Comparison of trimethoprim in combination with sulfadiazine or sulfamethoxazole in the treatment of respiratory infections.
Development of resistance by microorganisms has limited the use of sulfonamides in many infections but their effectiveness is enhanced when given in conjunction with another agent affecting folate metabolism such as trimethoprim. Trimethroprim affects the nucleoprotein metabolism of cells similarly to pyrimethamine by interference in the folic-acid systems. Its effects are considerably greater on the cells of micro-organisms than on mammalian cells. Sulfonamides interfere with the synthesis by micro-organisms of folic acid from paraaminobenzoic acid by inhibiting the formation of dihydrofolic acid. The combination with trimethoprim was demonstrated to be synergistic,, and trimethoprim (TMP) with sulfamethoxazole (SMZ) is now a well established therapeutic agent. However, other sulfonamides may also be equally effective and experimentally trimethoprim (75 mg) and sulfadiazine (SD) (225 mg) has been demonstrated to be equally effective as TMP and SMZ combination. This study was therefore undertaken to compare the efficacy of TMP with SD against TMP with SMZ in the lower respiratory tract infections.
A double blind randomized clinical trial was conducted using TMP, 75 mg with SD 225 mg (drug A) and TMP 80 mg with SMZ 400 mg (drug B) in lower respiratory tract infections.
Roth drugs were administered in the dose of 2 tablets 12 hourly. Patients attending general hospital out-patient department (OPD) and suffering from lower respiratory tract infections were included in this study. They were hospitalized and clinical evaluation, complete haemogram, chest X-ray and sputum examination including culture and sensivity were carried out on the 1st and 7th day of the trial. Patients, at the time of sputum collection, were asked to gargle with normal saline and were encouraged to cough. The sputum was collected in sterile screw capped bottles. Treatment according to the randomized table was initiated on the day of the trial without waiting for the culture and sensitivity report of the sputum sample. Results were analysed using standard statistical methods.
Of the total 50 patients, 41 completed the trial. Nine patients were excluded from the study; 3 of them were discharged against medical advice, while the remaining six patients were found to be suffering from pulmonary tuberculosis. Twenty-one of the total 41 patients received drug A and the remaining received drug B. The ages ranged from 12 to 75 years; majority of them were between 20 and 50 years of age in both groups. There were 14 males in each group while there were 7 females on drug A and 6 on drug B therapy.
Cough, dyspnoea, chest pain and fever were the initial symptoms. Cough with expectoration was present in all the 41 cases. There was a marked improvement in the cough following three days of therapy in both the groups and after 7 days of therapy 62% patients in group A and 70% in group B had no cough. The remaining patients showed only mild cough.
The data is analysed in [Table - 1]. The commonest organism in group A was Klebsiella pneumoniae and Staphylococcus aureus in drug B group. Mixed infections were found in 8 and 7 patients in drug A and drug B groups respectively. Microbiologically, responses were graded as good, fair and poor, on the basis of colony counts. These grades were based on the reduction observed in the total colony count of the respective isolated organism on the 7th day with reference to the colony count at the beginning of therapy. Accordingly, 17 patients on TMP with SD and 15 patients on TMP with SMZ had good response while it was fair in 4 patients in both drug groups. One patient from each group had poor response.
Clinically the response was considered as `good' when there was X-ray clearance and total relief from symptoms and signs. Marked improvement in symptoms and signs but no complete clearance of X-ray was considered as `fair'. Those with no or slight relief from symptoms and signs and persistence of X-ray findings as on the first day were considered as `poor' responders.
At the end of the 7 day therapy, 16 patients belonging to drug A group and 15 patients to drug B group showed good response. Fair response was noted in 3 and 5 patients on drug A and drug B groups respectively. The response was considered poor in 2 patients on TMP with SD and none on TMP with SMZ therapy [Table - 2].
In the group on TMP with SD, among the six cases showing drug resistance in vitro, one case had mixed infection with Klebsiella and E. coli organisms. In this group all the six patients showed 'fair' response clinically. In group on TMP with SMZ one case out of the four showing drug resistance in vitro had mixed infection with Klebsiella and Pseudomonas organisms; of these, these cases showed good' response clinically while in the fourth case with Pseudomonas infection. The clinical response was regarded as `fair'[Table - 3].
All the patients tolerated the therapy well. None complained of nausea and there were no gastro-intestinal disturbances. Analysis of haematological data revealed no abnormalities after 7 days of therapy in both the groups.
Animal experiments and human volunteer studies have shown that concentration of SD is high in the serum, bronchial tissue and bronchial secretions, which will exert a good therapeutic action in the lower respiratory tract infections. The lower ratio of SD in the combination of TMP with SD (1:3) was expected to reduce the side effects usually caused by high doses of sulfonamide. The goal of the clinical trial was to test the specificity and effectiveness of this combination in lower respiratory tract infections.
Cough with expectoration was the presenting symptom in all cases which subsided in 62% of patients on drug A and 70% of patients on drug B. Overall clinical response was good in 75% on drug A and drug B. Fair response was observed in 14% on drug A and 25% on drug B. The statistical analysis of the data did not indicate any significant difference between the two regimens.
Microbiologically, 8 and 9 patients had mixed infections in TMP with SD and TMP with SMZ groups respectively. The commonest organisms found were Klebsiella pneumoniae and Staphylococcus aureus. Good response was observed in 80% and 75% of patients on drug A and on drug B respectively.
In view of these findings, it is concluded that TMP 75 mg with SD 225 mg (drug A) is probably as effective as TMP 80 mg -T- 400 mg SMZ (drug B) in the lower respiratory tract infections. The combination certainly deserves further studies in more number of cases.
We thank the Dean, Seth G.S. Medical College and K.E.M. Hospital, Bombay 400 012, for permitting us to use the hospital data. We also thank M/s. Anglo French Drug Co. (Estn.) India, for supplying the drugs.