Enhancement of antibiotic susceptibility of Stenotrophomonas maltophilia using a polyclonal antibody developed against an ABC multidrug efflux pump.

Stenotrophomonas maltophilia is an emerging nosocomial pathogen capable of causing healthcare-associated infections, including pneumonia and bacteremia. Intrinsic resistance in S. maltophilia is exhibited towards many broad-spectrum antibiotics, and treatment recommendations are controversial.

Molecular cloning and characterization of SmrA, a novel ABC multidrug efflux pump from Stenotrophomonas maltophilia.

Objectives: Stenotrophomonas maltophilia is an emerging nosocomial pathogen that can cause difficult-to-treat infections and exhibits significant degrees of poorly understood multidrug resistance (MDR). The aim of this study was to identify and characterize a multidrug ATP-binding cassette (ABC) efflux pump in S. maltophilia.

Efungumab and caspofungin: pre-clinical data supporting synergy.

Objectives: Heat shock protein 90 (hsp90) is targeted by the humoral response in invasive candidiasis. This paper tests for synergy between caspofungin and efungumab--a human antibody fragment against hsp90.

Methods: The MIC-0, MIC-2 values and FICI were determined for a range of yeasts against efungumab and caspofungin.

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis.

Background: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species.

Methods: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs.

Fungal heat-shock proteins in human disease.

Heat-shock proteins (hsps) have been identified as molecular chaperones conserved between microbes and man and grouped by their molecular mass and high degree of amino acid homology. This article reviews the major hsps of Saccharomyces cerevisiae, their interactions with trehalose, the effect of fermentation and the role of the heat-shock factor. Information derived from this model, as well as from Neurospora crassa and Achlya ambisexualis, helps in understanding the importance of hsps in the pathogenic fungi, Candida albicans, Cryptococcus neoformans, Aspergillus spp.

Recommendations for managing Aspergillus osteomyelitis and joint infections based on a review of the literature.

Objectives: To produce recommendations for the management of Aspergillus osteomyelitis and joint infections.

Methods: Published literature was surveyed to identify both case reports of Aspergillus osteomyelitis and joint infections and anti-fungal pharmacology of anti-fungal agents. Included in the pharmacological review was an assessment of new and investigational anti-fungals to consider their potential role in the management of this infection.

Evaluation of Mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies.

This article reported the identification of heat shock protein 90 (hsp90) homologues by immunoblot in Cryptococcus neoformans. Mycograb, a genetically recombinant antibody against hsp90, was evaluated against 8 clinical isolates and the National External Quality Assessment Service for Microbiology strain of C. neoformans alone and in combination with amphotericin B, caspofungin, and fluconazole by checkerboard assay.

Recombinant antibodies: a natural partner in combinatorial antifungal therapy.

Monotherapy, in the form of amphotericin B or one of its liposomal derivatives, is the usual treatment for invasive fungal infections, due to lack of a safe, effective combination of antifungal drugs. Combination therapy is not necessarily beneficial-there may be mutual antagonism or indifference, increased toxicity or interference with concomitant medication. But the benefits of a well-tolerated, synergistic combination would be great-the enhanced efficacy would improve clinical outcome, reduce the need for prolonged courses of treatment and prevent the emergence of antifungal drug resistance.

Genetically recombinant antibodies: new therapeutics against candidiasis.

Historically, the therapy of serious fungal infection has been dominated by monotherapy with the polyene antibiotic amphotericin B. Clinical failures, side effects, the lack of alternatives and the toxicity of this drug have heightened the need to produce alternative therapies, which have included fluconazole, voriconazole and caspofungin. The observation that recovery from disseminated candidiasis was associated with an antibody response to the 47 kDa Candida heat-shock protein (HSP)90 homologue, coupled with the ability to sequence all the antibodies from patients who have recovered from the infection and to re-express the dominant ones as fragments in Escherichia coli, has opened the possibility of immunotherapy.

The role of antibodies against hsp90 in the treatment of fungal infections.

Advances in antibody engineering have solved many of the problems inherent in traditional sources of antibodies, and about a quarter of all biotechnology-based drugs now in development are antibodies. This has come at a time when it is apparent that reliance on antibiotics alone is beginning to select out resistant pathogens, fungi being a prime example. The development of antibody-based therapeutics, such as Mycograb, against novel fungal targets offers a new approach to combating the spread of resistance and reducing mortality.

Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90.

Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemotherapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs against Candida albicans [fluconazole [FLC]-sensitive and FLC-resistant strains], Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, 128 to 256 microg/ml).

Clostridium difficile, atopy and wheeze during the first year of life.

Differences have been suggested to occur in the composition of intestinal microflora from allergic and non-allergic children. In this study we used a semi-quantitative enzyme-linked immunosorbent assay (ELISA) for the measurement of Clostridium difficile-specific immunoglobulin G (IgG) (CDIgG). CDIgG was excellent in differentiating between adults with or without Cl.

Neutralising human recombinant antibodies to human cytomegalovirus glycoproteins gB and gH.

A phage antibody display library of single chain fragment variable (scFv) was applied to develop anti-HCMV glycoprotein B (gB) and glycoprotein H (gH) neutralising libraries. To enrich for specific scFvs, the phage antibody was panned against cytomegalovirus epitopes derived from the N-terminal part of gB, the C-terminal part of gB and the N-terminal part of gH (NETIYNTTLKYGDV, VTSGSTKD and AASEALDPHAFHLLLNTYGR). A number of clones were differentiated by Bst N1 fingerprinting.

Identification of ABC transporters in vancomycin-resistant Enterococcus faecium as potential targets for antibody therapy.

The occurrence of an outbreak of septicaemias due to vancomycin-resistant Enterococcus faecium (VRE), in Manchester, UK, provided an opportunity to examine the antibody responses in patients infected by the same strain. Immunoblotting sera from 24 cases, six of whom died, showed an immunodominant cluster of antigens at 34, 54 and 97 kDa, with a statistically significant correlate between survival and immunoglobulin G to the 34 and 97 kDa bands (P<0.05).