Comparative study of the in vitro activity of various antifungal drugs against Scedosporium spp. in aerobic and hyperbaric atmosphere versus normal atmosphere.

INTRODUCTION: Scedosporium spp. have been observed with increasing frequency over the last decade in immunocompromised patients and trauma patients. This mould is often multi-drug resistant and its mortality rate remains very high. AIM: The primary goal of this study was to obtain data concerning the in vitro susceptibility of 13 Scedosporium strains comparing the in vitro incubation in aerobic versus hyperbaric conditions. MATERIALS AND METHODS: Chemosensitivity of thirteen Scedosporium strains was evaluated after a 72h-incubation in a normoxic (21% O2) normobaric (1 ATA) atmosphere versus a hyperoxic (100% O2) hyperbaric (2-3 ATA), and after a re-incubation at room temperature for an additional 72h. RESULTS: All S. apiospermum and S. prolificans strains showed no growth after incubation in hyperbaric hyperoxic atmosphere. However, when plates were then maintained at room temperature in aerobic conditions, growth was systematically observed from 36 to 96h, and Minimal inhibitory concentration (MIC) values were the same obtained after incubation in aerobic conditions. CONCLUSIONS: These results suggest impressive in vitro fungistatic activity of the hyperoxic hyperbaric atmosphere, even if its effect is strictly time-dependent. This preliminary in vitro study has potential clinical relevance because it focuses on examining in vitro combination therapy using hyperoxic hyperbaric conditions plus a single antifungal agent, rather than using combinations of different antifungal drugs, to potentially increase the antifungal activity.

In vitro activity of multiple antibiotic combinations against Nocardia: relationship with a short-term treatment strategy in heart transplant recipients with pulmonary nocardiosis.

BACKGROUND/OBJECTIVES: Pulmonary nocardiosis (PN) chiefly affects immunocompromised patients, particularly transplant recipients. Cotrimoxazole is still the mainstay of treatment, but it is associated with nephro- and myelo-toxicity, and can show unpredictable activity against Nocardia isolates. METHODS: Over a 20-year period, Nocardia isolates were identified from 12 heart transplant (HTx) recipients with PN. The in vitro activity of various antibacterials, alone or in combination, was assessed using disk-diffusion, minimal inhibitory concentration (MIC), and time-kill methodology. The in vitro results were compared with the clinical outcome of the patients. RESULTS: Seven different Nocardia strains were identified. Disk diffusion and MIC determinations showed that all isolates were susceptible to amikacin, netilmicin, and linezolid, and that moxifloxacin was the most active of the fluoroquinolones. All but 1 of the isolates were susceptible to imipenem. Time-kill studies showed that imipenem/amikacin and imipenem/moxifloxacin combinations were bactericidal for most isolates. Of 12 patients who received 3-4 weeks' intravenous (IV) treatment with amikacin or ciprofloxacin in combination with a beta-lactam, followed by 1-3 months' oral cotrimoxazole, moxifloxacin, or linezolid, 11 were cured; 1 patient died, but not related to Nocardia. CONCLUSION: Initial PN treatment in HTx recipients can be successfully carried out with bactericidal combinations such as imipenem plus amikacin or moxifloxacin, administered IV for 3-4 weeks. Within 1 month, a significant clinical and radiological improvement may be observed. In our experience, a <3 month oral regimen with cotrimoxazole, moxifloxacin, or doxycycline may then be used. This may allow a reduction of side effects and treatment-related burden, without any recurrence.

Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies.

Pulmonary nocardiosis is an infrequent but insidious disease in transplant patients. It has occurred in our centre in 3 out of 233 heart-transplant recipients since 1988. Common clinical features were mild symptoms and a severe nodular lung involvement. Early diagnosis was based upon cultures of bronchoalveolar lavage or fine-needle aspirate specimens of the lung lesions. Susceptibility studies and tests of antibiotic synergism guided the therapy. Two patients were treated with a combination of piperacillin-tazobactam and ciprofloxacin, and one with imipenem and amikacin, for 3-4 wk followed by a 3-month course of trimethoprim-sulphamethoxazole. The nocardial disease was successfully treated in the 3 patients; however, one died of subsequent invasive pulmonary aspergillosis. In the absence of consensus on the length of therapy, this experience suggests that a synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of trimethoprim-sulphamethoxazole may be effective in eradicating nocardial disease and may reduce the need for long-term treatment.

Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression.

Ca2+-binding proteins containing EF-hands are important constituents of intracellular signaling pathways. Recently, three new members of the Neuronal Calcium Sensor subgroup have been cloned in humans. Calsenilin interacts with presenilins, DREAM is a calcium-regulated transcriptional repressor and KChIP3 binds and modulates A-type potassium channels. Here we describe the mouse full-length cDNA and the genomic locus, demonstrating that the three proteins are encoded by the same unique gene. Various mechanisms contribute to the coding potential of this locus. These include alternate translation starts in the first exon and alternative splicing yielding transcripts lacking the EF-hand domains. In situ hybridization, RT-PCR, and Northern blotting reveal nervous system-restricted expression largely coinciding with the distribution of the Kv4.2 alpha-subunit of potassium channels. The presence of transcripts in early embryonic stages suggests roles for the protein also during development.

Antenatal triiodothyronine improves neonatal pulmonary function in preterm lambs.

OBJECTIVE: To characterize 1) pulmonary gas exchange, 2) pulmonary function, 3) lung fluid and tissue phospholipid content, and 4) thyroid hormone in the premature lamb (0.85 of term) after intra-amniotic administration of 100 micrograms of triiodothyronine (T3) 2 weeks before delivery. METHODS: Nine fetal lambs were given 100 micrograms of intra-amniotic T3 under ultrasound guidance at 112 +/- 1 days' gestation and delivered at 126 +/- 1 days (term = 149 days). Five saline-injected animals served as controls. Arterial blood gases, pulmonary mechanics, and lung volumes were compared between groups for 1 hour after delivery. At delivery, tracheal fluid and blood was taken for T3, and thyroxine (T4) levels. Tracheal fluid and lung tissues were assayed for total phosphorus and disaturated phosphatidylcholine. RESULTS: Triiodothyronine-treated lambs had significantly higher mean arterial pH and lower PCO2 than controls (P < .05) with a trend toward higher mean PO2. The dynamic lung compliance was increased by 54% with a 40% proportional increase in tidal volume and minute ventilation in the T3-treated group (P < .05). Functional residual capacity increased 69% (P < .05) without a change in specific compliance. The tracheal fluid and pulmonary phospholipids and tracheal fluid and plasma T3 and T4 levels were not different between the two groups. CONCLUSION: A single 100 micrograms dose of antenatal T3 significantly improves neonatal gas exchange and lung compliance. The improvement in lung function was not accompanied by an increase in pulmonary surfactant production. It is inferred that T3 improved lung function via accelerated structural development of the lung with an alternative possible effect on parenchymal connective tissue matrix.

Evaluation of concentration procedures of mutagenic metabolites from urine of diesel particulate-treated rats.

Several concentration procedures of mutagenic metabolites contained in the urine of diesel particulate-treated rats were compared. Mutagenicity was monitored by the Salmonella/microsome assay. The procedures tested were: lyophilization; filtration on XAD-2, XAD-7 or Sephadex LH-20 matrices; ultrafiltration; and extraction with organic solvents. Urine extraction with dichloromethane (DCM) gave almost quantitative recovery of activity while leaving salts and other polar compounds in the aqueous phase, and is the method recommended.