Fleroxacin (Ro 23-6240): activity in virtro against 355 enteropathogenic and non-fermentative Gram-negative bacilli and Legionella pneumophila

The antibacterial activity of fleroxacin (Ro 23-6240, AM-833), a new 6-fluoroquinolone, was determined against 149 strains of enteropathogenic bacteria (17 species) and 191 strains (28 species) of glucose non-fermentative Gram-negative rods (excluding Pseudomonas aeruginosa), and against 15 strains of Legionella pneumophila. The cumulative susceptibility of these groups of bacteria to Ro 23-6240 at the 2 mg/l level were 99.2% 80.1 and 100% of tested strains, respectivel

Incidence of gallbladder lithiasis after ceftriaxone treatment

Ceftriaxone has potent activity against a broad range of Gram-positive and Gram-negative bacteria. While it is eliminated mainly by the kidney, 10-20% of the drug is eliminated in the bile and ceftriaxone salt precipitates have been described in the gallbladder of animals dosed with ceftriaxone. The purpose of the present study was to investigate the incidence of biliary lithiasis 6 and 12 months after treatment with ceftriaxone and to compare it with that in patients treated with amoxycillin/clavulanate. Biliary ultrasonography was performed at the start of treatment, at 6 months and at 12 months after the beginning of the study. One hundred patients were randomized and 74 were evaluable: 34 were given amoxycillin/clavulanate, 40 ceftriaxone. Gallbladder lithiasis developed in one patient 12 months after the amoxycillin/clavulanate treatment and in none in the ceftriaxone treatment arm. Biliary precipitate during ceftriaxone treatment was not looked for because this phenomenon was not known at the beginning of the study, but gallbladder precipitation that was seen in two patients given ceftriaxone during and at the end of treatment, respectively, resolved spontaneously. In conclusion, ceftriaxone treatment does not appear to lead to gallstone formation more often than an antibiotic that is not eliminated through the bil

Dual Microsporidial Infection Due to Vittaforma corneae and Encephalitozoon hellem in a Patient with AIDS

A 46-year-old human immunodeficiency virus-infected Swiss citizen living in Tanzania presented with respiratory, abdominal, and urogenital complaints. Microsporidial spores were isolated from urine and a sinunasal aspirate and were propagated in MRC-5 cell cultures. Western blot analysis and riboprinting identified the sinunasal isolate as Encephalitozoon hellem. Electron microscopic investigation of the urine isolate revealed spores with diplokaryotic nuclei and five to six isofilar coils of the polar tube and sporonts with two or three diplokarya. All stages were enveloped by two membranes, corresponding to a cisterna of host endoplasmic reticulum studded with ribosomes. These characteristics have been described for the genus Vittaforma. Western blot analysis of this isolate revealed a banding pattern identical to that of the Vittaforma corneae reference isolate. Part of the small subunit rRNA gene was amplified, sequenced (239 base pairs), and found to be identical to that of V. corneae. This is the second isolation of V. corneae and the first description of urinary tract infection due to V. corneae in a patient with AID

Dual microsporidial infection due to Vittaforma corneae and Encephalitozoon hellem in a patient with AIDS.

A 46-year-old human immunodeficiency virus-infected Swiss citizen living in Tanzania presented with respiratory, abdominal, and urogenital complaints. Microsporidial spores were isolated from urine and a sinunasal aspirate and were propagated in MRC-5 cell cultures. Western blot analysis and riboprinting identified the sinunasal isolate as Encephalitozoon hellem. Electron microscopic investigation of the urine isolate revealed spores with diplokaryotic nuclei and five to six isofilar coils of the polar tube and sporonts with two or three diplokarya. All stages were enveloped by two membranes, corresponding to a cisterna of host endoplasmic reticulum studded with ribosomes. These characteristics have been described for the genus Vittaforma. Western blot analysis of this isolate revealed a banding pattern identical to that of the Vittaforma corneae reference isolate. Part of the small subunit rRNA gene was amplified, sequenced (239 base pairs), and found to be identical to that of V. corneae. This is the second isolation of V. corneae and the first description of urinary tract infection due to V. corneae in a patient with AIDS

Cladribine with cyclophosphamide and prednisone in the management of low-grade lymphoproliferative malignancies

The feasibility of combining cladribine with cyclophosphamide and prednisone in the management of indolent lymphoid malignancies was determined. Nineteen patients [nine chronic lymphocytic leukaemia (CLL), seven non-Hodgkin's lymphoma (NHL) and three macroglobulinaemia (M))] received cladribine 0.1 mg kg−1 per day as a subcutaneous bolus injection on days 1–3 (up to 5 injections) with intravenous cyclophosphamide 500 mg m−2 on day 1 and oral prednisone 40 mg m−2 on days 1–5 at 4-weekly intervals up to a maximum of six courses. A total of 80 courses were given. Overall response rate was 88%, with four patients achieving a complete clinical and haematological response and 12 achieving a partial response. Neutropenia WHO grade 4 in two patients and WHO grade 3 infection in one patient were the limiting toxicities on treatment. During the follow-up, WHO grade ≥3 haematological complications occurred in five patients and WHO grade ≥3 non-haematological complications in five patients. There were no treatment-related deaths. This study demonstrates the feasibility of the cladribine/cyclophosphamide/prednisone (CCP) combination that appears highly active and safe in the management of indolent lymphoid malignancies. © 1999 Cancer Research Campaig

Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity

Aquaglyceroporins (AQPs) transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human-infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP-genes. Triple-null aqp1-2-3 T. b. brucei displayed only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM), octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO) can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for ‘druggable’ protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen