In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates

In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant Cryptococcus neoformans was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 microg/ml.     

In vitro activity of SCH 27899 (Ziracin) against Legionella species

PURPOSE: To report the efficacy of topical mitomycin C in preventing local recurrences after incomplete surgical excision of conjunctival squamous cell neoplasia. METHODS: Four patients presented with unilateral conjunctival tumors. Excisional biopsy results revealed conjunctival intraepithelial neoplasia with an intact basement membrane. Neoplastic cells were present in at least one of the surgical borders of the excised conjunctiva in all four cases. Patients were treated with topical mitomycin C 0.02% three times daily for 2 weeks to prevent recurrences. RESULTS: All four patients were free of clinically detectable tumors after a mean follow-up period of 20 months (range, 16-23 months). Side effects included mild discomfort, redness, photophobia, and punctate epithelial keratopathy that subsided on discontinuation of the medication. CONCLUSION: Postoperative topical mitomycin C application may be a useful adjunct to prevent recurrences in patients with incompletely excised conjunctival squamous cell neoplasia.     

In vitro activity of voriconazole against yeasts, moulds and dermatophytes in comparison with fluconazole, amphotericin B and griseofulvin

Voriconazole (CAS 137234-62-9, UK-109,496), a new antifungal triazole derivative, was studied in vitro against 650 clinical isolates, representing yeasts, moulds and dermatophytes, and was compared with fluconazole (CAS 86386-73-4), amphotericin B (CAS 1397-89-3), and griseofulvin (CAS 126-07-8). The mean minimum inhibitory concentrations (MICs) of voriconazole were 0.06 microgram/ml against yeasts (n = 187), 0.74 microgram/ml against moulds (n = 260) and 0.10 microgram/ml against dermatophytes (n = 203). Data from these in vitro studies showed that voriconazole was more potent than fluconazole against most species studied, but particularly against the isolates of moulds and dermatophytes. Overall, voriconazole and amphotericin B indicated comparably good activity against yeasts and moulds. Voriconazole was highly potent against 13 Aspergillus species studied (mean MIC 0.35 microgram/ml) and also showed noteworthy activity (mean MICs 0.08-0.78 microgram/ml) against emerging and less common clinical isolates of opportunistic moulds such as of Alternaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp., and Fusarium spp. In addition, voriconazole was more active in vitro than griseofulvin against most dermatophytes tested. The in vitro results confirmed that voriconazole has indeed a broad antifungal spectrum and could also be effective against a wide range of fungal infections in patients.     

In vitro activity of SCH-56592 and comparison with activities of amphotericin B and itraconazole against Aspergillus spp

In this study, we investigated the in vitro activity of SCH-56592 (SCH), a new triazole antifungal agent. We compared the activity of SCH with those of itraconazole (ITZ) and amphotericin B (AB) against 60 clinical isolates of Aspergillus spp. by using a microtiter format. Incubation was done at 37 degrees C for 48 h, and MIC endpoints (no growth) were read visually. The medium used for all of the drugs was RPMI 1640 buffered with morpholinepropanesulfonic acid (MOPS) and supplemented with 2% glucose. MICs and minimum fungicidal concentrations (MFCs; killing of > or = 99.99%) were measured for all isolates. The geometric mean (GM) MICs and ranges (in micrograms per milliliter) were as follows: SCH, 0.09 and < or = 0.01 to 1; ITZ, 0.25 and 0.06 to 32; AB, 1.46 and 0.25 to 32. Aspergillus terreus (n = 7) was markedly more susceptible to SCH (GM, 0.05 microg/ml) and ITZ (GM, 0.07 microg/ml) than to AB (GM, 8.8 microg/ml). For all isolates, the GM MFCs and ranges (in micrograms per milliliter) were as follows: SCH, 3.64 and 0.125 to 16; ITZ, 15.09 and 0.125 to 32; AB, 10.3 and 1 to 32. In the drug concentration range tested, 71, 32, and 64% of the isolates against which SCH, ITZ, and AB, respectively, were tested were killed. A reproducibility study was performed with 20% of the isolates; for 11 of the 12 isolates retested, the MIC was the same or within 1 well of the original MIC of each drug. Therefore, in vitro mould testing of SCH is feasible and reproducible. SCH was found to be very active against all species of Aspergillus and at lower concentrations than either ITZ or AB.     

In vitro comparative assessment of the antioxidant activity of nacystelyn against three reactive oxygen species

Thiol-containing molecules possess antioxidant properties that are of interest in the pharmacological inactivation of reactive oxygen species (ROS), particularly in the treatment of chronic inflammatory respiratory diseases. In the present study, the in vitro antioxidant activity of a new agent was examined and compared with other thiol containing molecules, N-acetylcysteine (NAC) and captopril. Nacystelyn (CAS 89344-48-9, NAL) is a L-lysine salt of NAC having demonstrated several advantages as compared to NAC. The deoxyribose assay used for assessing the scavenging effect of drugs against hydoxyl radicals (.OH) first showed a prooxidant effect for thiols at relatively low concentrations that was attributed to a reduction of Fe(III) ions added in the system. This interference could be corrected by increasing ascorbate concentration. Second order rate constants for reaction with OH were calculated by extrapolation of the linear part of competition plots. Both NAL and NAC appeared as potent .OH scavengers (Ks > 10(10) mol-1 s-1) and reacted faster than captopril. The horseradish peroxidase assay for assessing the activity of thiols against H202 could not be used because thiol derivatives were substrates for the enzyme. By using the dithio-bis-nitrobenzoic acid (DTNB) assay, first order rate constants for reaction with H2O2 were obtained showing that both NAL and NAC reacted quite slowly with this species (K approximately equal to 0.03 min-1) although faster than captopril. Finally, the elastase-alpha 1-antiproteinase assay for assessing the activity of thiols against HClO again demonstrated the superiority of NAC and NAL over captopril, but this time, NAL was more efficient in maintaining the protease/antiprotease balance than NAC. This last observation may be of importance and deserves further investigation as HClO has been implicated in lung tissue damages during inflammatory respiratory diseases.     

In vitro activities of antimicrobial agents against Candida species

A single surgeon's consecutive series of 50 arthroscopically repaired meniscal tears in 48 patients was retrospectively reviewed. None of these patients had concomitant ligament damage to the knee. The average follow-up period was 10 years, 9 months. Criteria for clinical success included 1) history of pain of grade 1 or less and absence of locking, catching, or giving way; 2) a physical examination demonstrating no significant effusion and a painless and negative jump sign; and 3) no subsequent surgical procedures on the repaired meniscus. Patient satisfaction was quite high, although clinical confirmation was possible in only 38 knees, indicating a clinical success rate of 76%. Bilateral standing radiographs were obtained on these 38 operated knees and were evaluated using Fairbank's classification. Evaluation of the radiographs revealed that 8% of the operated knees had minimal joint changes, as compared with 3% in the contralateral, nonoperated knee. This study demonstrates that arthroscopic meniscal repair in knees with isolated meniscal tears has the potential for a long-term successful clinical and radiographic outcome.     

In vitro activity of dirithromycin against Chlamydia trachomatis

Dirithromycin is a new macrolide antibiotic with an active metabolite, erythromycylamine. We evaluated the in vitro activities of both drugs against 16 isolates of Chlamydia trachomatis and compared them with that of doxycycline. In vitro susceptibility testing was performed with McCoy cell monolayers. The MIC was defined as the lowest concentration of antibiotic without inclusions. The MBC was defined as the lowest concentration of antibiotic yielding no inclusions after passage onto 24-h-old antibiotic-free McCoy cell monolayers. Dirithromycin and erythromycylamine appeared to be equally effective against these 16 strains of C. trachomatis (MIC for 90% of strains tested, 1 mg/ml; MBC for 90% of strains tested, 2 micrograms/ml). Both were less active than doxycycline (MIC for 90% of strains tested, 0.06 micrograms/ml; MBC for 90% of strains tested, 0.12 micrograms/ml). The combination of dirithromycin and erythromycylamine appeared to be additive.     

In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less-common mold pathogens

The in vitro activity of voriconazole was compared with that of itraconazole. Eighty-six isolates of pathogenic molds belonging to 23 species were tested by an agar dilution method in High Resolution medium. Voriconazole was more active than itraconazole against a number of hyaline molds, including several Fusarium spp. and Scedosporium prolificans. Voriconazole and itraconazole showed comparable good activity against several hyaline molds, including Penicillium marneffei and Scedosporium apiospermum, and a number of dematiaceous molds, including Bipolaris australiensis, Cladophialophora bantiana, several Exophiala spp., and several Fonsecaea spp. Our results suggest that voriconazole could be effective against a wide range of mold infections in humans.     

Potentiation of antifungal activity of amphotericin B by azithromycin against Aspergillus species

The potential role of azithromycin in combination with amphotericin B against 25 clinical isolates of Aspergillus was assessed. The MIC of amphotericin B was 1 microg/ml for 44% of the isolates, 0.5 microg/ml for 48%, and 0.25 microg/ml for 8%. All isolates were resistant to azithromycin. Synergism, defined as a > or = twofold reduction in the MIC of both drugs upon combination, was demonstrated between amphotericin B and azithromycin for all 25 isolates. To prove that azithromycin exerts its antifungal effect by inhibiting protein synthesis, we studied [35S]-methionine incorporation into protein in one Aspergillus isolate. Neither amphotericin B at 0.125 microg/ml (fourfold below its MIC) nor azithromycin at 16 microg/ml (> or = 16-fold below its MIC) had any effect on protein synthesis when tested alone. Upon combination, however, a 68% inhibition in protein synthesis was evident by the inhibition of [35S]-methionine incorporation.     

In vitro activity of biapenem against beta-lactamase producing Enterobacteriaceae

The activity of biapenem was compared with that of imipenem and cefotaxime against 108 strains of beta-lactamase producing Enterobacteriaceae. Biapenem and imipenem were very active, inhibiting 90% of the strains at a concentration of 0.5 microgram/ml. Both carbapenems were very active against plasmidic beta-lactamase producers, with MIC90s below 1 microgram/ml. However, the MIC90 of biapenem for cephalosporinase producers was 1 microgram/ml. Against strains producing extended-spectrum beta-lactamases, biapenem exhibited better activity against TEM-type producers (MIC90 0.25 microgram/ml) than against SHV-type producers (MIC90 0.5 microgram/ml). Overall, the in vitro antibacterial activity of biapenem is similar to that of imipenem.     

In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp

LY303,366 (LY) is a novel derivative of the echinocandin class of antifungal agents. The in vitro activities of LY, itraconazole (ITZ), and amphotericin B (AMB) were assessed against 60 Aspergillus isolates, including 35 isolates of A. fumigatus, eight isolates of A. terreus, eight isolates of A. flavus, eight isolates of A. niger and one isolate of A. nidulans. Four A. fumigatus isolates were resistant to ITZ. Susceptibility testing for all drugs was performed with a broth microdilution procedure. LY was tested in two media: antibiotic medium 3 (AM3) and Casitone with 2% glucose (CAS) with an inoculum of 2 x 10(3) spores/ml. ITZ and AMB were tested in RPMI 1640 with 2% glucose with an inoculum of 1 x 10(6) spores/ml. All tests were incubated at 37 degrees C for 48 h. A novel end point was used to determine a minimal effective concentration (MEC) for LY, i. e., almost complete inhibition of growth save a few tiny spherical colonies attached to the microplate. MICs were measured for ITZ and AMB with a no-growth end point. Ranges and geometric mean (GM) MECs were from 0.0018 to >0.5 and 0.0039 mg/liter and from 0.0018 to >0.5 and 0.008 mg/liter for LY in AM3 and LY in CAS, respectively. Differences between species were apparent, with A. flavus being significantly less susceptible to LY than any other species tested with both media (P 16 and 0.7 mg/liter for ITZ and from 0.25 to 16 and 1.78 mg/liter for AMB. Minimal fungicidal concentrations (MFCs) were also determined for all drugs. GM MFCs were 0.018, 0.09, 19.76, and 12.64 mg/liter for LY in AM3, LY in CAS, ITZ, and AMB, respectively. LY in AM3 and LY in CAS were fungicidal for 86.7 and 68% of isolates, respectively (98% killing). In comparison, ITZ and AMB were fungicidal for 35 and 70% of isolates, respectively (99.99% killing). A reproducibility study was performed on 20% of the isolates. For 12 isolates retested, the MEC or MIC was the same or was within 1 dilution of the original value for 11, 11, 10, and 9 isolates for LY in AM3, LY in CAS, ITZ, and AMB, respectively. In conclusion, LY seems to be a promising antifungal agent with excellent in vitro activity against Aspergillus spp.     

In vitro activity of macrolides against intracellular Legionella pneumophila

The antibacterial effects of clarithromycin, azithromycin, and erythromycin were determined against five strains of Legionella pneumophila including L. pneumophila ATCC 33823 and four clinical isolates. Extracellular minimum inhibitory concentrations (MICs) and MBCs were determined by a microdilution method. Clarithromycin was the most active drug (MIC < or = 0.015-0.06), followed by azithromycin (MIC 0.03-0.12) and erythromycin (MIC 0.06-0.25). The antibacterial effect of these macrolides was then determined against L. pneumophila grown intracellularly in MRC-5 human fetal lung fibroblast cells. At two and eight times the extracellular MBC, erythromycin, azithromycin, and clarithromycin were equally effective in inhibiting growth of these five strains of intracellular L. pneumophila.     

Imipenem inhibits in vitro activity of amphotericin B directed against Aspergillus fumigatus

A decrease of the susceptibility of Aspergillus fumigatus strains to amphotericin B was found when tested in combination with high concentrations (128-2048 mg/l) of the antibacterial agent imipenem by checkerboard titration and agar diffusion assay. Only bacteriologically active imipenem showed the antagonism. The mechanism of action is unknown. However, imipenem and amphotericin B did not react directly, as shown by checkerboard titration with bacterial strains as well as by HPLC analysis. It is concluded that imipenem medication may influence the efficacy of amphotericin B treatment in aspergillosis.     

In vitro and in vivo efficacy of the triazole TAK-187 against Cryptococcus neoformans

Multiple isolates of Cryptococcus neoformans, including those with fluconazole resistance, were tested to assess the in vitro activity of the new triazole TAK-187. MICs of TAK-187 were at least eightfold lower than those of fluconazole, and fungicidal concentrations for most isolates were 4 microg/ml or less. TAK-187 also was evaluated as intermittent therapy using two dosages in a rabbit model of experimental cryptococcal meningitis. Compared to daily treatment with fluconazole, as little as two doses of TAK-187 given 7 days apart were found to be effective. Plasma and cerebrospinal fluid TAK-187 concentrations were many times higher than MICs and fungicidal concentrations. Based upon its therapeutic efficacy and long half-life in the rabbit model, TAK-187 should be investigated for intermittent dosing in treatment or suppression of cryptococcal infections in humans.     

In vitro studies on the potential for biological control of Aspergillus flavus and Fusarium moniliforme by Trichoderma species. 1. Macroscopical and microscopical observations of fungal interactions

Since the advent of CT, secondary neoplastic lesions of the kidneys have been detected with increasing frequency. After reviewing a large series of cases of renal metastases, we have been able to classify the CT findings into seven major categories that are discussed and illustrated in this article. The differential diagnoses between metastatic disease of the kidneys and other lesions such as renal infarctions, renal lymphoma, and primary malignancies are also considered.     

In-vitro activities of amphotericin B, itraconazole and voriconazole against 150 clinical and environmental Aspergillus fumigatus isolates

The influence of CNS functional state and structural changes of neurons in spinal cord following local exposure to 38 or 76 Gy X-radiation. Morphological analysis show, that stimulation of peripheral nerves increase, but hypoxia or barbiturates decrease destruction of spinal neurons by radiation. Value destruction also depends of neurons volumes.     

In vitro and in vivo activities of trybizine hydrochloride against various pathogenic trypanosome species

Trybizine hydrochloride [O,O'-bis(4,6-diamino-1,2-dihydro-2, 2-tetramethylene-s-triazine-1-yl)-1,6-hexanediol dihydrochloride] was active in vitro against the sleeping sickness-causing agents Trypanosoma brucei subsp. rhodesiense and T. brucei subsp. gambiense; against a multidrug-resistant organism, T. brucei subsp. brucei; and against animal-pathogenic organisms Trypanosoma evansi, Trypanosoma equiperdum, and Trypanosoma congolense; but not against the intracellular parasites Trypanosoma cruzi and Leishmania donovani. Cytotoxic effects against mammalian cells were observed at approximately 10(6)-fold higher concentrations than those necessary to inhibit T. brucei subsp. rhodesiense. Trybizine hydrochloride was able to eliminate T. brucei subsp. rhodesiense and T. brucei subsp. gambiense in an acute rodent model with four intraperitoneal doses of 0.25 mg kg of body weight-1 or four doses of 1 mg kg-1, respectively, or with four oral doses of 20 mg kg-1. The compound expressed activity against suramin-resistant T. evansi strains in mice. However, these concentrations were not sufficient to cure mice infected with multidrug-resistant T. brucei subsp. brucei. A late-stage rodent model with central nervous system involvement could not be cured, indicating that trybizine may not pass the blood-brain barrier in sufficient quantities.     

In vitro activity of fluvastatin, a cholesterol-lowering agent, and synergy with flucanazole and itraconazole against Candida species and Cryptococcus neoformans

Fluvastatin, a cholesterol-lowering drug, exhibited minimal activity (MICs of 64 to >128 microg/ml) against Candida species and Cryptococcus neoformans. When fluvastatin was combined with fluconazole or itraconazole, both synergistic and additive effects were noted (fractional inhibitory concentration indices of < or = 0.156 to 0.625; fractional lethal concentration indices of < or = 0.156 to 0.75). This combined fungicidal activity was confirmed by time-versus-killing studies.     

In vitro blood schizonticidal activity of sera containing mefloquine-quinine against Plasmodium falciparum

INTRODUCTION: Since patient cooperation in neonates and infants up to 5 years is always reduced, deep sedation is usually recommended to obtain constant high-quality images during MRI. According to the widely accepted AAP Guidelines, deep sedation is not always distinguishable from general anesthesia, substantiating the demand for state-of-the-art anaesthesia. This is particularly true in this age group, where pharmacokinetics and pharmacodynamics show wide interindividual variation. In this review we outline the techniques required to provide safe and effective patient care in the unique MRI environment. CHOICE OF DRUGS AND PROCEDURE: From the viewpoint of induction time, half-life of action and success rate, we have found that inhalation anesthetics and propofol present clear advantages. Both offer rapid induction and emergence, allowing outpatient examinations in a tight schedule with a reliable sedation state. Tracheal intubation or a laryngeal mask airway is required to supply volatile anesthetics and to secure the airway, since propofol in appropriate doses causes respiratory depression and loss of the protective reflexes. Positive-pressure ventilation is recommended since the reduction of tidal volumes by sedative drugs (including high-dose chloral hydrate, barbiturates) may cause atelectasis and decreased oxygen saturation. ANESTHESIA MACHINES: Several respirators work well outside a critical magnetic field strength of 10 mT (e.g. Draeger: Titus, Siemens: Servo 900). The use of long low-compliance tubing (4-5 m) allows the respirator to be placed at the distal end of the patient table. Sidestream capnometry and spirometry at the proximal tube connector facilitate compensation for losses in tidal volume due to gas compression. Syringe pumps work properly when kept outside the 10 mT line. Some defibrillators (e.g., Lifepac, Physiocontrol) are approved for use in strong magnetic fields. MONITORING: State-of-the-art monitoring is also attainable for high-risk patients, including invasive pressure measurement. Since wiring without special filters may not cross the HF shield of the examination room, hydraulic and pneumatic systems are used (blood pressure by oscillometry, airway monitoring by side-stream spirometry). Optical fibers are used for pulse oximetry. A telemetric EKG is usually provided by the MRT manufacturer. Because oscilloscopes are distorted by the magnetic field, the monitors are placed outside the examination room. In addition, this eliminates the possibility of erasing the EPROMs contained in most monitors. PERSONNEL: With the setup described, the presence of a second anesthetist within the examination room is superfluous. A second anesthesia team can shorten the time lag between examinations by overlapping induction if a separate anesthesia induction and emergence room is provided. CONCLUSION: The level of sedation required for MRI in newborn and infants can only be achieved safely and efficiently by general anesthesia performed by trained staff. Complete state-of-the-art anesthesia care can be delivered if appropriate instrumentation is used.