Drugs 15 (Suppl. 1): 23-25 (1978) © AD IS Press 1978
Session III: Amoebic Liver Abscess Chairman: Dr J. Y. Perez, Jr.
Treatment of Amoebic Liver Abscess with Tinidazole and Metronidazole R.C. Khokhani, A.D. Garud, K.P. Deodhar, S.8. Sureka, Manisha Kulkarni, and V.8. Damle Lokmanya Tilak Municipal Medical College and Hospital. and Gokuldas Tejpal Hospital. Bombay
Summary
20 patients with amoebic liver abscess. confirmed by aspiration of typical amoebic ·pus·. were treated in random order with either tinidazole or metronidazole in a dose of 2g once daily for 2 days. Clinical. radiological. and biochemical follow-up was done for 1 month. One patient. given metronidazole. absconded and 19 completed the trial. Complete recovery occurred in all 10 patients given tinidazole but in only 5 of the 9 given metronidazole (p = 0.05). Patients on tinidazole required repeat aspirations less frequently than those on metronidazole. Mild gastrointestinal Side-effects occurred in 1 patient on metronidazole but in none on tinidazole. From the present study. tinidazole appears to be a more effective. better tolerated drug with a more rapid therapeutic effect than metronidazole.
Tinidazole, a nitroimidazole compound, has a longer half~life than metronidazole and produces higher serum levels in humans following a 2g oral dose (Monro, 1974). We therefore thought that its therapeutic effect in liver abscess might be better than that of metronidazole. A clinical trial was carried out to test this possibility.
1. Patients and Methods 20 adult patients with amoebic liver abscess, confIrmed by aspiration of typical 'pus' from the liver,
were included in the trial. Patients who were moribund, had co-existing complications, or had received anti-amoebic treatment during the previous 4 weeks were excluded. The investigations carried out before treatment consisted of full blood count; ESR; urine analysis; stool examination; screening and x-ray of the chest; sigmoidoscopy; radio-isotope hepatic scan; liver function tests, viz. serum bilirubin, SOOT, SGPT, serum alkaline phosphatase; serum proteins with electrophoretic pattern, and prothrombin time; blood sugar; blood urea; and electrocardiogram. A diagnosticcum-therapeutic liver aspiration was carried out in all
24
Tinidazole and Metronidazole in Amoebic Liver Abscess
cases before commencing treatment. The pus was examined for amoebic trophozoites and cultured for secondary bacterial infection. If required, the aspiration was repeated every 5th day. In random order, the patients were given either tinidazole or metronidazole in a dose of 2g once daily on 2 consecutive days. Progress of the patients was assessed daily for the ftrst 10 days and then twice-weekly till the 30th day. Radiological and laboratory investigations were repeated on the 5th, 10th and 30th days. Side-effects were noted only if voluntarily reported by. the patients. Final evaluation of each case was done on the 30th day. The response to therapy was graded as 'complete recovery' if there was rapid regression of symptoms and signs and full recovery on the 30th day by clinical and radiological criteria; it was classifted as 'partial recovery' if there were residual symptoms and signs requiring further treatment on the 30th day.
Table I. Therapeutic response of amoebic liver abscess to treatment with tinidazole or metronidazole'
Response
Complete recovery Partial recovery
Tinidazole
Metronidazole
(n = 10)
(n = 9)
10
5
o
4
1 Difference significant (p = 0.05) by Fisher's test.
Table II. Number of liver aspirations required in two treatment groups
No. of aspirations
2
Tinidazole
Metronidazole
(n = 10)
(n = 9)
no. of pats.
no. of pats.
8
3
2
4
12
18
o o
3 4 Total
2. Results Of the 20 patients I, given metronidazole, absconded from the ward on the 4th day. The remaining 19 patients completed the trial according to the protocol: lOon tinidazole and 9 on metronidazole. The mean age of the patients was 36.6 years (SD 11.2 yrs). 18 were male and 1 female. The most common presenting symptoms were an enlarged tender liver, intercostal tenderness, fever, and cough. A history of dysentery was given by 10 patients (52.6%). Amongst the liver function tests, serum alkaline phosphatase was most discriminative, being raised in I 8 out of 19 cases. The aspiration from the abscess was chocolate coloured in 17 cases; in 2 it was yellowish brown. Vegetative forms of Entamoeba histo[ytica were detected in 3 cases in the ftrst aspirate. They were not detected in the repeat aspirates. In all cases, the smears showed only necrotic debris with very little inflammation, which is characteristic of
amoebic 'pus'. The bacterial culture was negative in all cases. The therapeutic response of the 19 patients is shown in table I. All I 0 patients given tinidazole showed complete clinical and radiological recovery, whereas 5 of the 9 patients given metronidazole showed a similar response (p = 0.05 by Fisher's test). The 4 patients on metronidazole whose response was evaluated as 'partial recovery' had some residual signs on the 30th day, such as liver enlargement, tenderness, and limitation of diaphragmatic excursions. One of these 4 patients relapsed on the 30th day with worsening of hepatic enlargement and tenderness, but he responded to further aspiration and a second course of metronidazole. Of 10 patients in the tinidazole group, only 2 required a second aspiration; in the metronidazole group, 6 of the 9 patients required 2 or more aspirations (table II).
25
Tinidazole and Metronidazole in Amoebic liver Abscess
No side-effects were reported except by one patient, given metronidazole, who had anorexia, nausea, and diarrhoea.
3. Discussion Two in vitro studies from India (Prakash et al., 1970; Mahajan et al., 1974) showed that the minimum inhibitory concentrations (MIC) of tinidazole for local strains of E. histolytica (0.3122.5].1g/mI) were about twice that of metronidazole (0. 16-1.25].1g/ mI). However, the pharmacokinetic behavior of the two drugs in humans (Monro, 1974) suggested that the higher and more sustained serum levels of tinidazole might more than compensate for its higher in vitro MIC. Thus, after an oral dose of 2g the average serum level of tinidazole, even at the end of 48 hours, is 4.9].1g/ml, i.e. about twice the maximum MIC; under similar circumstances the serum level of metronidazole falls to 0.9].1g/ml, i.e. less than the maximum MIC. Our small trial shows that in amoebic liver abscess tinidazole produces a qualitatively better response. It also seems to bring about a more rapid and effective control of the infection, since fewer patients on it required repeat aspiration.
Acknowledgements This work was supported by a grant from the Staff Research Society of L.T.M. Medical College. Dr R.i::>. Ganatra. Head of the Radiation Medicine Centre. Tata Memorial Hospital. Bombay. carried out the liver scans.
References Mahajan. R.C.; Chitkara. N.L.; Vinayak. V.K. and Dutta. D.V.: In vitro comparative evaluation of tinidazole and metronidazole on strains of Entamoeba histolytica. Indian Journal of Pathology and Bacteriology 17: 226-228 (1974). Monro. A.M.: Blood levels of chemotherapeutic drugs and the pharmacokinetics of tinidazole and metronidazole. Current Medical Research and Opinion 2: 130-137 (1974). Prakash. 0.; Joshi. D.V.; Vinayak. V.K.; Dhingra. P.N. and Tarachand. A.: The in vitro activity of tinidazole and other amoebicidal drugs on locally isolated strains of Entamoeba histolytica. Indian Journal of Medical Research 58: 845-853 (1970).
Author's address: Dr R.C. Khokhani. Ambika Darshan. Mahatma Gandhi Road. Ghatkopar. Bombay 400077. India.
Session III: Amoebic Liver Abscess Chairman: Dr J. Y. Perez, Jr.
Treatment of Amoebic Liver Abscess with Tinidazole and Metronidazole R.C. Khokhani, A.D. Garud, K.P. Deodhar, S.8. Sureka, Manisha Kulkarni, and V.8. Damle Lokmanya Tilak Municipal Medical College and Hospital. and Gokuldas Tejpal Hospital. Bombay
Summary
20 patients with amoebic liver abscess. confirmed by aspiration of typical amoebic ·pus·. were treated in random order with either tinidazole or metronidazole in a dose of 2g once daily for 2 days. Clinical. radiological. and biochemical follow-up was done for 1 month. One patient. given metronidazole. absconded and 19 completed the trial. Complete recovery occurred in all 10 patients given tinidazole but in only 5 of the 9 given metronidazole (p = 0.05). Patients on tinidazole required repeat aspirations less frequently than those on metronidazole. Mild gastrointestinal Side-effects occurred in 1 patient on metronidazole but in none on tinidazole. From the present study. tinidazole appears to be a more effective. better tolerated drug with a more rapid therapeutic effect than metronidazole.
Tinidazole, a nitroimidazole compound, has a longer half~life than metronidazole and produces higher serum levels in humans following a 2g oral dose (Monro, 1974). We therefore thought that its therapeutic effect in liver abscess might be better than that of metronidazole. A clinical trial was carried out to test this possibility.
1. Patients and Methods 20 adult patients with amoebic liver abscess, confIrmed by aspiration of typical 'pus' from the liver,
were included in the trial. Patients who were moribund, had co-existing complications, or had received anti-amoebic treatment during the previous 4 weeks were excluded. The investigations carried out before treatment consisted of full blood count; ESR; urine analysis; stool examination; screening and x-ray of the chest; sigmoidoscopy; radio-isotope hepatic scan; liver function tests, viz. serum bilirubin, SOOT, SGPT, serum alkaline phosphatase; serum proteins with electrophoretic pattern, and prothrombin time; blood sugar; blood urea; and electrocardiogram. A diagnosticcum-therapeutic liver aspiration was carried out in all
24
Tinidazole and Metronidazole in Amoebic Liver Abscess
cases before commencing treatment. The pus was examined for amoebic trophozoites and cultured for secondary bacterial infection. If required, the aspiration was repeated every 5th day. In random order, the patients were given either tinidazole or metronidazole in a dose of 2g once daily on 2 consecutive days. Progress of the patients was assessed daily for the ftrst 10 days and then twice-weekly till the 30th day. Radiological and laboratory investigations were repeated on the 5th, 10th and 30th days. Side-effects were noted only if voluntarily reported by. the patients. Final evaluation of each case was done on the 30th day. The response to therapy was graded as 'complete recovery' if there was rapid regression of symptoms and signs and full recovery on the 30th day by clinical and radiological criteria; it was classifted as 'partial recovery' if there were residual symptoms and signs requiring further treatment on the 30th day.
Table I. Therapeutic response of amoebic liver abscess to treatment with tinidazole or metronidazole'
Response
Complete recovery Partial recovery
Tinidazole
Metronidazole
(n = 10)
(n = 9)
10
5
o
4
1 Difference significant (p = 0.05) by Fisher's test.
Table II. Number of liver aspirations required in two treatment groups
No. of aspirations
2
Tinidazole
Metronidazole
(n = 10)
(n = 9)
no. of pats.
no. of pats.
8
3
2
4
12
18
o o
3 4 Total
2. Results Of the 20 patients I, given metronidazole, absconded from the ward on the 4th day. The remaining 19 patients completed the trial according to the protocol: lOon tinidazole and 9 on metronidazole. The mean age of the patients was 36.6 years (SD 11.2 yrs). 18 were male and 1 female. The most common presenting symptoms were an enlarged tender liver, intercostal tenderness, fever, and cough. A history of dysentery was given by 10 patients (52.6%). Amongst the liver function tests, serum alkaline phosphatase was most discriminative, being raised in I 8 out of 19 cases. The aspiration from the abscess was chocolate coloured in 17 cases; in 2 it was yellowish brown. Vegetative forms of Entamoeba histo[ytica were detected in 3 cases in the ftrst aspirate. They were not detected in the repeat aspirates. In all cases, the smears showed only necrotic debris with very little inflammation, which is characteristic of
amoebic 'pus'. The bacterial culture was negative in all cases. The therapeutic response of the 19 patients is shown in table I. All I 0 patients given tinidazole showed complete clinical and radiological recovery, whereas 5 of the 9 patients given metronidazole showed a similar response (p = 0.05 by Fisher's test). The 4 patients on metronidazole whose response was evaluated as 'partial recovery' had some residual signs on the 30th day, such as liver enlargement, tenderness, and limitation of diaphragmatic excursions. One of these 4 patients relapsed on the 30th day with worsening of hepatic enlargement and tenderness, but he responded to further aspiration and a second course of metronidazole. Of 10 patients in the tinidazole group, only 2 required a second aspiration; in the metronidazole group, 6 of the 9 patients required 2 or more aspirations (table II).
25
Tinidazole and Metronidazole in Amoebic liver Abscess
No side-effects were reported except by one patient, given metronidazole, who had anorexia, nausea, and diarrhoea.
3. Discussion Two in vitro studies from India (Prakash et al., 1970; Mahajan et al., 1974) showed that the minimum inhibitory concentrations (MIC) of tinidazole for local strains of E. histolytica (0.3122.5].1g/mI) were about twice that of metronidazole (0. 16-1.25].1g/ mI). However, the pharmacokinetic behavior of the two drugs in humans (Monro, 1974) suggested that the higher and more sustained serum levels of tinidazole might more than compensate for its higher in vitro MIC. Thus, after an oral dose of 2g the average serum level of tinidazole, even at the end of 48 hours, is 4.9].1g/ml, i.e. about twice the maximum MIC; under similar circumstances the serum level of metronidazole falls to 0.9].1g/ml, i.e. less than the maximum MIC. Our small trial shows that in amoebic liver abscess tinidazole produces a qualitatively better response. It also seems to bring about a more rapid and effective control of the infection, since fewer patients on it required repeat aspiration.
Acknowledgements This work was supported by a grant from the Staff Research Society of L.T.M. Medical College. Dr R.i::>. Ganatra. Head of the Radiation Medicine Centre. Tata Memorial Hospital. Bombay. carried out the liver scans.
References Mahajan. R.C.; Chitkara. N.L.; Vinayak. V.K. and Dutta. D.V.: In vitro comparative evaluation of tinidazole and metronidazole on strains of Entamoeba histolytica. Indian Journal of Pathology and Bacteriology 17: 226-228 (1974). Monro. A.M.: Blood levels of chemotherapeutic drugs and the pharmacokinetics of tinidazole and metronidazole. Current Medical Research and Opinion 2: 130-137 (1974). Prakash. 0.; Joshi. D.V.; Vinayak. V.K.; Dhingra. P.N. and Tarachand. A.: The in vitro activity of tinidazole and other amoebicidal drugs on locally isolated strains of Entamoeba histolytica. Indian Journal of Medical Research 58: 845-853 (1970).
Author's address: Dr R.C. Khokhani. Ambika Darshan. Mahatma Gandhi Road. Ghatkopar. Bombay 400077. India.
