المؤلفون: STERGIOPOULOU, Theodouli, Meletiadis, Joseph, Sein, Tin, Papaioannidou, Paraskevi, Walsh, Thomas J., Roilides, Emmanuel

المصدر: Antimicrobial Agents and Chemotherapy, 55 (12), 5923-9 (2011-12)

مصطلحات موضوعية: Amphotericin B/pharmacology, Antifungal Agents/pharmacology, Aspergillus fumigatus/drug effects/growth & development/isolation & purification, Ciprofloxacin/pharmacology, Drug Synergism, Drug Therapy, Combination, Humans, Invasive Pulmonary Aspergillosis/microbiology, Microbial Sensitivity Tests, Neutrophils/immunology, Life sciences, Microbiology, Human health sciences, Pharmacy, pharmacology & toxicology, Immunology & infectious disease, Sciences du vivant, Microbiologie, Sciences de la santé humaine, Pharmacie, pharmacologie & toxicologie, Immunologie & maladie infectieuse

الوصف: Aspergillus is damaged by polymorphonuclear neutrophils (PMNs) by means of nonoxidative and oxidative mechanisms, which may be affected by antifungal and antibacterial agents that patients with invasive pulmonary aspergillosis often receive. The pharmacodynamic interactions among deoxycholate amphotericin B (AMB), ciprofloxacin (CIP), and human PMNs against Aspergillus fumigatus growth are unknown. We therefore studied the interactions between 0.032 to 2.0 mug/ml of AMB, 0.1 to 50 mug/ml of CIP at a fixed AMB/CIP ratio of 1:3.125, and PMNs from six donors at an effector-to-target (E:T) ratio of 400:1 against a clinical A. fumigatus isolate using an XTT metabolic assay and the Bliss independence pharmacodynamic-interaction model. CIP exhibited no antifungal activity alone or in combination with PMNs. Synergy was found between AMB and PMNs, with interaction indices (II) of 0.06 to 0.21; the highest interaction of 21% +/- 3.6% was observed at 0.22 +/- 0.09 mug/ml of AMB. The AMB and CIP (AMB+CIP) combination was synergistic (II = 0.39) at low AMB concentrations and antagonistic (II = 1.39) at high AMB concentrations, with a maximal synergistic interaction of 16% +/- 3.7% observed at 0.16 +/- 0.08 mug/ml of AMB. The triple combination AMB+CIP+PMNs was synergistic, with interaction indices of 0.05 to 0.20, and a maximal synergistic interaction of 24% +/- 4% was observed at 0.20 +/- 0.07 mug/ml of AMB. The increased percentage of Bliss synergy of the triple combination AMB+CIP+PMNs (24% +/- 4%) was the product of those of the constituent double combinations AMB+PMNs (21% +/- 3.6%) and AMB+CIP (16% +/- 3.7%). Thus, the antifungal activity of AMB, at clinically relevant concentrations, was enhanced in combination with PMNs and CIP against A. fumigatus growth in a concentration-dependent manner.

Relation: urn:issn:0066-4804; urn:issn:1098-6596

URL الوصول: https://orbi.uliege.be/handle/2268/170767

المؤلفون: Meletiadis, Joseph, STERGIOPOULOU, Theodouli, O'Shaughnessy, Elizabeth M., Peter, Joanne, Walsh, Thomas J.

المصدر: Antimicrobial Agents and Chemotherapy, 51 (6), 2053-64 (2007)

مصطلحات موضوعية: Amphotericin B/pharmacology, Antifungal Agents/pharmacology, Aspergillus/classification/drug effects, Dose-Response Relationship, Drug, Drug Antagonism, Drug Interactions, Drug Synergism, Echinocandins, Humans, Microbial Sensitivity Tests, Models, Biological, Peptides, Cyclic/pharmacology, Pyrimidines/pharmacology, Triazoles/pharmacology, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.

Relation: urn:issn:0066-4804; urn:issn:1098-6596

URL الوصول: https://orbi.uliege.be/handle/2268/249632

المؤلفون: Meletiadis, Joseph, Antachopoulos, Charalampos, STERGIOPOULOU, Theodouli, Pournaras, Spyros, Roilides, Emmanuel, Walsh, Thomas J.

المصدر: Antimicrobial Agents and Chemotherapy, 51 (9), 3329-37 (2007)

مصطلحات موضوعية: Amphotericin B/pharmacology, Antifungal Agents/pharmacology, Aspergillus/drug effects/growth & development, Colony Count, Microbial, Colorimetry, Culture Media, Microbial Sensitivity Tests/methods, Pyrimidines/pharmacology, Quality Control, Regression Analysis, Reproducibility of Results, Species Specificity, Spores, Fungal/drug effects, Tetrazolium Salts, Triazoles/pharmacology, Vitamin K 3/pharmacology, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: Antifungal agents may differ in their fungicidal activities against Aspergillus spp. In order to compare the fungicidal activities of voriconazole and amphotericin B against 40 isolates of Aspergillus fumigatus, A. flavus, and A. terreus, we developed a new microbroth colorimetric method for assessing fungicidal activities and determining minimal fungicidal concentrations (MFCs). This methodology follows the antifungal susceptibility testing reference method M-38A for MIC determination. After drug removal and addition of fresh medium, growth of viable conidia adhering to the bottoms of the microtitration wells was assessed by a colorimetric assay of metabolic activity after 24 h of incubation. The new method was faster (six times), reproducible (92 to 97%), and in agreement with culture-based MFCs (91 to 100%). Differential fungicidal activities of voriconazole and amphotericin B were found among the three Aspergillus species, with A. fumigatus and A. flavus having the lowest (1 and 2 mg/liter, respectively) and A. terreus the highest (>16 mg/liter) median amphotericin B MFCs; A. flavus had a lower median voriconazole MFC (4 mg/liter) than the other species (>8 mg/liter; P < 0.05). Amphotericin B was fungicidal (MFC/MIC 4) against 94% of A. fumigatus and 84% of A. terreus isolates. The new methodology revealed a concentration-dependent sigmoid pattern of fungicidal effects, indicating that fungicidal activity is not an all-or-nothing phenomenon and that some degree of fungicidal action can be found even for agents considered fungistatic based on the MFC/MIC ratio.

Relation: urn:issn:0066-4804; urn:issn:1098-6596

URL الوصول: https://orbi.uliege.be/handle/2268/249631

المؤلفون: O'Shaughnessy, Elizabeth M., Meletiadis, Joseph, STERGIOPOULOU, Theodouli, Demchok, Joanne P., Walsh, Thomas J.

المصدر: Journal of Antimicrobial Chemotherapy, 58 (6), 1168-76 (2006)

مصطلحات موضوعية: Amphotericin B/pharmacology, Antifungal Agents/pharmacology, Aspergillus/drug effects, Drug Antagonism, Drug Combinations, Drug Synergism, Echinocandins, Microbial Sensitivity Tests/methods, Peptides, Cyclic/pharmacology, Pyrimidines/pharmacology, Triazoles/pharmacology, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: OBJECTIVES: The in vitro effects of caspofungin combined with voriconazole and amphotericin B were tested in triplicate experiments against nine clinical isolates of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. METHODS: The isolates were tested against a range of concentrations of voriconazole (0.015-1.0 mg/L), caspofungin (0.125-256 mg/L) and five concentrations of amphotericin B (0.1-0.5 mg/L) with a microdilution chequerboard method based on the CLSI M38-A reference method and the results were analysed with the fractional inhibitory concentration (FIC) index. The effect of individual drugs on the FIC index of each of the double combinations was also evaluated. RESULTS: The triple combination of voriconazole, caspofungin and amphotericin B against all Aspergillus spp. was synergistic (FIC index 0.49-0.57) at low median concentrations of amphotericin B (0.10-0.22 mg/L) and voriconazole (0.07-0.15 mg/L) over a wide range of caspofungin concentrations (4.32-17.28 mg/L). Antagonistic interactions (FIC index 1.65-2.15) were found at higher median concentrations of amphotericin B (0.3-0.5 mg/L) and voriconazole (0.23-0.68 mg/L) over a similarly wide range of caspofungin concentrations (1.47-32 mg/L). CONCLUSIONS: These concentration-dependent interactions may have important clinical implications, which require further evaluation in animal models of invasive aspergillosis.

Relation: urn:issn:0305-7453; urn:issn:1460-2091

URL الوصول: https://orbi.uliege.be/handle/2268/249628

المؤلفون: Gil-Lamaignere, Cristina, Roilides, Emmanuel, Lyman, Caron A., Simitsopoulou, Maria, STERGIOPOULOU, Theodouli, Maloukou, Avgi, Walsh, Thomas J.

المصدر: Infection and Immunity, 71 (11), 6472-8 (2003)

مصطلحات موضوعية: Adult, Amphotericin B/pharmacology, Catalase/physiology, Humans, Hydrogen Peroxide/pharmacology, Hyphae/immunology, Hypochlorous Acid/pharmacology, Leukocytes, Mononuclear/immunology, Neutrophils/immunology, Peroxidase/physiology, Phagocytes/immunology, Phagocytosis, Respiratory Burst, Scedosporium/drug effects/immunology/metabolism, Superoxides/metabolism, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: Scedosporium apiospermum (Pseudallescheria boydii) is an emerging opportunistic filamentous fungus that causes serious infections in both immunocompetent and immunocompromised patients. To gain insight into the immunopathogenesis of infections due to S. apiospermum, the antifungal activities of human polymorphonuclear leukocytes (PMNs), mononuclear leukocytes (MNCs), and monocyte-derived macrophages (MDMs) against two clinical isolates of S. apiospermum were evaluated. Isolate SA54A was amphotericin B resistant and was the cause of a fatal disseminated infection. Isolate SA1216 (cultured from a successfully treated localized subcutaneous infection) was susceptible to amphotericin B. MDMs exhibited similar phagocytic activities against conidia of both isolates. However, PMNs and MNCs responded differently to the hyphae of these two isolates. Serum opsonization of hyphae resulted in a higher level of superoxide anion (O(2)(-)) release by PMNs in response to SA54A (amphotericin B resistant) than that seen in response to SA1216 (amphotericin B susceptible; P < 0.001). Despite this increased O(2)(-) production, PMNs and MNCs induced less hyphal damage to SA54A than to SA1216 (P < 0.001). To investigate the potential mechanisms responsible for these differences, hyphal damage was evaluated in the presence of antifungal oxidative metabolites as well as in the presence of a series of inhibitors and scavengers of antifungal PMN function. Mannose, catalase, superoxide dismutase, dimethyl sulfoxide, and heparin had no effect on PMN-induced hyphal damage to either of the two isolates. However, azide, which inhibits PMN myeloperoxidase activity, significantly reduced hyphal damage to SA1216 (P < 0.01) but not to SA54A. Hyphae of SA1216 were slightly more susceptible to oxidative pathway products, particularly HOCl, than those of SA54A. Thus, S. apiospermum is susceptible to antifungal phagocytic function to various degrees. The selective inhibitory pattern of azide with respect to hyphal damage and the parallel susceptibility to HOCl suggests an important difference in susceptibilities to myeloperoxidase products that may be related to the various levels of pathogenicity and amphotericin B resistance of S. apiospermum.

Relation: urn:issn:0019-9567; urn:issn:1098-5522

URL الوصول: https://orbi.uliege.be/handle/2268/249624

المؤلفون: Roilides, Emmanuel, Lyman, Caron A., Armstrong, Derek, STERGIOPOULOU, Theodouli, Petraitiene, Ruta, Walsh, Thomas J.

المصدر: Mycoses, 49 (2), 109-13 (2006)

مصطلحات موضوعية: Amphotericin B/pharmacology, Animals, Antifungal Agents/pharmacology, Cells, Cultured, Deoxycholic Acid/pharmacology, Drug Combinations, Female, Fusarium/drug effects/immunology, Humans, Macrophages, Alveolar/drug effects/immunology, Phosphatidylcholines/pharmacology, Phosphatidylglycerols/pharmacology, Rabbits, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: Fusarium spp. have emerged as important causes of invasive fungal infections in immunocompromised patients. Rabbit pulmonary alveolar macrophages (PAMs) exhibited fungicidal activity against conidia of Fusarium solani and achieved a time-dependent increase in killing. Neither deoxycholate amphotericin B (DAMB) nor amphotericin B lipid complex (ABLC) exerted a suppressive effect on PAMs by decreasing their conidiocidal activity against F. solani. On the contrary, at a concentration of 0.125 microg ml(-1), ABLC and, to a lesser degree, DAMB additively augmented the fungicidal activity of pulmonary alveolar macrophages against conidia of Fusarium solani.

Relation: urn:issn:0933-7407; urn:issn:1439-0507

URL الوصول: https://orbi.uliege.be/handle/2268/249626