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Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3'- and 4'-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4'-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4'-demethylation. TMP 3'-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.
The development of Nocardia keratitis in a patient with human immunodeficiency virus infection is rare, and we could find no cases reported in the literature.
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Twenty-one of the 27 isolates examined, all from the Accra metropolitan area, carried both SXT, an integrated chromosomal element, and a class 2 integron bearing dfrA1, sat and aadA1 cassettes. All these isolates had identical random amplification of polymorphic DNA profiles and two of them also carried a class 1 integron.
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Between January 2005 and August 2007, we randomized 252 postmenopausal women with recurrent UTIs taking part in a double-blind noninferiority trial to receive 12 months of prophylaxis with trimethoprim-sulfamethoxazole, 480 mg, once daily or oral capsules containing 109 colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. Primary end points were the mean number of symptomatic UTIs, proportion of participants with at least 1 UTI during 12 months, time to first UTI, and development of antibiotic resistance by Escherichia coli.
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Our results support combination treatment with intraventricular gentamicin for postneurosurgical GNB ventriculomeningitis. Meropenem seems to be an effective and safe alternative for the systemic antibiotic treatment of these neurointensive care infections.
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A 57-year-old immunocompetent African American man with a long-standing history of open-angle glaucoma in both eyes treated with trabeculectomy presented with a diffusely hyperemic, thin, cystic, leaky bleb with no discharge in his left eye. The patient underwent bleb revision using an amniotic membrane patch graft followed by 1 month of antibiotics. He presented second time with an inflamed eye and brisk leakage and underwent a second bleb revision. His cultures remained negative. Two months after this second surgery, an anterior staphyloma had formed within the bleb area, and visible leakage of purulent material and a dense hypopyon was noted. Gram stain of the material showed rare long-branching rods. The material was sent to an outside laboratory for culture and identification.
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One hundred seven patients were enrolled. All had HIV infection, < 200 CD4+ lymphocytes per mm3, and no history of PCP. Fifty-two were randomized to TMP/SMX twice daily (BID); of these, 26 were randomized to leucovorin with each dose. Fifty-five patients were randomized to TMP/SMX (BID) 3 times per week; of these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently.
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The antibacterial activity of the four possible combinations of the three drugs, colistin, sulphamethoxazole, and trimethoprim, has been investigated with Gram-negative bacteria. All of the strains examined, with the exception of the strains of Proteus, were sensitive to colistin. The combination of colistin and sulphamethoxazole was synergic against all 141 sulphamethoxazole-sensitive bacteria out of a total of 164 organisms against which it was tested. The sensitive strains comprised 27 of the 37 Esch. coli, 51 of the 54 Ps. aeruginosa, 24 of the 30 Kl. aerogenes, eight of the 12 shigellae, and all 21 Proteus and 10 salmonellae tested. The combined effect was indifference against the remaining 23 organisms which were resistant to sulphamethoxazole. The combination of colistin and trimethoprim was synergic against all 72 organisms against which it was tested, which comprised 10 Esch. coli, 14 Ps. aeruginosa, 14 Kl. aerogenes, 12 Proteus spp, 10 salmonellae, and 12 shigellae. The combination of sulphamethoxazole and trimethoprim was synergic against 61 of the same 72 organisms; the exceptions were three Esch. coli, four Kl. aerogenes, and four shigellae, all of which were sulphamethoxazole resistant. The combination of all three drugs-colistin, sulphamethoxazole, and trimethoprim-was more active than combinations of any two against 66 of the 72 organisms. The exceptions were three strains of Esch. coli, two of Kl. aerogenes, and one shigella, all of which were sulphamethoxazole resistant.
Trimethoprim-sulfamethoxazole may cause hyperkalaemia by the amiloride-like effect of trimethoprim on sodium channels in the distal nephron. Hyperkalaemia usually occurs after 7-10 days and has been reported in 20%-50% of patients receiving trimethoprim-sulfamethoxazole. Patients with Pneumocystis jiroveci pneumonia and severe hypoxaemia benefit from the use of prednisolone as an adjuvant to trimethoprim-sulfamethoxazole. The addition of prednisolone may lower the incidence of trimethoprim-related hyperkalaemia due, in part, to its mineralocorticoid activity. We studied the effect of concomitant prednisolone on trimethoprim-related hyperkalaemia.
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The activities of the 2,4-diamino-5-benzylpyrimidines brodimoprim and metioprim against anaerobic bacteria were tested alone and in combination with sulfonamides. Alone they were two to four times more active than trimethoprim, but in combination with sulfonamides, their activity was slightly lower than that of trimethoprim plus sulfamethoxazole.
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Listeriosis in HIV infected patients is uncommon and usually presents as meningitis or bacteraemia. Pleural fluid infections caused by this organism are extremely rare. A case is described of empyema caused by Listeria monocytogenes in an HIV infected patient that was successfully treated with medical treatment only.
We analysed data collected from January 1990 through August 1995 in more than 90 inpatient and outpatient medical facilities in nine US cities. Incidence was calculated as cases per 100 person-years and risk ratios (RR) for annual incidence were calculated using proportional hazards regression while controlling for city, sex, race, age, county of birth, HIV exposure mode, and prior prescription of trimethoprim-sulfamethoxazole (TMP-SMX).
The patient's symptoms regressed over several weeks without any specific treatment and 8 weeks after onset of the rash the laboratory tests also became normal. The allergic cause of the cholestatic hepatitis was confirmed by a lymphocyte transformation test.
A 57-year-old woman was hospitalized for exploration of migrating joint pain that had developed for 5 years. Histologically proven Whipple's disease was diagnosed on duodenal biopsies. The lung angiogram performed to explore signs of right heart failure demonstrated pulmonary hypertension and ruled out pulmonary embolism. Abundant pericardial effusion developed progressively. Antibiotic therapy using sulfamethoxazole-trimethoprime led to a systemic Jarisch Herxheilmer reaction. The pulmonary hypertension resolved rapidly, the pericardial effusion more slowly.
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Fourteen (3.8%) cases of NPCM were identified out of 367 patients with paracoccidioidomycosis (PCM). A combination of oral fluconazole and sulfamethoxazole/trimethoprim (SMZ/TMP) was the regimen of choice, with no documented death due to Paracoccidioides brasiliensis infection. Residual neurological deficits were observed in 8 patients. Residual calcification was a common finding in neuroimaging follow-up.
Cerebral toxoplasmosis or toxoplasmic meningoencephalitis (hereafter referred to as TE) was one of the first opportunistic infections to be described in human immunodeficiency virus (HIV) -infected patients. Treatment of TE has been relatively successful in comparison to other opportunistic infections. Prior to the introduction of highly active antiretroviral therapy (HAART), a median survival of over a year was reported for patients who could tolerate the toxicity of TE treatment. HAART is becoming increasingly widely available in sub-Saharan Africa, where the majority of HIV-infected patients live. Many patients in Africa are diagnosed with HIV only after developing opportunistic infections such as TE. Hence, the optimal management of opportunistic infections such as TE is important if the benefits of subsequently initiating HAART are to be seen.
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Urine cultures are not always performed for female Emergency Department (ED) patients with uncomplicated urinary tract infection (UTI). Accordingly, hospital, and even ED-specific, antibiograms might be skewed toward elderly patients with many comorbidities and relatively high rates of antimicrobial resistance, and thus do not accurately reflect otherwise healthy women. Our ED antibiogram indicates Escherichia coli resistance rates for ciprofloxacin, levofloxacin, and trimethoprim-sulfamethoxazole (TMP-SMX) of 42%, 26%, and 33%, respectively.
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Retrospective study of all patients who had OSST from 1997 to 2007 and received follow-up for systemic immunosuppression at the Cincinnati Eye Institute. Patients were analyzed for demographics, systemic immunosuppression exposure, ocular surface stability, efficacy, and toxicity variables.
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In 2005, we estimated that there were 135,300 new HIV infections (adult HIV incidence 0.96%), 691,900 asymptomatic prevalent infections, 88 100 AIDS cases, and 76 400 AIDS deaths. An estimated 647,000 (80%) HIV-infected adults were unaware of their infection; one third of all adult deaths were HIV related. As a result of population growth, by 2008 a similar number of people will be HIV infected (1.1 million) as during the peak of the epidemic in 1994. Although antiretroviral therapy (ART) coverage is expected to rise from 67,000 (2005) to 160,000 (2010), the number of persons needing but not receiving ART will decrease only slightly from 127,600 (2005) to 111,100 (2010). The use of single-dose in 2005 nevirapine probably averted only 4% of the estimated 20 400 vertical infections.
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With the increased movement of the world population, acquaintance with the clinical picture of the Madura foot is of growing importance beyond its original endemic areas. The characteristic triad of symptoms consists of indurated swelling, multiple sinus tracts with purulent discharge filled with grains and localization at the foot. An increasing number of new etiologic agents are recognized today. For a better choice of therapy an adequate diagnostic procedure is essential ; a deep biopsy for histology appears to give a more substantial contribution to identification of the causal organism than culture. The treatment which should be started early, is at first essentially a drug treatment. However, in spite of high expectations with regard to new antimycotic drugs, amputation or disarticulation is often inevitable even today, particularly when the lesion is caused by Eumycetes. The first two documented patients with this disease in the Netherlands are described. They developed serious deformities of the lower extremity despite long-term use of antimycotic and antibiotic medication.
A 55-year-old female recipient of an orthotopic liver transplant, who was receiving azathioprine, prednisone and cyclosporin, developed bacteremia due to Listeria monocytogenes. Because of a penicillin allergy, the patient was treated primarIly with trimethoprim-sulfamethoxazole, to which she responded well. The prior literature on use of trimethoprim-sulfamethoxazole in listeria infections is reviewed, and future recommendations are considered. On the basis of the experience described in this case report as well as a review of the literature, trimethoprim-sulfamethoxazole appears to be an effective treatment of listeria infections.
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In acute pyelonephritis, bacterial resistance to co-trimoxazole predicts treatment failure, but the clonal basis of such resistance is undefined. We did molecular and serological analyses of 170 Escherichia coli urine isolates obtained in 1994-96 from women with acute pyelonephritis. 12 (7%) of the pyelonephritis isolates were in clonal group A (CGA; responsible for 38-51% of co-trimoxazole resistance in acute cystitis), including ten (34%) of 29 isolates that were resistant to co-trimoxazole. CGA isolates were obtained from diverse locations across the USA and were related to the O15:K52:H1 clone of the 1986-87 outbreak in London, UK. Thus, CGA is broadly disseminated and contributes to co-trimoxazole resistance in pyelonephritis as well as in cystitis.
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Inpatient and outpatient use of potentially cross-reactive drugs was observed in 52% of patients, although numerous patients were unable to give an accurate allergy history. No adverse effects were reported or documented with outpatient or inpatient sulfonamide nonantibiotic use, even among patients with histories of life-threatening reactions to sulfonamides.
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The efficacy and tolerance of pentamidine aerosol were evaluated in the prophylaxis and therapy of murine Pneumocystis carinii pneumonia. P. carinii pneumonia was induced in rats by corticosteroid immunosuppression. Pentamidine was administered three times weekly via a Bird micronebulizer. The actual amount of pentamidine inhaled was estimated by monitoring the ventilation of the rats during the aerosol administration. Pentamidine levels in blood, lung, liver and kidney samples were determined by high-pressure liquid chromatography after completion of the treatment. Efficacy was evaluated by examination of lung imprints. In the prophylactic treatment, 4.8- and 8.6-mg/kg doses of aerosolized pentamidine administered three times weekly for 7 weeks were effective in preventing P. carinii pneumonia in 80 and 100% of the rats, respectively. In the therapeutic studies, a 14.6-mg/kg dose of aerosolized pentamidine administered three times weekly for 3 weeks was effective both in curing the pneumonia and in clearing P. carinii cysts in 70% of the rats. In the remaining animals, although the pneumonia was cured, the cysts persisted. A dose-dependent effect of the drug was demonstrated in both prophylactic and therapeutic treatments. High lung/kidney and lung/liver ratios of pentamidine levels were demonstrated and were associated with good clinical, biological, and histologic tolerance.
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First isolated in the 1960s methicillin-resistant Staphylococcus aureus (MRSA) has become a leading hospital acquired (HA) pathogen, although community acquired isolates (CA-MRSA) are on the rise, particularly in the USA. Treatment of serious MRSA infections has been based for many years upon the use of glycopeptides, i.e. vancomycin and teicoplanin. Other drugs indicated in particular clinical settings, such as prosthetic valve endocarditis or osteomyelitis, are rifampin, gentamycin, fusidic acid, minocycline, co-trimoxazole, clindamycin. Quinolones and doxycycline may be active on some MRSA isolates, and add some this important clinical setting. In the last few years new anti-MRSA drugs have been registered and patented, expanding therapeutic opportunities, i.e. linezolid, the first oxazolidinone, available both as oral and parenteral formulation in being the most widely used new anti-MRSA agent, quinupristin-dalfopristin, daptomycin, a novel lipopeptide, active on germs both in the replicating and in the resting phase, and tigecycline, the first approved glycylcycline. Other drugs from different classes are in the pipeline and will further enhance in the next few years our therapeutic armamentarium: three glycopeptides, i.e. dalbavancin, telavancin, and oritavancin, two broad spectrum cephalosporins, ceftobiprole and ceftaroline, iclaprim, a diaminopyrimidine, as well as a carbapenem, CS-023/RO-4908463, and adjuvant therapies such as the monoclonal antibody tefibazumab.
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Unit costs (US$ in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness expressed as cost per life-year saved, cost per quality adjusted life-year (QALY) saved, cost per disability adjusted life-year (DALY) averted was calculated across a number of different scenarios at tertiary and primary healthcare centres.
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A total of 2842 samples were collected from both outpatient and inpatient departments. The majority of samples in this study were midstream urine specimens, others included catheterized urine samples. Standard parameters were followed for isolation and identification of clinical isolates and further antimicrobial susceptibility test was done by Kirby Bauer disk diffusion method.
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Although anaphylaxis due to trimethoprim seems to be rare, it may be more common than previously thought. Apparently, anaphylaxis to cotrimoxazole is not always caused by sulphamethoxazole.
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The scientific basis for using folinic acid in combination with the antiparasitic drugs prescribed to AIDS patients has been reviewed. In vitro and experimental data are unclear. On the basis of folinic acid metabolism and pharmacology and of clinical experience, we suggest that folinic acid should not be systematically added to the curative treatment of pneumocystosis with cotrimoxazole. Folinic acid may be added to prophylactic regimens using high-dose cotrimoxazole (i.e. 800 mg sulfamethoxazole twice a day) and in malnourished patients. It should be administered as soon as cytopenia occurs in the course of treatment. Concerning toxoplasmosis, the addition of folinic acid is recommended in doses of 10 to 20 mg/day in acute therapy and 5 to 10 mg/day in maintenance therapy. Dosage must be adjusted to the results of blood counts.
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Fifty-eight percent (152/261) CF Foundation accredited programs completed the survey. Ninety-eight percent (149/152) of respondents reported using antibiotics (oral or intravenous) against MRSA. Variability exists in the use of antibiotics amongst the programs and in the dosages utilized. For oral outpatient treatment, sulfamethoxazole/trimethoprim was the most commonly utilized antibiotic by both pediatric (109/287, 38%) and adult (99/295, 34%) respondents, of which, ten percent of reported to use it in combination with rifampin. For inpatient treatment, linezolid (both intravenous (IV) and oral) was most commonly utilized in both pediatric (IV 35/224, 16%; oral 41/224, 18%), and adult (IV 44/235, 19%; oral 38/235, 16%) respondents for inpatient treatment. IV vancomycin was the second most commonly utilized antibiotic by pediatric (70/224, 31%) and adult (71/235, 30%) respondents. Most respondents reported dose titration to achieve a vancomycin trough level of 15-20 mg/L (150/179, 84%). Topical or inhaled antibiotic utilization was reported to be an uncommon practice with approximately 70% of pediatric and adult respondents reporting to use them either rarely or never. The concomitant use of anti-MRSA and anti-pseudomonal antibiotics was common with 96% of pediatric and 99% of adult respondents answering in the affirmative.