-positive patients entered the trial (Table 1), thirty being treated with amoxycillin 1 g every 8 hours and thirtytwo with chloramphenicol 750 mg every 6 hours, both drugs being given by mouth for fourteen days.
Patients and Methods Patients Seventy-three African patients of both sexes were initially admitted to the medical wards of ABUTH for the study on a clinical diagnosis of typhoid fever and were then randomly assigned to treatment with either amoxycillin or chloramphenicol. On admission and before specific therapy was started (often within 24 hours of admission) blood, marrow, urine and stool samples were obtained from all patients for culture and those patients subsequently
Investigations Blood, stool and urine cultures were obtained on admission and after five, ten and fifteen days; marrow cultures were done at the beginning and end of treatment only. Blood was also taken for haemoglobin, platelets and white cell count and differential before treatment and after five, ten and fifteen days. Haemoglobin genotype, blood group and blood for malaria parasites were examined on admission, and G-6- P-D enzyme estimation at admission and after fifteen days. Serum electrolytes, blood urea, liver function tests (alkaline phosphatase, transaminases, serum bilirubin and serum cholesterol) and Widal agglutination testing were also carried out. Patients had chest X-ray and ECG on admission, and follow-up stools and urine cultures were taken for up to three months or longer if indicated. All organisms were assessed for sensitivity by antibiotic discs c o n t a i n i n g either amoxycillin or chloramphenicol. A rectal snip for histological examination was also taken in cases where stool examination was negative for S.mansoni or S.haematobium. Any side-effects from drug therapy were inquired for daily and noted.
Table 1 Age, sex and duration of illness in typhoid patients studied beforeadmission Duration ofillness before admission Sex
No. of patients
M
F
Age range (in years)
Mean age (in years)
Range (days)
Mean (days)
Amoxycillin
30
13
17
16-56
20·6
1-29
9·3
Chloramphenicol
32
14
18
16-65
22·3
I-3D
9·3
249
C U Abengowe
Results
Clinical response as judged by general welIbeing, relief of toxaemia and return of appetite was good and preceded temperature response by 2-3 days. The majority of patients (fortyone out of sixty-two) showed a remarkable improvement over 72-96 hours. There was a satisfactory response within five days in twenty-seven patients (90%) of the amoxycillin group and in twenty-four patients (75%) of the chloramphenicol group, the difference being statisticaIly significant (p < 0·001). Clinical response could not be correlated with the severity of illness nor with the length of history before admission. Temperature response is shown in Table 2. Sixty per cent of patients in each group had an initial high fever (39°C). The number of days taken for the temperature to return to normal was significantly longer in the chloramphenicol group than in the amoxyciIIin-treated group (p < 0·00 I). Interestingly, in the three patients
with S.mansoni in their stools, temperature returned to normal by crisis. Three patients treated with amoxycillin and nine patients treated with chloramphenicol had persistent fever throughout the course of treatment. These twelve patients (19·4%) accounted for the cases with complications in the trial and are summarized together with the one relapse and convalescent carrier occurring in the chloramphenicol-treated group in Table 3. Laboratory findings Blood culture was negative by the fifteenth day in twenty-eight (93·3%) of the amoxyciIIin group and twenty-two (68·7%) of the chloramphenicol group showing a significant difference (p < 0·001). S.typhi was recovered from one patient in the chloramphenicoltreated group at 7 and 21 days and treatment was changed to amoxyciIIin with a good response. There were four convalescent
Table 2 Response to treatment with amoxycillin and chloramphenicol of the two groups of patients with typhoid in terms of temperature response
Time taken for return to normal temperature (37 to 37·5°C) Treatment
Range (days)
Mean (days)
No return offever
Amoxycillin
2-14
6·9
27 patients (90·0%)
Chloramphenicol
3-15
8·0
24 patients (75·0%)
Table 3 Complications
Complications
Amoxycillin
Chloramphenicol
Fulminating toxaemia (shock) Relapse Convalescent carrier Peritonitis and GI haemorrhage Meningitis (acute) Lobar pneumonia Psychosis Deaths
None None None 1 I 1 I None
1 I 4 3 None 1 2 None
250
The Journal ofInternational Medical Research
carriers (patients excreting S. typhi) in the chloramphenicol group; all four were successfully treated with amoxycillin 1 g 8hourly for fourteen days. S.typhi isolated from all patients on admission, from the relapsed case and from the four carriers, were sensitive to both antibiotics. Schistosome ova were seen at microscopy in stool or rectal snip samples in three patients on amoxycillin and in four patients on chloramphenicol. Ova were still present in six patients at Day 15. These patients were treated with niridazole immediately after typhoid treatment. Agglutination tests (Widal) were significantly raised (> 1/350) on admission, or became rapidly so shortly afterwards in fortythree patients (70%) and also positive for paratyphi A in seven patients (11%). On admission, anaemia of less than 10 g/IOO ml was present in 1% of patients in each group. The haemoglobin did not drop more than 2 g/100 ml and tended to fall more in the chloramphenicol group. Leucocyte counts ranged from 2300-3600/mm 3 with a mean of 2500/mm 3 in both groups. An interesting feature was the presence of a disproportionate eosinopenia in 70% which disappeared as the patient recovered (Africans often have a raised eosinophil count because of chronic parasitization since childhood). Moderate thrombocytopenia was present in three patients of each group and severe thrombocytopenia in one patient of each group. Five patients were jaundiced before treatment and had slightly raised serum unconjugated bilirubin and transaminase levels. Reticulocyte counts were raised indicating haemolysis and all five patients had G-6-P-D deficiency (three in the amoxycillin and two in the chloramphenicol group). Raised transaminases were seen in 66% of both groups, all returning to normal with treatment. Raised blood ureas were seen in twenty patients but all normalized. with rehydration. Urine analysis was non-contributory.
addition but after six days of treatment he was still febrile and was changed to amoxycillin, following which, defervescence occurred within 48 hours. One patient treated with amoxycillin and three treated with chloramphenicol remained ill and febrile, developing definite abdominal signs compatible with peritonitis and/or intestinal haemorrhage on the 7th-10th day of treatment. All had laparotomy - three treated with chloramphenicol had perforation with a leak and one treated with amoxycillin had intestinal haemorrhage. Two patients had lobar pneumonia (one in each treatment goup) and one patient in the amoxycillin group had meningitis. Psychosis (typhoid madness) occurred in one patient receiving amoxycillin 24 hours after admission (Day 2). Two patients receiving chloramphenicol became confused three and four days respectively after treatment had been started, one becoming so bad after seven days that his treatment was changed to amoxycillin with considerable improvement. One patient treated with chloramphenicol relapsed with reisolation of S.typhi from blood cultures on the 21st day of treatment. He responded well to amoxycillin 1 g 8-hourly for fourteen days. Four patients became convalescent carriers; all had been treated with chloramphenicol. Post-treatment stools were positive for S.typhi in two patients, urine culture positive in one and both urine and stool cultures positive in one. These patients were similarly successfully treated with a full course of amoxycillin.
Complications Altogether sixteen patients had complications (Table 3). One patient in the chloramphenicol group was admitted in a state of shock with high fever and fulminating toxaemia. Parenteral hydrocortisone was given in
Discussion The treatment groups in this study were comparable with regard to age, sex and length of history before admission. All patients in the study had either positive blood or marrow cultures.
Adverse reactions One patient developed a maculoerythematous rash on her body after eight days of amoxycillin therapy and although not distressed by it was changed to chloramphenicol with consequent improvement. Two patients developed transient diarrhoea during the first week of amoxycillin treatment, and four patients complained of a bad taste in the mouth and noisy abdomen during chloramphenicol therapy.
C U Abengowe
The finding of a negative blood culture is a frequent occurrence since the patient may have had antibiotics already prescribed by the referring doctor or may have given himself antibiotics before admission, since antibiotic abuse in Nigeria, as in many developing countries, is a common problem. Bone marrow cultures were always taken in this study as in our experience proven cases of typhoid invariably have a positive marrow culture when the initial blood culture is negative. Patients presenting with complications were not excluded from the trial because it was felt that the effectiveness of the trial drug in a developing country should be assessed in complicated as well as uncomplicated cases in order that its full worth might be evaluated. Clinical and temperature responses were found to be significantly better with amoxycillin than with chloramphenicol. The trial revealed a high cure rate of 90% following amoxycillin, compared with 75% in the chloramphenicol group. There were no relapses or carriers in the amoxycillin-treated group whereas there was one relapse in the chloramphenicol group, four convalescent carriers, one psychotic and one fulminating toxaemic patient, all of whom failed to recover with chloramphenicol but did well when re-treated with amoxycillin. The complications observed developed early in the course of treatment (2-3 days) in the chloramphenicol group and so it would appear that chloramphenicol was slower in controlling the infection than amoxycillin in the early days of the illness, thus complications occurred somewhat more frequently in the chloramphenicol group. The differences however were small and not enough to cause a significant bias in the results. All Styphi isolated during the trial were sensitive to both amoxycillin and chloramphenicol. Despite the comparatively high dose schedule of amoxycillin it was well tolerated and there were no serious side-effects. This high dose probably contributed greatly to the rapid clinical response, high cure rate, lack of relapse and absence of early carrier cases obtained in this study. The essentially bacteriostatic mode of action of chloramphenicol possibly did not help the drug much in a comparative trial with a good bactericidal competitor.
251 Successful treatment of typhoid carriers has previously been reported with both amoxycillin (Kosmidis et at 1972, Miinnich et at 1974) and trimethoprim-sulphamethoxazole (Geddes, Pugh & Nye 1975), and comparative trials between amoxycillin and trimethoprimsulphamethoxazole in the therapy of typhoid fever have shown both drugs to be effective and of comparable value in the treatment of chloramphenicol-resistant infections (Gilman et at 1975). In view of the greater efficacy of amoxycillin compared to chloramphenicol found in this trial, it is considered fair comment to suggest that amoxycillin may well become the drug of choice in the treatment of typhoid fever, especially in patients with haematological idiosyncrasies due to chloramphenicol or sulphonamides. However, in developing countries where money is scarce, amoxycillin should be reserved for the treatment of fulminating cases or those with severe complications. Acknowledgement I am grateful to my clinical and laboratory colleagues for their co-operation and to the Medical Department of Beecham International Division for supplies of Amoxil and advice on the conduct of the study.
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