Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans. (57/488)

Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMX-specific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg-1) or SMX-NO (1 mg kg-1). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n = 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMXNO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.  (+info)

Escherichia coli O157:H7 Shiga toxin-encoding bacteriophages: integrations, excisions, truncations, and evolutionary implications. (58/488)

As it descended from Escherichia coli O55:H7, Shiga toxin (Stx)-producing E. coli (STEC) O157:H7 is believed to have acquired, in sequence, a bacteriophage encoding Stx2 and another encoding Stx1. Between these events, sorbitol-fermenting E. coli O157:H(-) presumably diverged from this clade. We employed PCR and sequence analyses to investigate sites of bacteriophage integration into the chromosome, using evolutionarily informative STEC to trace the sequence of acquisition of elements encoding Stx. Contrary to expectations from the two currently sequenced strains, truncated bacteriophages occupy yehV in almost all E. coli O157:H7 strains that lack stx(1) (stx(1)-negative strains). Two truncated variants were determined to contain either GTT or TGACTGTT sequence, in lieu of 20,214 or 18,895 bp, respectively, of the bacteriophage central region. A single-nucleotide polymorphism in the latter variant suggests that recombination in that element extended beyond the inserted octamer. An stx(2) bacteriophage usually occupies wrbA in stx(1)(+)/stx(2)(+) E. coli O157:H7, but wrbA is unexpectedly unoccupied in most stx(1)-negative/stx(2)(+) E. coli O157:H7 strains, the presumed progenitors of stx(1)(+)/stx(2)(+) E. coli O157:H7. Trimethoprim-sulfamethoxazole promotes the excision of all, and ciprofloxacin and fosfomycin significantly promote the excision of a subset of complete and truncated stx bacteriophages from the E. coli O157:H7 strains tested; bile salts usually attenuate excision. These data demonstrate the unexpected diversity of the chromosomal architecture of E. coli O157:H7 (with novel truncated bacteriophages and multiple stx(2) bacteriophage insertion sites), suggest that stx(1) acquisition might be a multistep process, and compel the consideration of multiple exogenous factors, including antibiotics and bile, when chromosome stability is examined.  (+info)

Cross-resistance and associated resistance in 2478 Escherichia coli isolates from the Pan-European ECO.SENS Project surveying the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections. (59/488)

The antimicrobial resistance profiles, comprising 12 antibiotics, of 2478 isolates of Escherichia coli from the ECO.SENS Project involving women with acute uncomplicated urinary tract infection at 252 community health care centres in 17 countries were determined. Resistance to ampicillin alone (6.3%) and sulfamethoxazole alone (5.4%) were the most common 'single resistances'. Multiple resistance was most common in Spain and least common in Finland. The main associated-resistance profiles involved ampicillin/sulfamethoxazole (8.7%) and ampicillin/sulfamethoxazole/trimethoprim/trimethoprim-sulfamethoxazole (6.4%). The most common profile of multiple resistance was ampicillin/sulfamethoxazole/trimethoprim/trimethoprim-sulfamethoxazole/nalidixic acid/ciprofloxacin. Twenty-one isolates, half of which came from Spain, were resistant to seven antibiotics or more. Three isolates, one from Spain and two from Portugal, were resistant to nine of the 12 antibiotics investigated.  (+info)

Dihydrofolate reductase and dihydropteroate synthase genotypes associated with in vitro resistance of Plasmodium falciparum to pyrimethamine, trimethoprim, sulfadoxine, and sulfamethoxazole. (60/488)

A total of 70 Plasmodium falciparum isolates were tested in vitro against pyrimethamine (PYR), trimethoprim (TRM), sulfadoxine (SDX), and sulfamethoxazole (SMX), and their dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genotypes were determined. dhfr genotypes correlated with PYR and TRM drug responses (r = 0.93 and 0.85). Isolates with wild-type alleles showed mean half inhibitory concentrations (IC50 +/- SD) of 0.10 +/- 0.10 and 0.15 +/- 0.06 microg/100 microl for PYR and TRM. Parasites with mutations at codons 108 and 51 alone or combined with codon 59 have IC50 of 11.46 +/- 0.86 (PYR) and 2.90 +/- 0.59 microg/100 microl (TRM). For both drugs, the differences in the mean IC50 between wild and mutant parasites were statistically significant (P < 0.001). Isolates with mixed wild and mutant alleles showed an intermediate level of susceptibility. Our data show partial cross-resistance between PYR/TRM and SDX/SMX (r = 0.85 and 0.65). Correlation was not observed between different dhps genotypes and the in vitro outcome to SDX and SMX (r = 0.30 and 0.34). The lack of correlation could be due to folates and para-aminobenzoic acid in the RPMI medium and the serum used to supplement the cultures.  (+info)

Activity in vitro of ten antimicrobial agents against Neisseria gonorrhoeae. A study of the correlation between the sensitivities. (61/488)

105 Belgian strains of Neisseria gonorrhoeae were tested for their sensitivity to penicillin, ampicillin, rifampicin, erythromycin, tetracycline, streptomycin, spectinomycin, sulphamethoxazole, trimethroprim, and a combination of sulphamethoxazole and trimethroprim in a 5:1 ratio. Distribution and median values of minimum inhibitory concentrations (MICs) are given and discussed. 42 per cent. of strains were relatively resistant to penicillin (MIC greater than or equal to 0-04 mug/ml.), but only 2 per cent. showed high-level resistance (MIC greater than or equal to 0-38 mug/ml.), which is comparable with the prevalence of decreased sensitivity found in other European countries. A significant positive correlation (P less than or equal to 0-01, rank correlation coefficient) is found between the sensitivities to penicillin, ampicillin, erythromycin, tetracycline, and streptomycin, except for the ampicillin-erythromycin and ampicillin-tetracycline pairs. Rifampicin is correlated with tetracycline. No correlation is found between the sensitivities to spectinomycin and any of the other drugs. The combination of sulphamethoxazole and trimethoprim in a 5:1 ratio also shows a significant positive correlation with penicillin and ampicillin and with sulphamethoxazole and trimethoprim separately.  (+info)

Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia. (62/488)

The efficacy of antifolate, antiviral, and other drugs was compared in an experimental model of pneumocystosis. Sulfamethoxazole (SMX) administered alone in doses of greater than or equal to 60 mg/kg/day was highly effective in treatment and prophylaxis. Low (less than or equal to 15 mg/kg/day) doses of SMX showed limited, dose-related anti-Pneumocystis carinii activity in therapy but were more effective in prophylaxis. The dihydrofolate reductase (DHFR) inhibitors trimethoprim (TMP), pyrimethamine, and trimetrexate exhibited little anti-P. carinii activity when administered alone and did not enhance the efficacy of SMX; the effects of the DHFR inhibitors could not be related to the dose or the concentration in serum. These data suggested that the rat model is an excellent system for studying the anti-P. carinii activity of sulfonamides but is of limited value in studying DHFR inhibitors. The antiviral drugs azidothymidine, dideoxyinosine, inosine pranobex (Isoprinosine), amantadine, and acyclovir displayed little or no activity against P. carinii; however, azidothymidine did not impair the efficacy of SMX or TMP-SMX. These results supported the clinical practice of giving antiviral agents together with antifolate drugs to patients infected with human immunodeficiency virus and suggested that the beneficial effects of antiviral agents on the occurrence of pneumocystosis are due mainly to their effects on the virus or the host immune response. In contrast to the antiviral drugs, 9-deazainosine, a nucleoside analog with antiprotozoal properties, demonstrated marked activity against P. carinii which was related to dose and route of administration. These data raised the possibility that anti-P. carinii activity is a general property of purine nucleosides and suggested that further exploration of this class of compounds might lead to clinically useful agents.  (+info)

Urinary lithiasis induced by sulfamethoxazole in a patient with tetraplegia. Case report. (63/488)

Bladder lithiasis is a frequent complication in paraplegics and tetraplegics. We report on a patient where treatment of a urinary infection with antibacterial sulfamides was the causative factor in the formation of bladder stones.  (+info)

N-Glycosylation-dependent block is a novel mechanism for drug-induced cardiac arrhythmia. (64/488)

Voltage-gated potassium channels formed with the cardiac subunit HERG and a polymorphic variant of MinK-related peptide 1 (MiRP1) exhibit increased susceptibility to the antibiotic sulfamethoxazole (SMX) compared with channels formed with wild-type (WT) subunits. Here the molecular bases for SMX high-affinity block are investigated. The polymorphism causes a benign T to A amino acid mutation at position 8 (T8A) that destroys an N-glycosylation site of MiRP1. In vitro disruption of glycosylation by mutagenesis or in vivo by treatment with neuraminidase is associated with increased susceptibility to SMX and to other elementary agents such as divalent cations. Defective glycosylation does not affect the ability of T8A to form stable complexes with HERG, but rather it increases drug susceptibility through structural modifications in the channel complex. We conclude that N-glycosylation may play a key role in the etiology of life-threatening arrhythmia.  (+info)