This study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistant Staphylococcus aureus (MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.
N-Chlorotaurine (NCT) (Cl-HN-CH 2 -CH 2 -SO 3 Ϫ ), the Nchloro derivative of the amino acid taurine, is the main representative of long-lived oxidants produced by stimulated human leukocytes (19). Besides immune modulatory effects (11), NCT has bactericidal, virucidal, and vermicidal activities (12,14,15,20), including a lag of regrowth of bacteria (postantibiotic effect) after short, sublethal incubation times accompanied by a loss of virulence (13). It has been conceived to be useful as an antimicrobial agent in local treatment of, e.g., eye and urinary tract infections (16).The aim of this study was a quantitative evaluation of fungicidal and postantifungal effects of NCT against Candida albicans at a concentration of 1%, which is well tolerated by human tissue in vivo (16). In addition, the influence of NCT on the production of secreted aspartyl proteinases, a superfamily of enzymes important for cell adhesion and invasion and thus fungal virulence factors, was investigated (3, 10, 18).Pure NCT as a crystalline sodium salt (M r ϭ 181.57 g/mol; kindly prepared by Waldemar Gottardi, Institute of Hygiene and Social Medicine, Innsbruck, Austria) was dissolved in 0.01 M phosphate-buffered saline at pH 7.0 to 7.4.C. albicans strains CBS 5982 (Centraal Bureau voor Schimmelculturen, Baarn, The Netherlands), ATCC 5314, ATCC 15053, and five clinical Candida sp. isolates, C. krusei ATCC 6128 and a clinical isolate, C. glabrata ATCC 6425, C. tropicalis ATCC 13803, and C. dubliniensis (kindly provided by D. Coleman, University of Dublin, Ireland) were grown on Sabouraud dextrose agar (Oxoid, Basingstoke, United Kingdom) for 48 h. Yeast cells were suspended in saline, washed twice, adjusted to ca. 1 ϫ 10 8 CFU/ml, and diluted 50-fold (0.1 to 4.9 ml) to 2 ϫ 10 6 CFU/ml in buffered 1% NCT solutions. For testing of the fungicidal activity, aliquots of 250 l were removed after incubation times of 1 to 5 h at 20 or 37°C and mixed with 125 l of 6% sodium thiosulfate solution to inactivate NCT. Quantitative cultures of adequate dilutions on tryptic soy agar (Merck) were performed by using an automatic spiral plater (model WASP; Whitley, Shipley, United Kingdom), and CFU were counted after incubation at 37°C for 48 h (detection limit, 20 CFU/ml). Controls without NCT and controls with fungi added to NCT previously inactivated by sodium thiosulfate were performed in parallel.For testing of the postantifungal effect (PAFE), yeasts were incubated at 20°C in 1% NCT solution for sublethal incubation times of 1 to 45 min. Subsequent to inactivation of NCT and a washing step in saline, yeasts were diluted 100-fold in prewarmed tryptic soy broth (Merck) and regrown at 37°C. Quantitative cultures were performed hourly. The lag of regrowth was calculated as the difference between the test and control cultures in the time taken to increase 1 log 10 above the count at zero time (2).For testing of the effect of NCT on production of secreted aspartyl proteinases (Saps), yeasts (2 ϫ 10 6 CFU) were incubated at 20°C in 1 ml of Sap induction med...
Objectives To explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability. Methods Lefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study. Results Single and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE. Conclusions The PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.
The Candida antigen CR3-RP (complement receptor 3-related protein) is supposed to be a 'mimicry' protein because of its ability to bind antibody directed against the a subunit of the mammalian CR3 (CD11b/CD18). This study aimed to (i) investigate the specific humoral isotypic response to immunization with CR3-RP in vivo in a rabbit animal model, and (ii) determine the role of CR3-RP in the adherence of Candida albicans in vitro using the model systems of buccal epithelial cells (BECs) and biofilm formation. The synthetic C. albicans peptide DINGGGATLPQ corresponding to 11 amino-acids of the CR3-RP sequence DINGGGATLPQALXQITGVIT, determined by N-terminal sequencing, was used for immunization of rabbits to obtain polyclonal anti-CR3-PR serum and for subsequent characterization of the humoral isotypic response of rabbits. A significant increase of IgG, IgA and IgM anti-CR3-RP specific antibodies was observed after the third (P,0.01) and the fourth (P,0.001) immunization doses. The elevation of IgA levels suggested peptide immunomodulation of the IgA1 subclass, presumably in coincidence with Candida epithelial adherence. Blocking CR3-RP with polyclonal anti-CR3-RP serum reduced the ability of Candida to adhere to BECs, in comparison with the control, by up to 35 % (P,0.001), and reduced biofilm formation by 28 % (P,0.001), including changes in biofilm thickness and integrity detected by confocal laser scanning microscopy. These properties of CR3-RP suggest that it has potential for future vaccine development. INTRODUCTIONCandida albicans is the most frequently isolated fungal pathogen associated with infection of immunocompromised patients in hospital settings. The high propensity to cause disease is due to the expression of many virulence factors including highly immunogenic cell surface proteins (Alberti-Segui et al., 2004;Jeng et al., 2005;Pietrella et al., 2006) able to trigger cellular and humoral response (Viudes et al., 2001;Ló pez-Ribot et al., 2004;Omaetxebarria et al., 2005;Fukuizumi et al., 2006). Additionally, a variety of cell surface molecules expressed by Candida help it to evade the host immune response by mimicry of host receptors (Gustafson et al., 1991;Phan et al., 2007). The receptor MAC-1 (CD11b/CD18) on lymphocytes is the surface b 2 integrin that mediates lymphocyte adhesion to C. albicans (Forsyth & Mathews, 2002). However, Candida is not only the target for MAC-1, but also CR3-RP identified on the yeast surface might be classified as a member of the integrin family due to its antigenic, structural and functional relation to the a subunit of the mammalian neutrophil receptor CD11b/CD18 (Gilmore et al., 1988;Abbreviations: BEC, buccal epithelial cell; CLSM, confocal laser scanning microscopy; RT, room temperature; XTT, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide.The GenBank/EMBL/DDBJ accession number for the N-terminal sequence fragment of CR3-RP is P85437. Hostetter et al., 1990;Hostetter, 1996). Binding the human complement fragment iC3b to this receptor results i...
Oropharyngeal candidiasis is one of the first and most commonly reported opportunistic infections of untreated AIDS patients. With the introduction of the new antiviral HAART therapy, including HIV protease inhibitors, this mucocutaneous infection is nowadays only rarely observed in treated patients. It was recently shown that HIV protease inhibitors have a direct attenuating effect on Candida albicans secreted aspartic proteinases (Saps), an investigation prompted by the fact that both Sap and HIV protease belong to the superfamily of aspartic proteinases and by the observation that mucocutaneous infections sometimes resolve even in the absence of an immunological improvement of the host. As these Saps are important fungal virulence factors and play a key role in adhesion to human epithelial cells we tried to assess the effect of the HIV protease inhibitors Ritonavir, Indinavir and Saquinavir on fungal adhesion to these cells. The effect on phagocytosis by polymorphonuclear leukocytes was also assessed. Ritonavir was found to be the most potent inhibitor of fungal adhesion. A dose-dependent inhibition of adhesion to epithelial cells was found already at 0.8 microM and was significant at 4 microM or higher, at 500 microM the inhibition was about 55%. Indinavir and Saquinavir inhibited significantly at 4 microM or 20 microM, respectively; at 500 microM the inhibition was 30% or 50%. In contrast, no protease inhibitor was able to modulate phagocytosis of Candida by polymorphonuclear leukocytes. In conclusion, inhibition of Saps by HIV protease inhibitors may directly help to ease the resolution of mucosal candidiasis. In future, derivatives of HIV protease inhibitors, being more specific for the fungal Saps, may form an alternative in the treatment of mucosal candidiasis insensitive to currently available antimycotics.
SUMMARYTat, the human immunode®ciency virus type 1 (HIV-1) transactivating protein, binds through its RGD-motif to human integrin receptors. Candida albicans, the commonest cause of mucosal candidiasis in subjects infected with HIV-1, also possesses RGD-binding capacity. The present study reveals that Tat binds to C. albicans but not to C. tropicalis. Tat binding was markedly reduced by laminin and to a lesser extent by a complement C3 peptide containing the RGD motif, but not by a control peptide. The outgrowth of C. albicans was accelerated following binding of Tat, but phagocytosis of opsonized C. albicans was also increased after Tat binding. Thus, Tat binding promotes fungal virulence by inducing hyphae but may also reduce it by augmenting phagocytosis. The net effect of Tat in vivo is dif®cult to judge but in view of the many disease-promoting effects of Tat we propose that accelerating the formation of hyphae dominates over the augmentation of phagocytosis.
Oral candidiasis in HIV-1-infected individuals is widely believed to be triggered by the acquired T-lymphocyte immunodeficiency. Recently, binding of the HIV-1 envelope protein gp160 and its subunit gp41, and also of the whole virus itself, to Candida albicans has been shown. The present study shows that, in addition to C. albicans, HIV-1 gp41 also binds to yeast and hyphal forms of Candida dubliniensis, a species which is closely related to C. albicans, and to Candida tropicalis but not to Candida krusei, Candida glabrata or Saccharomyces cerevisiae. The previous finding that gp41 binding to C. albicans augments fungal virulence in vitro is supported by the observation that the yeast showed an enhanced adhesion to HIV-infected H9 cells in comparison to uninfected cells. In line with these results soluble gp41 itself reduced binding of C. albicans to both endothelial and epithelial cell lines, confirming a dominant role of the gp41 binding moiety on the surface of Candida for adhesion. Surface-associated secreted aspartic proteinases (Saps) play an important role in candidial adhesion, but are not likely to be involved in the interaction as gp41 binding to the C. albicans parental wild-type strain was comparable to that of three different isogenic Sap deletion mutants. Furthermore, gp41 binding to the yeast killer toxin-susceptible C. albicans strain 10S was not inhibitable by an anti-YKT receptor antibody. In conclusion, HIV-1 interacts with different clinically important Candida spp., and may thereby affect the outcome of the respective fungal infection.
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