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Trimethoprim
Selected AbstractsPharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole in alpacasJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2002J. Chakwenya The pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) were studied in six healthy male-castrate alpacas (Lama pacos) after intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP-SMX using a crossover design with a 2-week washout period. After 90 days one group (n = 3) was given a p.o. dose of 30 mg/kg TMP-SMX and the other group (n = 3) was given a p.o. dose of 60 mg/kg TMP-SMX. After i.v. administration of 15 mg/kg of TMP-SMX the mean initial plasma concentration (C0) was 10.75 ± 2.12 ,g/mL for trimethoprim (TMP) and 158.3 ± 189.3 ,g/mL for sulfamethoxazole (SMX). Elimination half-lives were 0.74 ± 0.1 h for TMP and 2.2 ± 0.6 h for SMX. The mean residence times were 1.45 ± 0.72 h for TMP and 2.8 ± 0.6 h for SMX. The areas under the respective concentration vs. time curves (AUC) were 2.49 ± 1.62 ,g h/mL for TMP and 124 ± 60 ,g h/mL for SMX. Total clearance (Clt) for TMP was 21.63 ± 9.85 and 1.90 ± 0.77 mL/min kg for SMX. The volume of distribution at steady state was 2.32 ± 1.15 L/kg for TMP and 0.35 ± 0.09 L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak concentration (Cmax) of SMX were 1.9 ± 0.8, 2.6 ± 0.4 and 2.8 ± 0.7 ,g/mL, respectively. The AUC was 9.1 ± 5, 25.9 ± 3.3 and 39.1 ± 4.1 ,g h/mL, respectively. Based upon these AUC values and correcting for dose, the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not detected in plasma after intragastric administration. These data demonstrate that therapeutic concentrations of TMP-SMX are not achieved after p.o. administration to alpacas. [source] ChemInform Abstract: An Efficient Benzyltriethylammonium Chloride Catalyzed Preparation of Electrophilic Alkenes: A Practical Synthesis of Trimethoprim.CHEMINFORM, Issue 37 2001D. Subhas Bose Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ANTIMICROBIAL RESISTANCE IN SALMONELLA ENTERITIDIS ISOLATED FROM FOODS INVOLVED IN HUMAN FOODBORNE OUTBREAKS THAT OCCURRED IN THE SOUTH OF BRAZIL, 1999,2000JOURNAL OF FOOD SAFETY, Issue 3 2005M. P. GEIMBA ABSTRACT Antimicrobial resistance was determined for 73 isolates of Salmonella enteritidis isolated from foods involved in human foodborne outbreaks that occurred in the South of Brazil, from 1999 to 2000. The isolates were individually tested against 10 antimicrobial agents using a disc diffusion method. Most isolates were susceptible to all drugs tested. No S. enteritidis isolates were resistant to sulfamethoxazole/trimethoprim or chloramphenicol. The predominant resistance observed was to streptomycin (S) (37%), gentamicin (GEN) (13.7%) and nalidixic acid (NAL) (13.7%), while intermediate resistance was observed most often for tetracycline (53.4%), neomycin (NEO) (30.1%) and GEN (15.1%). Resistance was verified in 40 isolates (54%), which were grouped in 15 different patterns. Multiple resistance was presented in 17 (23%) of the isolates, and one isolate exhibited resistance to four drugs (NEO, kanamycin, S and NAL), demonstrating the involvement of multiresistant S. enteritidis strains with foodborne outbreaks. [source] Antibiotic resistance in Listeria species isolated from catfish fillets and processing environmentLETTERS IN APPLIED MICROBIOLOGY, Issue 6 2010B.-Y. Chen Abstract Aims:, To investigate the susceptibility of 221 Listeria spp. (86 Listeria monocytogenes, 41 Listeria innocua and 94 Listeria seeligeri-Listeria welshimeri-Listeria ivanovii) isolated from catfish fillets and processing environment to 15 antibiotics. Methods and Results:,Listeria isolates were analysed by disc-diffusion assay for their resistance to 15 drugs. All isolates were resistant to cefotaxime and clindamycin but were sensitive to ampicillin, cephalothin, chloramphenicol, erythromycin, gentamycin, kanamycin, rifampin, streptomycin, sulfamethoxazole/trimethoprim and vancomycin. Unlike L. monocytogenes and L. seeligeri-L. welshimeri-L. ivanovii isolates, 22% of L. innocua isolates displayed tetracycline/oxytetracycline resistance. Screening of tet genes by PCR identified tet(M) gene in the chromosome of all tetracycline/oxytetracycline-resistant L. innocua. However, this gene was not associated with the integrase gene of Tn1545. Repetitive extragenic palindromic- and enterobacterial repetitive intergenic consensus-PCR typing methods showed no genotype-specific tetracycline resistance in the tet(M)-positive strains. Conclusions:, Catfish fillets and processing environment were currently free of L. monocytogenes resistant to antibiotics commonly used in human listeriosis treatment. However, the presence of tet(M) gene in L. innocua raises the possibility of future acquisition of resistance by L. monocytogenes. Significance and Impact of the Study:, These data will be helpful in improving background data on antibiotics resistance strains isolated from food and processing environment. [source] Cross-reactivity among p -amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testingCONTACT DERMATITIS, Issue 2 2004P. Tornero We studied 28 patients with fixed drug eruption (FDE) caused by sulfonamide antibiotics to investigate cross-reactivity between sulfonamide derivatives and p -amino compounds and to explore the usefulness of patch testing, as an alternative to controlled oral challenge testing (COCT), in diagnosis within this clinical area. COCT with sulfamethoxazole (SMX), sulfadiazine (SDZ), sulfamethizole (SMZ), furosemide (FU), procaine (PRO) and glipizide (GPZ) was performed. Patch testing (PT) with SMX and SDZ was carried out. In all patients, the diagnosis of FDE was confirmed by positive COCT and allergy to trimethoprim ruled out by COCT. 42.8 and 31.8% of the SMX-induced FDE patients reacted to SMZ and SDZ, respectively. All patients (n = 28) tolerated FU, PRO and GPZ. COCT performed with the 3 sulfonamide antibiotics in 12 patients was positive in 2 subjects with the 3 drugs, in 2 patients only with SMX and SMZ and in the remaining 8, SMX was the only causative drug. PT was positive in 5 of 25 patients positive on COCT. The probability of obtaining a positive PT was higher among patients who had a residual lesion than that among those who lacked this. Cross-reactivity between different sulfonamide antibiotics is thus variable, being most likely between SMX and SMZ. We have found no cross-reactivity between sulfonamide antibiotics and other sulfonamide derivatives or p -amino drugs in FDE. PT is a useful tool in the diagnosis of FDE, especially if there are residual lesions, because it avoided the need for COCT in 20% of patients. [source] Acute effects of the antibiotic oxytetracycline on the bacterial community of the grass shrimp, Palaemonetes pugio,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2009Miguel Uyaguari Abstract The toxicity of oxytetracycline (OTC) was evaluated in adult grass shrimp, Palaemonetes pugio. Initially, static acute (96 h) toxicity tests were conducted with shrimp exposed from 0 to 1,000 mg/L OTC. A calculated lethal concentration 50% value of 683.30 mg/L OTC (95% confidence interval 610.85,764.40 mg/L) was determined from these tests, along with a lowest-observable-effect concentration of 750 mg/L and no-observable-effect concentration of 500 mg/L. Moreover, chronic sublethal effects of OTC exposure on grass shrimp intestinal bacterial population were assessed using doses from 0 to 32 mg/L OTC. The total viable counts in digestive tract content had levels between 5.2 and 1 × 104 colony-forming units per gram of tissue at times 0 and 96 h, respectively. Aeromonas hydrophila were the most resistant isolates (27.78%) to OTC exposure. Vibrio alginolyticus showed significant positive growth following exposure to OTC, whereas other bacterial species abundance declined over time. A total of 268 bacterial isolates were screened using antibiotic resistance analysis from a library containing 459 isolates. Among the tested isolates from the OTC treatments, 15.4% were resistant to OTC and 84.6% were OTC sensitive. Oxytetracycline was generally not consistently quantifiable with liquid chromatography-mass spectroscopy technique in shrimp homogenates. The only peak detected was at the 32 mg/L dose of OTC at 96 h. Nevertheless, OTC had a significant biological effect on the bacterial population. Antibiotic resistance to five other antibiotics (penicillin G, sulfathiazole, trimethoprim, trimethoprim and sulfamethoxazole, and tetracycline) was strongly associated with OTC exposures. The present study indicates that OTC toxicity effects in P. pugio and changes in the shrimp microbial community would only be expected under special circumstances. [source] Wastewater treatment plants as a pathway for aquatic contamination by pharmaceuticals in the Ebro river basin (Northeast Spain)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2007Meritxell Gros Abstract The occurrence of 28 pharmaceuticals of major human consumption in Spain, including analgesics and anti-inflam-matories, lipid regulators, psychiatric drugs, antibiotics, antihistamines, and ,-blockers, was assessed along the Ebro river basin, one of the biggest irrigated lands in that country. Target compounds were simultaneously analyzed by off-line solid-phase extraction, followed by liquid chromatography-tandem mass spectrometry. The loads of detected pharmaceuticals and their removal rates were studied in seven wastewater treatment plants (WWTPs) located in the main cities along the basin. Total loads ranged from 2 to 5 and from 0.5 to 1.5 g/d/1,000 inhabitants in influent and effluent wastewaters, respectively. High removal rates (60,90%) were achieved mainly for analgesics and anti-inflammatories. The other groups showed lower rates, ranging from 20 to 60%, and in most cases, the antiepileptic carbamazepine, macrolide antibiotics, and trimethoprim were not eliminated at all. Finally, the contribution of WWTP effluents to the presence of pharmaceuticals in receiving river waters was surveyed. In receiving surface water, the most ubiquitous compounds were the analgesics and anti-inflammatories ibuprofen, diclofenac, and naproxen; the lipid regulators bezafibrate and gemfibrozil; the antibiotics erythromycin, azithromycin, sulfamethoxazole, trimethoprim, and less frequently, ofloxacin; the antiepileptic carbamazepine; the antihistamine ranitidine; and the ,-blockers atenolol and sotalol. Although levels found in WWTP effluents ranged from low ,g/L to high ng/L, pharmaceuticals in river waters occurred at levels at least one order of magnitude lower (low ng/L range) because of dilution effect. From the results obtained, it was proved that WWTP are hot spots of aquatic contamination concerning pharmaceuticals of human consumption. [source] Seasonality effects on pharmaceuticals and s -triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit RiverENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2006Wen Yi Hua Abstract The influence of seasonal changes in water conditions and parameters on several major pharmacologically active compounds (PhACs) and s -triazine herbicides was assessed in the wastewater and sewage treatment plant (WSTP) effluent as well as the downstream surface water from sites on the Canadian side of the upper Detroit River, between the Little River WSTP and near the water intake of a major drinking water treatment facility for the City of Windsor (ON, Canada). The assessed PhACs were of neutral (carbamazepine, cotinine, caffeine, cyclophosphamide, fluoxetine, norfluoxetine, pentoxifylline, and trimethoprim) and acidic (ibuprofen, bezafibrate, clofibric acid, diclofenac, fenoprofen, gemfibrozil, indomethacin, naproxen, and ketoprofen) varieties. The major assessed s -triazine herbicides were atrazine, simazine, propazine, prometon, ametryn, prometryn, and terbutryn. At sampling times from September 2002 to June 2003, 15 PhACs were detected in the WSTP effluent at concentrations ranging from 1.7 to 1,244 ng/L. The PhAC concentrations decreased by as much 92 to 100% at the Little River/Detroit River confluence because of the river dilution effect, with further continual decreases at sites downstream from the WSTP. The only quantifiable s -triazine in WSTP effluent, atrazine, ranged from 6.7 to 200 ng/L and was higher in Detroit River surface waters than in WSTP effluent. Only carbamazepine, cotinine, and atrazine were detectable at the low-nanogram and subnanogram levels in surface waters near a drinking water intake site. Unlike the PhACs, atrazine in the Detroit River is not attributable to point sources, and it is heavily influenced by seasonal agricultural usage and runoff. Detroit River surface water concentrations of carbamazepine, cotinine, and atrazine may present a health concern to aquatic wildlife and to humans via the consumption of drinking water. [source] Substrate and inhibitor specificity of Mycobacterium avium dihydrofolate reductaseFEBS JOURNAL, Issue 13 2007Ronnie A. Böck Dihydrofolate reductase (EC 1.5.1.3) is a key enzyme in the folate biosynthetic pathway. Information regarding key residues in the dihydrofolate-binding site of Mycobacterium avium dihydrofolate reductase is lacking. On the basis of previous information, Asp31 and Leu32 were selected as residues that are potentially important in interactions with dihydrofolate and antifolates (e.g. trimethoprim), respectively. Asp31 and Leu32 were modified by site-directed mutagenesis, giving the mutants D31A, D31E, D31Q, D31N and D31L, and L32A, L32F and L32D. Mutated proteins were expressed in Escherichia coli BL21(DE3)pLysS and purified using His-Bind resin; functionality was assessed in comparison with the recombinant wild type by a standard enzyme assay, and growth complementation and kinetic parameters were evaluated. All Asp31 substitutions affected enzyme function; D31E, D31Q and D31N reduced activity by 80,90%, and D31A and D31L by >,90%. All D31 mutants had modified kinetics, ranging from three-fold (D31N) to 283-fold (D31L) increases in Km for dihydrofolate, and 12-fold (D31N) to 223 077-fold (D31L) decreases in kcat/Km. Of the Leu32 substitutions, only L32D caused reduced enzyme activity (67%) and kinetic differences from the wild type (seven-fold increase in Km; 21-fold decrease in kcat/Km). Only minor variations in the Km for NADPH were observed for all substitutions. Whereas the L32F mutant retained similar trimethoprim affinity as the wild type, the L32A mutation resulted in a 12-fold decrease in affinity and the L32D mutation resulted in a seven-fold increase in affinity for trimethoprim. These findings support the hypotheses that Asp31 plays a functional role in binding of the substrate and Leu32 plays a functional role in binding of trimethoprim. [source] No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2009An Thyssen Abstract Objective The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. Methods Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6,mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200,mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. Results Creatinine clearance decreased from 119 to 102,mL,min,1 with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC, by 9%, and t˝ by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80,125% range for Cmax, AUClast, and renal clearance. For AUC,, 90% CI was 79.37,101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. Conclusions No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors. Copyright © 2009 John Wiley & Sons, Ltd. [source] Lymphocutaneous nocardiosis and cutaneous pheohyphomycosis in a liver transplant recipientINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 6 2008Isabel Hidalgo Parra Background, Infections are the leading cause of morbidity and mortality in transplanted patients. The increasing number of immunocompromised patients has not only augmented infections by specific pathogens, but also by opportunistic microbial agents. Methods, A mixed cutaneous infection caused by Nocardia brasiliensis and Exophiala jeanselmei is reported in a liver transplant patient. Results, The cutaneous lesions were painful nodules which drained purulent material. They were located on the right lower limb, with lymphadenopathies in the groin. Conclusions, The patient was treated with itraconazole (600 mg/day) plus trimethoprim (1600 mg/day),sulfamethoxazole (320 mg/day) for 8 weeks, with complete remission of the lesions. [source] Fixed drug eruption in NigeriaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 9 2006Edith N. Nnoruka MBBS Fixed drug eruption (FDE) causes cosmetic embarrassment in Nigerian patients, particularly when the characteristic hyperpigmented patches affect the face and lips. Drugs that have been implicated in the etiology of FDE, and the sites of lesions, may vary from country to country. Antimalarials, such as Fansidar, Fancimef, Maloxine, Amalar, and Metakelfin, were the most common offending agents, accounting for 38% of FDEs, followed by trimethoprim + sulfamethoxazole (co-trimoxazole) (28%), dipyrones (10%), Butazolidin (6%), thiacetazone (6%), metronidazole (4%), paracetamol (3%), and naproxen (3%). Lesions induced by the combination of sulfadoxine and pyrimethamine (in antimalarials) mainly involved the face and lips. In most cases, patients took these sulfa-containing antimalarials in combination with numerous other drugs, particularly analgesics. Unlike chloroquine-induced pruritus, which affects most Africans, the association between antimalarials and FDE has not been well documented in our region. Co-trimoxazole was associated more often than antimalarials with FDEs involving the mucocutaneous junctions of the genitalia and lips. Males with genital lesions on the glans penis represented 11 (48%) of those with co-trimoxazole hypersensitivity. The trunk and limbs were affected mainly by pyrazoles and Butazolidin, respectively; however, solitary lesions on the trunk were usually due to co-trimoxazole, whereas solitary lesions on the limbs were associated with Butazolidin. [source] 7-Methyl Trimethoprim Analogues as Inhibitors of the Folate Metabolizing Enzymes,JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2003Aleem Gangjee A series of 5-(1-phenylethyl)pyrimidines 2,10 (Table I) were designed and synthesized as potent and selective inhibitors of Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii) and Mycobacterium avium (M. avium) dihydrofolate reductases (DHFR). The structure of 2,10 incorporates a 7-methyl group to increase the potency of monocyclic trimethoprim (TMP). The target compounds were synthesized by an acid catalyzed condensation of ethyl cyanoacetate and appropriately substituted benzaldehydes followed by a Michael addition using methyl copper-lithium. The resulting adduct was cyclocondensed with guanidine to afford 2,6-diamino-4-hydroxy-5-(1-phenylethyl)pyrimidines 2,7. Both amino moieties of 2,4 were protected with pivaloyl groups and their 4-hydroxy group chlorinated with phosphorus oxychloride. The resulting intermediates were subjected to hydrogenation and deprotection to afford 8,10. Compound 7 was a good inhibitor of DHFR, however the other compounds were poor inhibitors of P. carinii, T. gondii and M. avium DHFR. [source] Uptake of lamivudine by rat renal brush border membrane vesiclesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2002Takatoshi Takubo Uptake of lamivudine, a nucleoside analogue antiviral agent, by brush border membrane vesicles (BBMV) prepared from rat renal cortex was investigated. Initial uptake of lamivudine by BBMV was stimulated in the presence of an outward pH gradient. Determination of the kinetic parameters of the initial uptake yielded apparent Km and Vmax values of 2.28 mM and 1.56 nmol (mg protein),1 (20 s),1, respectively. The pH-driven uptake of lamivudine was inhibited by organic cations such as trimethoprim and cimetidine. The inhibitory effect of trimethoprim on lamivudine uptake was competitive, with an apparent Ki of 27.6 ,M. The uptake of lamivudine was also inhibited by nitrobenzylthioinosine, a representative inhibitor of nucleoside transport, and by other nucleoside analogues, such as azidothymidine and dideoxycytidine, that are excreted by renal tubular secretion. These findings suggest that efflux of lamivudine at the brush border membrane of renal tubular epithelium is mediated by an H+/lamivudine antiport system, which may correspond to the H+/organic cation antiport system, and that this system is also involved in the renal secretion of other nucleoside analogues. [source] Multi-residue method for the analysis of pharmaceutical compounds in sewage sludge, compost and sediments by sonication-assisted extraction and LC determinationJOURNAL OF SEPARATION SCIENCE, JSS, Issue 12 2010Julia Martín Abstract A method for the simultaneous determination of 16 pharmaceutical compounds in three types of sewage sludge (primary, secondary and anaerobically digested dehydrated sludge), compost and sediment samples is described. Pharmaceutical compounds evaluated were nonsteroidal anti-inflammatory drugs (acetaminophen, diclofenac, ibuprofen, ketoprofen, naproxen and salicylic acid), antibiotics (sulfamethoxazole and trimethoprim), an anti-epileptic drug (carbamazepine), a ,-blocker (propranolol), a nervous stimulant (caffeine), estrogens (17,-ethinylestradiol, 17,-estradiol, estriol and estrone) and lipid regulators (clofibric acid, metabolite of clofibrate and gemfibrozil). The method is based on the ultrasonic-assisted extraction, clean-up by SPE and analytical determination by HPLC with diode array and fluorescence detectors. The best extraction recoveries were achieved in a three-step extraction procedure with methanol and acetone as extraction solvents. Extraction recoveries of several pharmaceutical compounds as caffeine were highly dependent on the type of sample evaluated. The applicability of the method was tested by analyzing primary, secondary and anaerobically digested dehydrated sludge, compost and sediment samples from Seville (Southern Spain). Ten of the sixteen pharmaceutical compounds were detected in sludge samples and five in compost and sediment samples. The highest concentration levels were recorded for ibuprofen in sewage samples, whereas salicylic acid and 17,-ethinylestradiol were detected in all of the samples analyzed. [source] Simultaneous determination of macrolides, sulfonamides, and other pharmaceuticals in water samples by solid-phase extraction and LC-(ESI) MSJOURNAL OF SEPARATION SCIENCE, JSS, Issue 12 2008Marta Pedrouzo Abstract This paper describes a method for determining 11 pharmaceuticals in various water sources by SPE followed by LC-(ESI) MS. SPE was carried out with OasisTM HLB and the recoveries were 33,67% for 250 and 100 mL sewage water, 55,77% for 500 mL river water and 72,98% for 1 L tap water, with the exception of sulfamethoxazole and omeprazole which showed lower recoveries in all kinds of sample. The LODs in river water were of 5 ng/L for sulfadiazine, trimethoprim, sulfamethazine, sulfamethoxazole, and ranitidine and 10 ng/L for the other compounds. The highest concentrations found in river waters were for sulfamethoxazole (50 ng/L). In influent sewage waters, ranitidine was the most commonly detected compound with a maximum value of 0.24 ,g/L. [source] Efficacy of trimethoprim-sulfadoxine against Escherichia coli in a tissue cage model in calvesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2002C. Greko Tissue cages implanted subcutaneously in calves were infected with Escherichia coli. Twenty-four hours later, the calves were treated either with single doses of 2.5 + 12.5 or 5 + 25 mg/kg trimethoprim (TMP) + sulfadoxine (SDX) or with five doses of 7.5 + 37.5 mg/kg TMP + SDX at 12-h intervals. In addition, one cage in each of three calves in the highest dose group was infected 3 h after initiation of treatment. Untreated calves were kept as controls. Concentrations of TMP and SDX in plasma and tissue cage fluid (TCF) and counts of viable bacteria in TCF were determined. In the highest dose group, concentrations of TMP in TCF remained above the minimum inhibitory concentration of the test strain for 94,101 h and peak to minimum inhibitory concentration (MIC) ratio was close to 10. In spite of this, an effect of treatment was noted only in cages infected after initiation of treatment. In vitro studies and analysis of thymidine content in serum and TCF from calves suggest that levels of thymidine in TCF are high enough to antagonize the antibacterial effect of TMP. The results indicate that soft tissue infections in secluded infection sites of calves are refractory to treatment with TMP + SDX. [source] Pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole in alpacasJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2002J. Chakwenya The pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) were studied in six healthy male-castrate alpacas (Lama pacos) after intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP-SMX using a crossover design with a 2-week washout period. After 90 days one group (n = 3) was given a p.o. dose of 30 mg/kg TMP-SMX and the other group (n = 3) was given a p.o. dose of 60 mg/kg TMP-SMX. After i.v. administration of 15 mg/kg of TMP-SMX the mean initial plasma concentration (C0) was 10.75 ± 2.12 ,g/mL for trimethoprim (TMP) and 158.3 ± 189.3 ,g/mL for sulfamethoxazole (SMX). Elimination half-lives were 0.74 ± 0.1 h for TMP and 2.2 ± 0.6 h for SMX. The mean residence times were 1.45 ± 0.72 h for TMP and 2.8 ± 0.6 h for SMX. The areas under the respective concentration vs. time curves (AUC) were 2.49 ± 1.62 ,g h/mL for TMP and 124 ± 60 ,g h/mL for SMX. Total clearance (Clt) for TMP was 21.63 ± 9.85 and 1.90 ± 0.77 mL/min kg for SMX. The volume of distribution at steady state was 2.32 ± 1.15 L/kg for TMP and 0.35 ± 0.09 L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak concentration (Cmax) of SMX were 1.9 ± 0.8, 2.6 ± 0.4 and 2.8 ± 0.7 ,g/mL, respectively. The AUC was 9.1 ± 5, 25.9 ± 3.3 and 39.1 ± 4.1 ,g h/mL, respectively. Based upon these AUC values and correcting for dose, the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not detected in plasma after intragastric administration. These data demonstrate that therapeutic concentrations of TMP-SMX are not achieved after p.o. administration to alpacas. [source] The use of ribotyping and antibiotic resistance patterns for identification of host sources of Escherichia coli strainsLETTERS IN APPLIED MICROBIOLOGY, Issue 1 2005M. Samadpour Abstract Aims:, To compare antibiotic resistance and ribotyping patterns ability to identify triplicate isolates sent from a group of 40 Escherichia coli taken from seven host sources. Methods and Results:, Of the 120 isolates, 22 isolates were resistant to ampicillin, streptomycin, tetracycline and trimethoprim and 98 isolates were susceptible. Antibiotic patterns identified 33 of the triplicates and three of the six groups had isolates from multiple hosts. Ribotyping divided the isolates into 27 ribotype groups with all triplicates grouped into the same ribotype group with one host per group. Conclusions:, Antibiotic susceptibility pattern placed 98 of the isolates in a single group with 50% of the antibiotic susceptibility pattern groups containing multiple host species. Ribotyping groups were host specific with each host having one to seven ribotype groups. Significance and Impact of the Study:, Antibiotic susceptibility pattern groups have been used for environmental source identification and faecal pollution tracking, however these groups do not always distinguish between host species. Stability of the markers is a potential concern and this system can only be used if antibiotic resistance levels are high in the isolates studied. All isolates have a ribotype group which was stable and like other molecular methods has advantages over antibiotic susceptibility pattern groups which uses a phenotypic method. [source] Antibiotics in Dutch general practice: nationwide electronic GP database and national reimbursement rates,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2008Annemiek E. Akkerman PhD Abstract Purpose In order to assess whether different databases generate information which can be reliable compared with each other, this study aimed to assess to which degree prescribing rates for systemic antibiotics from a nationwide electronic general practitioner (GP) database correspond with national reimbursement rates, and to investigate for which indications antibiotics are prescribed. Methods Nationwide GP prescribing data were collected from the Second Dutch National Survey of General Practice (DNSGP-2) based on 90 general practices serving 358 008 patients in 2001. Dutch national reimbursement rates for GPs were derived from claims data of the Dutch Drug Information System/Health Care Insurance Board (GIP/CVZ) from 2001. We calculated antibiotic prescribing rates per 1000 patients/inhabitants for each database, and these rates were compared for the total rates and according to antibiotic subgroups. Indications for which GPs prescribed antibiotics were described. Results In national reimbursement data, 339 antibiotic prescriptions per 1000 inhabitants were prescribed by GPs, while the nationwide GP database showed 255 prescriptions per 1000 patients (75% coverage with reimbursement rates). The nationwide GP database showed high volumes of sulphonamides & trimethoprim, and small volumes of macrolides and quinolones. Half of the prescriptions (48%) were prescribed for respiratory diseases, a quarter (26%) for urinary diseases and 7% for ear diseases. Conclusions GPs voluntarily participating in a research network prescribe less antibiotics than Dutch GPs in general, and are cautious in prescribing newer and more broad-spectrum antibiotics. This point has to be taken into account when databases will be compared with each other. Copyright © 2007 John Wiley & Sons, Ltd. [source] Photodamage to Multidrug-resistant Gram-positive and Gram-negative Bacteria by 870 nm/930 nm Light Potentiates Erythromycin, Tetracycline and CiprofloxacinPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2010Eric Bornstein We have previously shown that 870 nm/930 nm wavelengths cause photodamage at physiologic temperatures in methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli via generation of endogenous radical oxygen species (ROS) and decreased plasma membrane potentials (,,p). We tested MRSA (Strain HSJ216) in vitro with sublethal 870 nm/930 nm laser energy and subinhibitory concentrations of erythromycin, tetracycline, penicillin, rifampin and trimethoprim to surmise whether photodamage could potentiate these antimicrobials. We also tested patient isolates of fluoroquinolone-resistant MRSA and E. coli with subinhibitory concentrations of ciprofloxacin. In MRSA (Strain HSJ216) we observed 97% potentiation (a 1.5 log10 CFU decrease) with erythromycin and tetracycline. In patient isolates of E. coli, we observed 100% potentiation (>3 log10 CFU decrease) in all irradiated samples with ciprofloxacin. To assess whether staphyloxanthin pigment conferred protection against the generated ROS, we created an isogenic carotenoid-deficient mutant of S. aureus that was significantly less tolerant of 870 nm/930 nm exposure than the wild type strain (P < 0.0001). We suggest that antibiotic potentiation results from a photobiological attenuation of ATP-dependent macromolecular synthetic pathways, similar to that observed with daptomycin, via disruption of ,,p and endogenous generation of ROS. With erythromycin, tetracycline and ciprofloxacin, attenuation of energy-dependent efflux systems is also a possibility. [source] Improved detection of reactive metabolites with a bromine-containing glutathione analog using mass defect and isotope pattern matchingRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 9 2010André LeBlanc Drug bioactivation leading to the formation of reactive species capable of covalent binding to proteins represents an important cause of drug-induced toxicity. Reactive metabolite detection using invitro microsomal incubations is a crucial step in assessing potential toxicity of pharmaceutical compounds. The most common method for screening the formation of these unstable, electrophilic species is by trapping them with glutathione (GSH) followed by liquid chromatography/mass spectrometry (LC/MS) analysis. The present work describes the use of a brominated analog of glutathione, N -(2-bromocarbobenzyloxy)-GSH (GSH-Br), for the invitro screening of reactive metabolites by LC/MS. This novel trapping agent was tested with four drug compounds known to form reactive metabolites, acetaminophen, fipexide, trimethoprim and clozapine. Invitro rat microsomal incubations were performed with GSH and GSH-Br for each drug with subsequent analysis by liquid chromatography/high-resolution mass spectrometry on an electrospray time-of-flight (ESI-TOF) instrument. A generic LC/MS method was used for data acquisition, followed by drug-specific processing of accurate mass data based on mass defect filtering and isotope pattern matching. GSH and GSH-Br incubations were compared to control samples using differential analysis (Mass Profiler) software to identify adducts formed via the formation of reactive metabolites. In all four cases, GSH-Br yielded improved results, with a decreased false positive rate, increased sensitivity and new adducts being identified in contrast to GSH alone. The combination of using this novel trapping agent with powerful processing routines for filtering accurate mass data and differential analysis represents a very reliable method for the identification of reactive metabolites formed in microsomal incubations. Copyright © 2010 John Wiley & Sons, Ltd. [source] Bis[2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium] dl -malateACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2009S. Franklin Racemic malic acid and trimethoprim [5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine] form a 1:2 salt (monoclinic, P21/c), 2C14H19N4O3+·C4H4O52,, in which the malate component is disordered across a centre of inversion. The crystal structure of the salt consists of protonated trimethoprim residues and a malate dianion. The carboxylate group of the malate ion interacts with the trimethoprim cation in a linear fashion through pairs of N,H...O hydrogen bonds to form a cyclic hydrogen-bonded motif. This is similar to the carboxylate,trimethoprim cation interaction observed earlier in the complex of dihydrofolate reductase with trimethoprim. The structure of the salt of trimethoprim with racemic dl -malic acid reported here is the first of its kind. The present study investigates the conformations and the hydrogen-bonding interactions, which are very important for biological functions. The pyrimidine plane makes a dihedral angle of 78.08,(7)° with the benzene ring of the trimethoprim cation. The cyclic hydrogen-bonded motif observed in this structure is self-organized, leading to novel types of hydrogen-bonding motifs in supramolecular patterns. [source] Antimicrobial resistance 1979,2009 at Karolinska hospital, Sweden: normalized resistance interpretation during a 30-year follow-up on Staphylococcus aureus and Escherichia coli resistance developmentAPMIS, Issue 9 2010GÖRAN KRONVALL Kronvall G. Antimicrobial resistance 1979,2009 at Karolinska hospital, Sweden: normalized resistance interpretation during a 30-year follow-up on Staphylococcus aureus and Escherichia coli resistance development. APMIS 2010; 118: 621,39. To utilize a material of inhibition zone diameter measurements from disc diffusion susceptibility tests between 1979 and 2009, an objective setting of epidemiological breakpoints was necessary because of methodological changes. Normalized resistance interpretation (NRI) met this need and was applied to zone diameter histograms for Staphylococcus aureus and Escherichia coli isolates. The results confirmed a slow resistance development as seen in Northern countries. The S. aureus resistance levels for erythromycin, clindamycin and fusidic acid in 2009 were 3.2%, 1.8% and 1.4% with denominator correction. A rise in resistance to four antimicrobials in 1983 was probably because of a spread of resistant Methicillin Susceptible Staphylococcus Aureus (MSSA). For E. coli, the denominator-corrected resistance levels in 2009 were 27% for ampicillin, around 3% for third-generation cephalosporins, 0.1% for imipenem, 2.5% for gentamicin, 19% for trimethoprim, 4.5% for co-trimoxazole, 1.2% for nitrofurantoin and 9% for ciprofloxacin. The temporal trends showed a rise in fluoroquinolone resistance from 1993, a parallel increase in gentamicin resistance, a substantial increase in trimethoprim and sulphonamide resistance in spite of decreased consumption, and a steady rise in ampicillin resistance from a constant level before 1989. A short review of global resistance surveillance studies is included. [source] Integrons and multidrug resistance among Escherichia coli causing community-acquired urinary tract infection in southern IndiaAPMIS, Issue 3 2004ELIZABETH MATHAI Antimicrobial resistance genes are often clustered in integrons, genetic elements capable of recombination. There is a paucity of data on the prevalence and role of integrons from community-acquired infections in developing countries where resistance to co-trimoxazole is high. We determined the prevalence of integrons among Escherichia coli causing community-acquired urinary tract infection (UTI). Consecutive isolates of E. coli obtained from UTI of pregnant women at the Christian Medical College Hospital, Vellore, India, during 2002 were included. All isolates were tested for susceptibility to 16 antimicrobials using the disc diffusion method and for integrons of classes 1 and 2 by PCR. Of the 58 isolates tested, 28 (48.3%) were resistant to co-trimoxazole and trimethoprim. All these isolates carried integrons. Three additional isolates were sulfonamide resistant but integron negative. Class 1 integrons were present in 21 (36.2%) isolates. Resistance to ampicillin (p=0.000), nalidixic acid (p=0.001), chloramphenicol (p=0.02), tetracycline (p=0.004) and gentamicin (p=0.02) was significantly more common in isolates with integrons. DNA sequencing of two isolates with integrons showed the presence of aadA, dfr1 and dfr7 genes. This study demonstrated that integrons are widely prevalent in India and that they might play a role in multidrug resistance in E. coli from community-aquired UTI. [source] Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureusACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Christian Oefner Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative. Iclaprim exhibits potent bactericidal activity against major Gram-positive pathogens, notably methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) phenotypes, including TMP-resistant strains. The inhibition properties of racemic iclaprim and of the two enantiomers, termed AR-101 and AR-102, towards S. aureus wild-type DHFR and TMP-resistant F98Y mutant DHFR were determined and compared. Similar to TMP, AR-101, AR-102 and iclaprim are all competitive inhibitors with respect to the substrate dihydrofolate. Iclaprim, AR-101 and AR-102 demonstrated little or no difference in activity towards these enzymes and were significantly more potent than TMP. The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim. The binding modes of the inhibitors were analysed and compared. The X-ray crystallographic data explain the binding modes of all molecules well and can be used to rationalize the equipotent affinity of AR-101, AR-102 and iclaprim, which is also reflected in their antibacterial properties. [source] Evidence-based prescription of antibiotics in urology: a 5-year review of microbiologyBJU INTERNATIONAL, Issue 6 2009Ranan DasGupta OBJECTIVE To analyse the results of positive urine cultures over a 5-year period in a large hospital and urology department (amongst both inpatients and outpatients), assess the prevalence of different organisms and the resistance profiles of a range of antibiotics, and thus provide information on which organisms are likely to cause urosepsis. METHODS The use of antibiotics should be based on knowledge of which pathogens are present and what resistance patterns are emerging, particularly relevant in surgical disciplines like urology, as antibiotics are now routinely administered peri-operatively, whereby evidence-based prescription is preferable to generic guidelines. We therefore examined almost 25 000 positive urine cultures in our hospital over a 5-year period, and focused on the infections encountered amongst urology patients during this time. RESULTS A significant proportion of inpatient urinary infection (40%) is caused by Gram-positive bacteria such as Streptococcus faecalis, underlining the need for including Gram-positive cover during urological prophylaxis. The commonest pathogen remains Escherichia coli among both inpatients and outpatients. The ineffectiveness of common antibiotics such as ciprofloxacin and trimethoprim was identified, as was the increase in gentamicin resistance. CONCLUSION We propose using an aminoglycoside with a penicillin for high-risk cases (e.g. endoscopic stone surgery) while low-risk cases (e.g. flexible cystoscopy with no risk factors) might be managed without such prophylaxis. Pathogenic patterns and resistance rates should be monitored regularly. [source] Oral ciprofloxacin or trimethoprim reduces bacteriuria after flexible cystoscopyBJU INTERNATIONAL, Issue 4 2007Mark I. Johnson OBJECTIVE To report a large prospective, pragmatic, double-blind randomized controlled trial to determine whether oral prophylactic antibiotics reduce the risk of bacteriuria after flexible cystoscopy (FC), as up to 10% of patients develop urinary infection afterwards, with significant morbidity and costs for health services. PATIENTS AND METHODS In all, 2481 patients were recruited into a three-arm placebo controlled trial and 2083 completed it. Patients were randomly assigned to one of three treatments; (i) placebo; (ii) one oral dose of trimethoprim (200 mg); or (iii) one oral dose of ciprofloxacin (500 mg), each administered 1 h before a FC under local anaesthetic. A mid-stream urine specimen was taken before and 5 days after FC; significant bacteriuria was defined as a pure growth of >105 colony-forming units/mL. RESULTS The rate of bacteriuria after FC was reduced from 9% in the placebo group to 5% and 3% in patients receiving trimethoprim and ciprofloxacin prophylaxis, respectively. When rates of bacteriuria before FC were considered the odds of developing bacteriuria after FC relative to baseline were 5, 2 and 0.5 for placebo, trimethoprim and ciprofloxacin, respectively. CONCLUSION This large trial shows clearly that one dose of oral ciprofloxacin significantly reduces bacteriuria after FC. [source] Isolation of both Sporothrix schenckii and Nocardia asteroides from a mycetoma of the forefootBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2000K. Pelzer Mycetoma is a localized primary subcutaneous infection due to fungi (eumycetoma) or aerobic actinomycetes (actinomycetoma). We report a patient who acquired an implantation infection on the forefoot following a motorcycle accident in Crete. Both Sporothrix schenckii and Nocardia asteroides were isolated simultaneously from the lesion. Under combined therapy with itraconazole and trimethoprim,sulphamethoxazole for 7 months the lesion healed completely. A combination of causative organisms in mycetomas is rare, and the combination of S. schenckii and N. asteroides together has not been reported from one lesion. [source] Linking Pneumocystis jiroveci sulfamethoxazole resistance to the alleles of the DHPS gene using functional complementation in Saccharomyces cerevisiaeCLINICAL MICROBIOLOGY AND INFECTION, Issue 5 2010R. Moukhlis Clin Microbiol Infect 2010; 16: 501,507 Abstract Curative and prophylactic therapy for Pneumocystis jiroveci pneumonia relies mainly on cotrimoxazole, an association of trimethoprim and sulfamethoxazole (SMX). SMX inhibits the folic acid pathway through competition with para-aminobenzoic acid (pABA), one of the two substrates of the dihydropteroate synthase (DHPS), a key enzyme in de novo folic acid synthesis. The most frequent non-synonymous single nucleotide polymorphisms (SNPs) in P. jiroveci DHPS are seen at positions 165 and 171, the combination leading to four possible different genetic alleles. A number of reports correlate prophylaxis failure and mutation in the P. jiroveci DHPS but, because of the impossibility of reliably cultivating P. jiroveci, the link between DHPS mutation(s) and SMX susceptibility is not definitively proven. To circumvent this limitation, the yeast Saccharomyces cerevisiae was used as a model. The introduction of the P. jiroveci DHPS gene, with or without point mutations, directly amplified from a clinical specimen and cloned in a centromeric plasmid into a DHPS-deleted yeast strain, allowed a fully effective complementation. However, in the presence of SMX at concentrations >250 mg/L, yeasts complemented with the double mutated allele showed a lower susceptibility compared with strains complemented with either a single mutated allele or wild-type alleles. These results confirm the need for prospective study of pneumocystosis, including systematic determination of the DHPS genotype, to clarify further the impact of mutations on clinical outcome. Additionally, the S. cerevisiae model proves to be useful for the study of still uninvestigated biological properties of P. jiroveci. [source] | ||||||||||||||||