Sulphamethoxazole-trimethoprim: effect on antibody response in man.

The possible immunosuppressive properties of the combination sulphamethoxazole-trimethoprim or either of the agents alone were studied in healthy human volunteers. The effect of the 4-day drug treatment on the antibody synthesis after vaccination was measured by titrating tetanus antitoxin, mumps antibody and Salmonella Hb antibody levels 4 and 5 weeks after vaccination. No significant differences were found in mumps or Salmonella antibody titres in the drug-treated group compared to controls. Tetanus antitoxin levels, however, were significantly lower than in controls after the combined drug. When a fourfold or greater increase in tetanus antitoxin titre was obtained in 75% of controls, the respective figures were 38% in the sulphamethoxazole-trimethoprim-treated group (p less than 0.05), 45% in the trimethoprim group (p greater than 0.05), and 50% in the sulphamethoxazole group (p greater than 0.05). The implications of these findings are discussed.     

Preventive effects of trimethoprim/sulphamethoxazole on experimental staphylococcic pyelonephritis in rats.

108 white rats weighing 170-250 G were given trimethoprim, sulphamethoxazole and the combination trimethoprim 1/sulphamethoxazole orally and parenterally in order to test the preventive effect of these substances on experimental hematogenous pyelonephritis due to Staphylococcus aureus. Oral applications of 48 mg/kg/24h of trimethoprim/sulphamethoxazole prevented abscess formation. Intraperitoneal applications of 48mg/24h of the combination did not seem as effective as the oral applications. On the other hand, there was no difference between the effects of oral and parenteral applications when the doses were 96 mg/kg/24h. The preventive effects of trimethoprim and sulphamethoxazole alone were much less than those observed when the combination trimethoprim/sulphamethoxazole was given. No peritoneal or other tissue damage was observed after intraperitoneal injections of trimethoprim/sulphamethoxazole in rats.     

Trimethoprim, sulphamethoxazole, bacterial adhesion and polymorphonuclear leucocyte function

Culturing Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae in the presence of subinhibitory concentrations (1/4 MIC) of trimethoprim, sulphamethoxazole or their combination, resulted in reduced adherence of all the above strains. The number of phagocytosed bacteria pre-exposed to subinhibitory concentrations of the above antibiotics was not significantly changed, but a significant increase of bactericidal activity of the polymorphonuclear leucocytes was observed. Furthermore, filtrates of K. pneumoniae and P. mirabilis grown in the presence of trimethoprim alone or in combination with sulphamethoxazole induced an increased chemotactic response of human polymorphonuclear leucocytes.     

Resistance among fecal flora of patients taking sulfamethoxazole-trimethoprim or trimethoprim alone.

Because of the widespread occurrence of resistance to sulfonamides among Enterobacteriaceae, some researchers have suggested using trimethoprim (TMP) alone instead of the combination sulfamethoxazole-trimethoprim (SMX-TMP) in treating infections with TMP-susceptible organisms. To answer whether SMX-TMP suppresses the emergence of resistant organisms compared with TMP alone, quantitative fecal cultures were made for total and TMP-resistant organisms before, during, and after SMX-TMP (800/160 mg twice a day) or TMP (200 or 100 mg twice a day) was given to 48 patients for 4 weeks in a prospective, randomized study. All three regimens left anaerobes intact and reduced the total aerobic coliform fecal flora by approximately 4 logs throughout the 4-week treatment period. In 11 of 19 (58%) patients taking TMP 200 mg twice daily, TMP-resistant organisms emerged or increased during therapy (P less than 0.01, compared with none of the 12 controls), whereas in only 4 of 18 (22%) patients on SMX-TMP did TMP-resistant organisms increase. These TMP-resistant organisms increased by less than 1 log and were predominantly Pseudomonas and Acinetobacter species. In only one instance did an SMX-TMP-resistant Escherichia coli strain emerge after 4 weeks of SMX-TMP therapy. The slight increase in Pseudomonas and Acinetobacter species seen with TMP alone in this study raises a potential risk of giving TMP alone in settings where these organisms may cause serious infections, as in immunosuppressed patients.     

High prevalence of antibiotic resistant Escherichia coli in faecal samples of students in the south-east of The Netherlands

From December 1988 to March 1989 172 faecal samples from first and second year students at the University of Limburg, Maastricht, The Netherlands, were collected and analysed for the presence of Escherichia coli strains resistant to ampicillin, sulphamethoxazole, tetracycline, trimethoprim and nitrofurantoin. In addition, the antibiotic susceptibility (MIC) to these agents and six other compounds (i.e. aminoglycosides, nitrofurantoin, nalidixic acid and cephalothin) was determined. The prevalence of resistance of the samples analysed ranged from 86% (i.e. 148 out of 172) for sulphamethoxazole to 25% for trimethoprim. The prevalence figures for ampicillin, tetracycline and nitrofurantoin resistance were 76%, 47% and 29%, respectively. The percentages of the faecal samples with a high proportion of E. coli (greater than 50% of the total number of E. coli) resistant to ampicillin, tetracycline and sulphamethoxazole were 8%, 11% and 37%, respectively. For nitrofurantoin and trimethoprim the figures were 3% and 1%, respectively. Of the isolated E. coli (n = 797), 84% was resistant to ampicillin, 82% resistant to sulphamethoxazole. The lowest percentages (9%) were observed for both nalidixic acid and nitrofurantoin.     

Antimicrobial susceptibility of Enterobacteriaceae isolated from vegetables.

There is potential for the normal faecal flora of humans to be augmented by resistant strains of bacteria, acquired from food. The frequency of resistance in the aerobic Gram-negative faecal flora is often very high. The purpose of this study was to find out whether food strains contribute to this resistance. One hundred and thirty-seven vegetable samples were studied, 48 of Finnish origin, and 89 imported. From these samples, 535 different strains of bacteria belonging to the family Enterobacteriaceae were isolated. Enterobacter spp. were most frequent, Escherichia coli was rare. Sensitivity testing was undertaken only for isolates with different biotypes and antibiograms. No resistance was found to cefotaxime, aztreonam, imipenem, gentamicin, nalidixic acid or ciprofloxacin. The frequency of trimethoprim resistance was 0.2%, sulphamethoxazole resistance 1.3%, and tetracycline resistance 5.5%. These frequencies were much lower than those found in faecal flora. Chloramphenicol and cefuroxime resistance was found in 12% and 14% of isolates, respectively. The only statistically significant differences between the Finnish and imported strains were for these two; the Finnish isolates were more resistant to cefuroxime, whereas the imported ones were more resistant to chloramphenicol. Consequently, bacteria from vegetables are not responsible for the high prevalence of resistant Enterobacteriaceae in faecal flora in Finland; they are in fact unusually susceptible to the antibiotics studied. Multiresistance profiles, typical of strains associated with human activities, were not identified in these isolates.     

Susceptibility of Branhamella catarrhalis to sulphamethoxazole and trimethoprim

Fifty strains of Branhamella catarrhalis were examined for susceptibility to sulphamethoxazole, trimethoprim and a combination of the two by determinating minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs). All strains were susceptible to sulphamethoxazole and resistant to trimethoprim. On the basis of the MIC results it was predicted that greater synergy between sulphamethoxazole and trimethoprim would be observed with approximately equal proportions of each component. The lowest FIC values were obtained with a ratio of 1:1 and the greatest synergy was observed at this ratio with 39 strains (78%). Only seven strains were most synergistically inhibited at the ratio of 20:1 (sulphamethoxazole: trimethoprim) although this ratio was still synergic for most strains. Overall the 1:20 ratio was not synergic.     

A clinical comparison between Macrodantin and trimethoprim for prophylaxis in women with recurrent urinary infections

Seventy-two patients with a history of at least three attacks of urinary infection in the previous 12 months were assigned randomly to long-term prophylaxis with 100 mg at night of either Macrodantin (34 patients) or trimethoprim (38 patients). The mean interval between symptomatic attacks while on either treatment was increased three-fold compared with the pretreatment period. Macrodantin was significantly more effective (P less than 0.05) at preventing bacteriuria. Prophylaxis was equally effective in patients with and without a radiological abnormality. Side effects were significantly more common (P less than 0.05) in the group taking Macrodantin. In patients taking trimethoprim acquisition of resistance by faecal coliforms occurred at a rate of about 5%/month, and breakthrough infections were almost exclusively caused by trimethoprim-resistant coliforms. No acquisition of resistance occurred in patients taking Macrodantin, and the few breakthrough infections noted were due to sensitive bacteria.     

An immunoassay for the detection of IgE antibodies to trimethoprim in the sera of allergic patients

An immunoassay was developed to detect IgE antibodies to the widely used antibacterial drug trimethoprim. Significant levels of trimethoprim-reactive IgE antibodies were found in the sera of two patients who had experienced life-threatening allergic reactions following administration of a combination of trimethoprim and sulphamethoxazole. No IgE antibodies reactive with sulphamethoxazole were found in the sera of either patient. Inhibition experiments revealed that a high degree of cross-reactivity occurs between the drug-reactive IgE antibodies and two structural analogues of trimethoprim, 6-hydroxy- and 6-chlorotrimethoprim. These experiments also indicated that the combining sites of the trimethoprim-reactive IgE antibodies in the two sera were probably complementary to different parts of the trimethoprim molecule. The assay should supplement skin testing in determining the offending drug in patients with suspected allergic sensitivity to trimethoprim-sulphamethoxazole complex.     

Interactions in vitro between agents used to treat melioidosis

Combinations of antimicrobial agents are usually recommended for the treatment of melioidosis. In Thailand, the conventional treatment regimen for Pseudomonas pseudomallei infections is a combination of chloramphenicol, doxycycline and cotrimoxazole. We have consistently observed antagonism between these agents during routine disc susceptibility testing. Interactions between these antimicrobials were studied further by a chequerboard microdilution method, using five clinical isolates of P. pseudomallei. Both trimethoprim and sulphamethoxazole antagonised the bacteriostatic activity of chloramphenicol and doxycycline. The combination of trimethoprim and sulphamethoxazole was synergistic, but not bactericidal. Bacteriostatic drugs antagonised the bactericidal activity of ceftazidime, which is undergoing clinical trials in severe melioidosis. These findings may be of therapeutic relevance.     

Stability of cotrimoxazole in peritoneal dialysis fluid

This study examines the stability of both components of the antibacterial combination, cotrimoxazole (trimethoprim and sulphamethoxazole) in peritoneal dialysis fluid stored in polyvinyl chloride bags and glass ampoules at room temperature for up to nine days. Greater than 10% loss of trimethoprim occurred within three days for admixtures stored in plastic bags, whereas the original concentration remained virtually unchanged after nine days for similar solutions stored in glass ampoules. This indicated that the loss of trimethoprim observed in solutions stored in plastic bags was associated primarily with the nature of the container, presumably due to some form of uptake by or loss through the plastic. Greater than 10% loss of sulphamethoxazole occurred within two days for all admixtures examined, stored in either glass or plastic containers. This degree of loss was achieved within 12 h for one admixture stored in plastic. There was also the time-dependent appearance of an additional peak in HPLC analyses of these solutions, indicating that loss of sulphamethoxazole was due to chemical decomposition of the drug in the peritoneal dialysis fluid. The shelf-life of such admixtures would be limited by the stability of the sulphamethoxazole component, with the available data suggesting a shelf-life of 12 h for solutions stored at room temperature.     

The ECO.SENS Project: a prospective, multinational, multicentre epidemiological survey of the prevalence and antimicrobial susceptibility of urinary tract pathogens--interim report

The ECO.SENS Project is the first international survey to investigate the prevalence and susceptibility of pathogens causing community-acquired, uncomplicated urinary tract infections (UTIs) in women. At 240 centres in 17 countries, female patients presenting with symptoms of uncomplicated UTIs were asked to provide a urine sample for testing for the presence of leucocytes and bacteria. The bacteria were identified and their susceptibility to 12 antibiotics commonly used in the treatment of UTIs was determined. The objective of the survey was to collect 5000 urine samples to obtain approximately 3500 isolates of defined uropathogens. This interim report includes the results from 1960 urine samples, 75% of which contained a uropathogen. Escherichia coli accounted for the majority (80%) of uropathogens isolated in all 17 countries. The rates of resistance among E. coli strains were: ampicillin and sulphamethoxazole, 30%; trimethoprim alone or with sulphamethoxazole, 15%; nalidixic acid, 6%; ciprofloxacin, 3%; amoxycillin-clavulanic acid, mecillinam, cefadroxil, nitrofurantoin and fosfomycin, < or =2%. The use of ampicillin, sulphonamides and trimethoprim alone or with sulphamethoxazole needs to be reconsidered. The seemingly rapid increase in quinolone resistance among community-acquired E. coli in some of the countries gives cause for concern.     

Trimethoprim sulphamoxole in the treatment of chancroid. Comparison of two single dose treatment regimens with a five day regimen

In a prospective blinded study, 135 men with genital ulcers culture positive for Haemophilus ducreyi, were randomized to one of three regimens. Two single dose regimens, either the combination of sulphamoxole 3200 mg/trimethoprim 640 mg or trimethoprim 700 mg alone were compared to a five day regimen of sulphamoxole 800 mg/trimethoprim 160 mg twice daily. All 31 treated with a five day regimen of trimethoprim sulphamoxole healed without further treatment. Of 27 patients treated with the single dose sulphamoxole/trimethoprim regimen, only 21 were cured and of 34 treated with trimethoprim alone, 25 responded. Antibacterial susceptibilities were performed on 31 H. ducreyi isolates. The laboratory susceptibility of these strains to trimethoprim correlated with the clinical response to the single agent. Trimethoprim alone in a dose of 700 mg or the combination of sulphamoxole (3200 mg) and trimethoprim (640 mg) is not satisfactory for the single dose treatment of genital ulcer disease. However, when prescribed for five days, sulphamoxole/trimethoprim is effective and compares favourably with other treatment regimens.     

Long-term treatment with sulphamethoxazole/trimethoprim (Bactrim) and nitrofurantoin in chronic urinary tract infections. A controlled clinical trial.

In a controlled clinical trial based on 30 geriatric patients with recurrent urinary tract infection, 12 out of 17 patients fulfilled a 12-month treatment with sulphamethoxazole/trimethoprim (Bactrim) with continuous sterile urine compared to 1 out of 13 patients treated with nitrofurantoin (p less than 0.05). There was a slight but statistically significant increase in serum creatinine during treatment for 12 months in the sulphamethoxazole/trimethoprim group, but this probably does not reflect any deterioration in kidney function. The remaining laboratory values showed no significant changes whatsoever.     

Comparison of long-term, low-dose pivmecillinam and nitrofurantoin in the control of recurrent urinary tract infection in children. An open, randomized, cross-over study

Thirty-five children with a history of vesicoureteric reflux or with recurrent urinary tract infections were randomly allocated to low-dose prophylactic treatment with pivmecillinam or nitrofurantoin. After 6-10 months they were crossed over to the alternate drug for another 6 months, but only 24 completed the study because of lack of compliance or intolerance to nitrofurantoin. There was no significant difference in the long-term prophylactic effect between the two drugs, the overall infection rate being 0.7/patient-year. Pivmecillinam was significantly better tolerated than nitrofurantoin (P = 0.01). Nitrofurantoin effected no major change in the faecal flora, and nearly all urinary infections occurring during long-term treatment were caused by Escherichia coli. In contrast, a marked reduction of E. coli and a marked increase in Gram-positive cocci were found in the faecal flora during treatment with pivmecillinam. Seventy per cent of infections were caused by Streptococcus faecalis and only 20% by E. coli during pivmecillinam treatment (P = 0.001).     

Synergistic Activity of Gentamicin with Trimethoprim or Sulfamethoxazole-Trimethoprim Against Escherichia coli and Klebsiella pneumoniae

The effect of combinations of gentamicin with trimethoprim or sulfamethoxazole-trimethoprim against clinical isolates of Escherichia coli (11 strains) and Klebsiella pneumoniae (12 strains) was examined by using a microdilution checkerboard technique. All isolates were susceptible to each antimicrobial agent. Synergism, defined as at least a 2-log(2)-dilution lowering of the minimal inhibitory concentration of either antibiotic in the combination compared with the minimal inhibitory concentration of the antibiotic alone, was observed with 15 of 23 (65%) isolates tested against trimethoprim and gentamicin and 14 of 23 (61%) isolates tested against sulfamethoxazole-trimethoprim and gentamicin. A 3-log(2)-dilution lowering of the minimal inhibitory concentration of either antibiotic was observed in 7 of 23 (30%) trimethoprim and gentamicin trials and 3 of 23 (13%) sulfamethoxazole-trimethoprim and gentamicin trials. Antagonism was observed in 3 of 46 combination trials and only with strains of K. pneumoniae.     

Alteration of plasma lipids and intermediates of lipid metabolism in healthy fasting volunteers by ethanol and fructose

After healthy persons, aged between 20 and 35 years, had consumed either ethanol or ethanol and fructose, triglycerides, free glycerol, FFA, phospholipids and total cholesterol were determined. After a basic dosage of 0.5 g ethanol/kg body weight, each person received a maeintenance dosage of 0.1 g ethanol/kg body weight and hour. Control experiments were carried out on persons receiving only fructose and on fasting persons who consumed no ethanol.After 8 hrs, triglyerides rose in the ethanol group by 107 % , in the ethanol-fructose group by 63 %. FFA exhibited in both ethanol and ethanol-fructose groups an initial decrease, with a secondary increase in the ethanol group. The initial decrease was greater in the ethanol-fructose group. A significant rise in free glycerol by 419 % was observed 30 min after the intake of combined ethanol/fructose. Free glycerol rose under ethanol alone by 144 %. The öhospholipids exhibited a slight rise in the ethanol group; no significant changes occured in the cholesterol. The blood ethanol level was lower under ethanol-fructose than under ethanol alone. The addition of fructose diminishes the ethanol-induced hypertriglyceridemia.     

The penetration of co-trimoxazole into alveolar macrophages and its effect on inflammatory and immunoregulatory functions

The pharmacokinetics of co-trimoxazole in serum, bronchoalveolar lavage-fluid (BAL-fluid) and alveolar macrophages (AM) of guinea pigs receiving sulphamethoxazole (100 mg/kg) and trimethoprim (20 mg/kg) were studied. HPLC showed that peak co-trimoxazole levels were obtained in serum at 30 min, in BAL-fluid at 1 h and in AM at 3 h. A comparison between mean concentrations in serum, BAL-fluid and AM showed a six-fold higher concentration of trimethoprim in cells than in serum, but only 0.25-fold of sulphamethoxazole. The BAL-fluid/serum ratio was four to ten times higher for trimethoprim than for sulphamethoxazole (0.6-to-one-fold). Sulphamethoxazole/trimethoprim ratios (30 min, 1 and 3 h) were lower in BAL-fluid (4.9 +/- 0.5) and in AM (1.4 +/- 0.5) than in serum (30.7 +/- 1.6). The influence of co-trimoxazole in vitro on microbicidal capacities (superoxide anion and hydrogen peroxide generations), immunoregulation (production of interleukin 1) and pro-inflammatory agent production (tumour necrosis factor) of guinea pigs' AM was also studied. No significant effect of co-trimoxazole on superoxide anion and hydrogen peroxide generations, or on interleukin 1 and TNF production, was demonstrable.     

Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination.

Rifampin and trimethoprim were used alone and in combination in the treatment of chronic osteomyelitis due to Staphylococcus aureus in rabbits. Rifampicin levels in infected bone were well above the minimum inhibitory concentration of the infecting strain of S. aureus for at least 4 h after injection. In contrast, trimethoprim levels in diseased bone were below the minimum inhibitory concentration as early as 1 h after injection. Trimethoprim or rifampin, administered alone for 14 days, were ineffective in sterilizing infected rabbit bones. The combination of rifampin plus trimethoprim was significantly more effective (P less than 0.005) than either agents given alone for a comparable duration of time. Staphylococci isolated from the bones of rabbits treated with rifampin alone or rifampin plus trimethoprim were uniformly resistant to rifampin, but retained their susceptibility to trimethoprim.