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.     

The penetration of trimethoprim and sulphamethoxazole into synovial fluid

A group of six patients with non-infected synovial effusions requiring diagnostic or therapeutic aspiration, were given a short oral course of 'Septrin' (two tablets bd for two doses, each tablet containing 80 mg of trimethoprim plus 400 mg of sulphamethoxazole). Serum and synovial fluid (SF) were sampled frequently following antibiotic administration. It was found that concentrations of trimethoprim in SF approached serum levels after a short lag time (about 3 h) and thereafter approximated to the serum levels, whereas sulphamethoxazole did not as readily penetrate into SF. With the regimens used MIC levels for trimethoprim were achieved in SF, which suggests that this drug could be usefully prescribed in normal doses for the treatment of septic arthritis due to bacterial infection.     

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.     

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.     

Effect of trimethoprim on the occurrence of drug-resistant coliform bacteria in the faecal flora.

The occurrence of drug-resistant coliform bacteria was studied in the faecal flora of 30 persons receiving for 3 weeks either trimethoprim alone, a combination of sulphamethoxazole and trimethoprim, or a combination of sulphamethoxydiazine and sulphamethoxazole. Bacterial sensitivity was tested against trimethoprim, sulphamethoxazole-trimethoprim, sulphamethoxazole, and sulphaisodimidine. After treatment with trimethoprim alone, no increase in the occurrence of strains resistant to either trimethoprim or sulphonamides was observed. After treatment with sulphamethoxazole-trimethoprim, the faecal flora contained an increased percentage of sulphonamide-resistant coliforms but significantly less than found after treatment with sulphamethoxydiazine-sulphamethoxazole. In the persons receiving the sulphonamides only, a rapid increase in sulphonamide-resistant coliforms was observed. During the whole study, only one trimethoprim-resistant coliform strain was detected.     

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.     

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.     

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.     

Drug monitoring during the treatment of AIDS-associated Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole

Objective: To monitor trimethoprim and sulfamethoxazole plasma levels in patients with AIDS-associated Pneumocystis carinii pneumonia Method: Trimethoprim–sulfamethoxazole steady-state plasma concentrations were measured by high-pressure liquid chromatography during 37 episodes of Pneumocystis carinii pneumonia in patients with AIDS. Initially, 15–23 mg/kg/day trimethoprim and 75–115 mg/kg/day sulfamethoxazole were given i.v. Assuming a therapeutic range for trimethoprim from 4 to 10 μg/ml, the doses were adjusted if trimethoprim levels were found to be outside this range Results: Mean concentrations were 6·7±3·3 μg/ml for trimethoprim and 187±56 μg/ml for sulfamethoxazole. A widespread inter-patient range was found and could be decreased after dose adjustment. Enzyme inducing co-medication did not influence plasma concentrations. In patients with coexisting chronic liver disease, significantly increased sulfamethoxazole plasma levels were observed. A correlation could be demonstrated between serum creatinine and trimethoprim plasma levels. Adverse reactions associated with co-trimoxazole occurred during 65% of treatment periods and increased with increasing trimethoprim-sulfamethoxazole levels, as well as increasing length of treatment. Therapy only had to be prematurely discontinued in one patient. Overall mortality was 2·7%Conclusion: Monitoring of co-trimoxazole levels during the treatment of P. carinii pneumonia in AIDS may help in reducing the high variability of plasma-concentrations and in avoiding severe side-effects especially associated in patients with chronic liver disease or renal failure     

Therapeutic efficacy of chloramphenicol, co-trimoxazole (trimethoprim/sulphamethoxazole), cefmenoxime and ceftriaxone in experimental bacteraemia and meningitis caused by ampicillin-resistant Haemophilus influenzae type b

Therapeutic efficacy of two newer cephalosporins, cefmenoxime and ceftriaxone, was evaluated in newborn rats with experimental bacteraemia and meningitis due to an ampicillin-resistant strain of Haemophilus influenzae type b, and the results were compared with those of ampicillin, chloramphenicol and co-trimoxazole (trimethoprim/sulphamethoxazole). Measured by MICs and MBCs, cefmenoxime and ceftriaxone were at least a hundred-fold more active in vitro than chloramphenicol. Co-trimoxazole was bacteriostatic in vitro. For in-vivo studies, the following daily doses were used: 200 mg/kg for ampicillin; 100 mg/kg and 200 mg/kg for chloramphenicol; 10/50 mg/kg, 20/100 mg/kg and 100/500 mg/kg for trimethoprim/sulphamethoxazole; 10 mg/kg and 50 mg/kg for cefmenoxime; and 10 mg/kg and 25 mg/kg for ceftriaxone. Cefmenoxime and ceftriaxone were highly efficacious, even at a dose of 10 mg/kg/day, in eradicating the organism from blood and CSF, preventing bacteriological relapse and improving the survival rate. In contrast, chloramphenicol was effective in reducing mortality, but failed to eradicate the organism or to prevent relapse, while co-trimoxazole was least effective in that all but one survivors suffered relapse with positive blood and CSF cultures. Ampicillin gave unexpected results in that the organism was eradicated in all survivors and bacteriological relapse was prevented in most animals (73-75%).     

Potentiation of sulphamethoxazole by trimethoprim in Neisseria gonorrhoeae strains.

Quantiative determinations of the sensitivity of 322 Neisseria gonorrhoeae strains to sulphamethoxazole (Su), trimethoprim (Tr) and a combination of Su and Tr in a ratio of 5:1 are described. Data are also given on the potentiation of Su by tr. It was striking that the Su-sensitive N. gonorrheoeae strains showed no potentiation of Su by Tr when a Su/Tr ratio of 5:1 is used. The sensitivity to combinations of Su and Tr in various ratios was determined for seven N. gonorrhoeae strains with known senstivity to Su and Tr. On the basis of these data, the rules according to which Su is potentiated by Tr. could be formulated.     

Effects of the antimigraine compound zolmitriptan ('Zomig') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Zolmitriptan (Zomig^TM) is a 5HT_1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg+diazepam 10 mg, zolmitriptan 5 mg+diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.     

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.     

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 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.     

In-vitro antimicrobial susceptibility of Rhodococcus equi.

Rhodococcus equi is an intracellular facultative, Gram-positive cocco-bacillary organism of increasing importance as a pulmonary pathogen in HIV-positive patients. This study was carried out to evaluate the optimal antibiotic combinations for treating such infections. Four human R. equi isolates and one reference strain were tested for their susceptibilities to 36 antibiotics. In-vitro the most active antibiotics were amikacin, gentamicin, netilmicin, erythromycin, clarithromycin, roxithromycin, ciprofloxacin, sparfloxacin, rifampicin, vancomycin, teicoplanin, doxycycline, minocycline, imipenem, meropenem and trimethoprim/sulphamethoxazole. The only bactericidal antibiotics were the aminoglycosides, ciprofloxacin, sparfloxacin and vancomycin. As determined by FIC indices, four combinations were synergistic: rifampicin-erythromycin, rifampicin-minocycline, erythromycin-minocycline and imipenem-amikacin. However, no antibiotic combinations were synergistic with the time-kill kinetic method at achievable serum concentrations or at ten-fold and half-fold the MICs. Frequencies of selection of antibiotic-resistant mutants determined at concentrations of five- and ten-fold the MICs ranged from less than 1 x 10(-8) for erythromycin and trimethoprim/sulphamethoxazole to 5 x 10(-4) for amikacin. These results may be of help in selecting the antibiotics for treating infected HIV-positive patients.     

Trimethoprim, creatinine and creatinine-based equations

Co-trimoxazole is a frequently prescribed antibiotic worldwide. It is composed of both trimethoprim and sulfamethoxazol (Sfx) and is used in the treatment and prophylaxis of urinary tract and Pneumocystis jirovecii infections. The Sfx component appears to be nephrotoxic at high doses or doses inappropriately adjusted for glomerular filtration rate (GFR). The trimethoprim component, even at recommended doses, inhibits tubular creatinine secretion, leading to a rapid but ultimately reversible increase in serum creatinine independent of any changes in GFR. This translates into a falsely low estimated GFR when creatinine-based equations are used. This review focuses on evidence of the differential effects of trimethoprim and Sfx on serum creatinine concentrations and GFR and their relevance to clinical practice, with particular attention to kidney transplantation.