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P M Sullam

Publications and source records attributed to P M Sullam.

At least 19 recordsLinked to original sources
PubMed2001

Proteins PblA and PblB of Streptococcus mitis, which promote binding to human platelets, are encoded within a lysogenic bacteriophage.

The binding of platelets by bacteria is a proposed central mechanism in the pathogenesis of infective endocarditis. Platelet binding by Streptococcus mitis strain SF100 (an endocarditis isolate) was recently shown to be mediated in part by the surface proteins PblA and PblB. The genes encoding PblA and PblB are clustered with genes nearly identical to those of streptococcal phages r1t, 01205, and Dp-1, suggesting that pblA and pblB might reside within a prophage. To address this possibility, cultures of SF100 were exposed to either mitomycin C or UV light, both of which are known to induce the lytic cycle of many temperate phages. Both treatments caused a significant increase in the transcription of pblA. Treatment with mitomycin C or UV light also caused a substantial increase in the expression of PblA and PblB, as detected by Western blot analysis of proteins in the SF100 cell wall. By electron microscopy, phage particles were readily visible in the supernatants from induced cultures of SF100. The phage, designated SM1, had a double-stranded DNA genome of approximately 35 kb. Southern blot analysis of phage DNA indicated that pblA and pblB were contained within the SM1 genome. Furthermore, Western blot analysis of phage proteins revealed that both PblA and PblB were present in the phage particles. These findings indicate that PblA and PblB are encoded by a lysogenic bacteriophage, which could facilitate the dissemination of these potential virulence determinants to other bacterial pathogens.

Base Sequence↗
PubMed2001

Genetic loci of Streptococcus mitis that mediate binding to human platelets.

The direct binding of bacteria to platelets is a postulated major interaction in the pathogenesis of infective endocarditis. To identify bacterial components that mediate platelet binding by Streptococcus mitis, we screened a Tn916deltaE-derived mutant library of S. mitis strain SF100 for reduced binding to human platelets in vitro. Two distinct loci were found to affect platelet binding. The first contains a gene (pblT) encoding a highly hydrophobic, 43-kDa protein with 12 potential membrane-spanning segments. This protein resembles members of the major facilitator superfamily of small-molecule transporters. The second platelet binding locus consists of an apparent polycistronic operon. This region includes genes that are highly similar to those of Lactococcus lactis phage r1t and Streptococcus thermophilus phage 01205. Two genes (pblA and pblB) encoding large surface proteins are also present. The former encodes a 107-kDa protein containing tryptophan-rich repeats, which may serve to anchor the protein within the cell wall. The latter encodes a 121-kDa protein most similar to a tail fiber protein from phage 01205. Functional mapping by insertion-duplication mutagenesis and gene complementation indicates that PblB may be a platelet adhesin and that expression of PblB may be linked to that of PblA. The combined data indicate that at least two genomic regions contribute to platelet binding by S. mitis. One encodes a probable transmembrane transporter, while the second encodes two large surface proteins resembling structural components of lysogenic phages.

Amino Acid Sequence↗
PubMed2001

Clumping factor A mediates binding of Staphylococcus aureus to human platelets.

The direct binding of bacteria to platelets may be an important virulence mechanism in the pathogenesis of infective endocarditis. We have previously described Staphylococcus aureus strain PS12, a Tn551-derived mutant of strain ISP479, with reduced ability to bind human platelets in vitro. When tested in an animal model of endocarditis, the PS12 strain was less virulent than its parental strain, as measured by bacterial densities in endocardial vegetations and incidence of systemic embolization. We have now characterized the gene disrupted in PS12 and its function in platelet binding. DNA sequencing, Southern blotting, and PCR analysis indicate that PS12 contained two Tn551 insertions within the clumping factor A (ClfA) locus (clfA). The first copy was upstream from the clfA start codon and appeared to have no effect on ClfA production. The second insertion was within the region encoding the serine aspartate repeat of ClfA and resulted in the production of a truncated ClfA protein that was secreted from the cell. A purified, recombinant form of the ClfA A region, encompassing amino acids 40 through 559, significantly reduced the binding of ISP479C to human platelets by 44% (P = 0.0001). Immunoprecipitation of recombinant ClfA that had been incubated with solubilized platelet membranes coprecipitated a 118-kDa platelet membrane protein. This protein does not appear to be glycoprotein IIb. These results indicate that platelet binding by S. aureus is mediated in part by the direct binding of ClfA to a novel 118-kDa platelet membrane receptor.

Bacterial Adhesion↗
PubMed1999

Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects.

BACKGROUND: Platelets are integral to cardiac vegetations that evolve in infectious endocarditis. It has been postulated that the antiplatelet aggregation effect of aspirin (ASA) might diminish vegetation evolution and embolic rates. METHODS AND RESULTS: Rabbits with Staphylococcus aureus endocarditis were given either no ASA (controls) or ASA at 4, 8, or 12 mg. kg-1. d-1 IV for 3 days beginning 1 day after infection. Vegetation weights and serial echocardiographic vegetation size, vegetation and kidney bacterial densities, and extent of renal embolization were evaluated. In addition, the effect of ASA on early S aureus adherence to sterile vegetations was assessed. In vitro, bacterial adherence to platelets, fibrin matrices, or fibrin-platelet matrices was quantified with either platelets exposed to ASA or S aureus preexposed to salicylic acid (SAL). ASA at 8 mg. kg-1. d-1 (but not at 4 or 12 mg. kg-1. d-1) was associated with substantial decreases in vegetation weight (P<0.05), echocardiographic vegetation growth (P<0.001), vegetation (P<0.05) and renal bacterial densities and renal embolic lesions (P<0.05) versus controls. Diminished aggregation resulted when platelets were preexposed to ASA or when S aureus was preexposed to SAL (P<0.05). S aureus adherence to sterile vegetations (P<0.05) or to platelets in suspension (P<0.05), fibrin matrices (P<0.05), or fibrin-platelet matrices (P<0.05) was significantly reduced when bacteria were preexposed to SAL. CONCLUSIONS: ASA reduces several principal indicators of severity and metastatic events in experimental S aureus endocarditis. These benefits involve ASA effects on both the platelet and the microbe.

Animals↗
PubMed1999

A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex.

Current guidelines suggest that disseminated Mycobacterium avium complex (MAC) infection be treated with a macrolide plus ethambutol or rifabutin or both. From 1993 to 1996, 198 AIDS patients with MAC bacteremia participated in a prospective, placebo-controlled trial of clarithromycin (500 mg b.i.d.) plus ethambutol (1,200 mg/d), with or without rifabutin (300 mg/d). At 16 weeks, 63% of patients in the rifabutin group and 61% in the placebo group (P = .81) had responded bacteriologically. Changes in clinical symptoms and time to survival were similar in both groups. Development of clarithromycin resistance during therapy was similar in the two groups; of patients who had a bacteriologic response, however, only 1 of 44 (2%) receiving rifabutin developed clarithromycin resistance, vs. 6 of 42 (14%) in the placebo group (P = .055). Thus, rifabutin had no impact on bacteriologic response or survival but may protect against development of clarithromycin resistance in those who respond to therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Physical proximity and functional interplay of the glycoprotein Ib-IX-V complex and the Fc receptor FcgammaRIIA on the platelet plasma membrane.

Although the glycoprotein (GP) Ib-IX-V complex and FcgammaRIIA are distinct platelet membrane receptors, previous studies have suggested that these structures may be co-localized. To determine more directly the proximity of GP Ib-IX-V and FcgammaRIIA, we assessed the effects of anti-GP Ibalpha monoclonal antibodies on FcgammaRIIA-mediated platelet aggregation and on the direct binding of polymeric IgG to human platelets. In addition, we directly examined the proximity of FcgammaRII and GP Ib-IX-V using flow cytometric fluorescence energy transfer and immunoprecipitation studies. Preincubation of platelets with either of two monoclonal antibodies (AN51 or SZ2) directed against GP Ibalpha completely blocked platelet aggregation by polymeric IgG. Similarly, these antibodies totally inhibited platelet aggregation by two strains of viridans group streptococci known to induce aggregation via FcgammaRIIA. In addition, AN51 and SZ2 significantly reduced the binding of polymeric IgG to washed fixed platelets. When assessed by flow cytometry, significant levels of bidirectional energy transfer were detected between FcgammaRIIA and GP Ibalpha, indicating a physical proximity of less than 10 nm between these receptors. This energy transfer was not due to high receptor density, because no homoassociative energy transfer was seen. Moreover, immunoprecipitation of FcgammaRIIA from platelet lysates also co-precipitated GP Ibalpha. These results indicate that GP Ibalpha and FcgammaRIIA are co-localized on the platelet membrane and that this association is not random.

Antibodies, Monoclonal↗
PubMed1998

Platelet microbicidal proteins and neutrophil defensin disrupt the Staphylococcus aureus cytoplasmic membrane by distinct mechanisms of action.

Platelet microbicidal proteins (PMPs) are hypothesized to exert microbicidal effects via cytoplasmic membrane disruption. Transmission electron microscopy demonstrated a temporal association between PMP exposure, damage of the Staphylococcus aureus cytoplasmic membrane ultrastructure, and subsequent cell death. To investigate the mechanisms of action of PMPs leading to membrane damage, we used flow cytometry to compare the effects of two distinct PMPs (thrombin-induced PMP-1 [tPMP-1] or PMP-2) with human neutrophil defensin-1 (hNP-1) on transmembrane potential (Deltapsi), membrane permeabilization, and killing of S. aureus. Related strains 6850 (Deltapsi -150 mV) and JB-1 (Deltapsi -100 mV; a respiration-deficient menadione auxotroph of 6850) were used to assess the influence of Deltapsi on peptide microbicidal effects. Propidium iodide (PI) uptake was used to detect membrane permeabilization, retention of 3,3'-dipentyloxacarbocyanine (DiOC5) was used to monitor membrane depolarization (Deltapsi), and quantitative culture or acridine orange accumulation was used to measure viability. PMP-2 rapidly depolarized and permeabilized strain 6850, with the extent of permeabilization inversely related to pH. tPMP-1 failed to depolarize strain 6850, but did permeabilize this strain in a manner directly related to pH. Depolarization, permeabilization, and killing of strain JB-1 due to PMPs were significantly less than in strain 6850. Growth in menadione reconstituted Deltapsi of JB-1 to a level equivalent to 6850, and was associated with greater depolarization due to PMP-2, but not tPMP-1. Reconstitution of Deltapsi also enhanced permeabilization and killing of JB-1 due to tPMP-1 or PMP-2. Both PMP-2 and tPMP-1 caused significant reductions in viability of strain 6850. In contrast to tPMP-1 or PMP-2, defensin hNP-1 depolarized, permeabilized, and killed both strains 6850 and JB-1 equally, and in a manner directly related to pH. Collectively, these data indicate that membrane dysfunction and cell death due to tPMP-1, PMP-2, or hNP-1 likely involve different mechanisms. These findings may also reveal new insights into the microbicidal activities versus mammalian cell toxicities of antimicrobial peptides.

Animals↗
PubMed1997

A simple, fluorescent method to internally label platelets suitable for physiological measurements.

Current methods for studying platelet survival in vivo are limited by the use of radioisotopes, with their inherent safety and regulatory concerns, systemic drug administrations that produce biochemical modifications of platelet functions, or external labeling techniques, which may produce artifacts due to surface modifications. For these reasons, we sought to develop a simple, nonisotopic method for labeling platelets internally, thereby producing platelets more likely to have in vivo properties equivalent to native cells. Murine platelets in protein-free buffer were fluorescently labeled internally by incubation with 2.5 microM 5-chloromethyl fluorescein diacetate (CMFDA), and without washing, were injected into mice for platelet survival studies. CMFDA-labeled platelets were unactivated, as shown by minimal P-selectin expression. When tested in vitro for function by aggregometry, the response of CMFDA-labeled platelets to collagen and thrombin was identical to that of unlabeled platelets. Flow cytometric analysis demonstrated that CMFDA platelets were an intensely stained, unimodal population that was completely separated from unlabeled platelets. The mean half-life of labeled platelets in the murine circulation was 37.5 +/- 4.5 hr (+/-1 SD), and the mean survival time was 3.1-3.3 days (n = 24), similar to results reported using 51Cr and (111)In. No evidence of in vivo transfer of dye from labeled platelets to unlabeled cells was observed. CMFDA produces a population of platelets that are nonradioactively, internally labeled with a highly fluorescent, stable product. The labeled platelets function equivalently to native platelets, as demonstrated by immunocytometry and aggregometry, and importantly, in vivo, by normal platelet survival.

Animals↗
PubMed1997

Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation.

A nested case-control study was conducted in two trials of prophylaxis for Mycobacterium avium complex (MAC) infection to describe the specific signs, symptoms, and laboratory abnormalities of MAC disease in AIDS. Patients had < or =200/mm3 CD4 cells and a prior AIDS-defining illness. Of 571 patients, 102 (17.9%) developed MAC bacteremia during a mean follow-up of 256 days. Among cases of MAC disease, 90 were compared with 180 matched controls. Patients with MAC disease were more likely than controls to have lower weights (66.3 vs. 71.1 kg, P = .001) and Karnofsky scores (74.3 vs. 84.4, P < .001); a higher proportion had fever (48% vs. 26%, P = .003), abdominal pain (23% vs. 13%, P =.05), decreased hemoglobin levels (10.9 vs. 12.1 g/dL, P < .001), and elevated alkaline phosphatase (203 vs. 138 U/L, P=.04) and lactate dehydrogenase (334 vs. 280 U/L, P = .02) levels. Characteristics of MAC disease that occurred before bacteremia were weight loss (3 months prior), fever (2 months), and anemia and elevated lactate dehydrogenase (1 month). These data suggest that patients have symptomatic MAC disease for several months prior to the occurrence of bacteremia.

Adult↗
PubMed1997

Geographic and seasonal variation in Mycobacterium avium bacteremia among North American patients with AIDS.

Analysis of geographic risk was performed for Mycobacterium avium complex (MAC) bacteremia among North American patients with AIDS. Monthly mycobacterial blood cultures were taken from patients who were placebo recipients in a prospective evaluation of MAC prophylaxis. Of 571 patients, 102 (17.9%) acquired MAC bacteremia during an average follow-up of 256 days. The area with the highest risk for MAC was the South Central region (27.9%; P < 0.02), whereas the area with the lowest risk was Canada (11.3%; P = 0.12). When the southern states were combined and compared with the northern states and Canada, the incidence of MAC bacteremia was higher in the southern states (21.6% versus 14.0%, P < 0.03). Proportional hazards analysis was performed for the difference between the North and South and controlled for baseline CD4 cell count. In this analysis, time to MAC was significantly longer in the North (hazard ratio = 0.587, 95% confidence interval 0.390 to 0.883, P = 0.01). Although overall variation in seasonality was not marked, there was a significant decrease in cases in the North during the summer months (P < 0.01). We conclude that geographic location is a risk factor for MAC bacteremia in patients with advanced AIDS, with decreased risk in northern North America.

AIDS-Related Opportunistic Infections↗
PubMed1997

Phenotypic resistance to thrombin-induced platelet microbicidal protein in vitro is correlated with enhanced virulence in experimental endocarditis due to Staphylococcus aureus.

Thrombin-induced platelet microbicidal protein (tPMP) is secreted by rabbit platelets following thrombin stimulation, and it kills common endovascular pathogens in vitro, including Staphylococcus aureus. Therefore, pathogens which exhibit tPMP resistance in vitro possess a potential survival advantage in vivo at sites of endovascular damage. We generated an isogenic S. aureus strain pair, differing in tPMP susceptibility, by transposon (Tn551) mutagenesis of a tPMP-susceptible (tPMPs) parental strain (ISP479) to derive a stably tPMP-resistant (tPMPr) strain, ISP479R. ISP479 and ISP479R were equivalent in vitro in the following phenotypes: biotyping, antiobiograms, platelet adherence and aggregation, growth kinetics, cell wall-associated protein A expression, and fibrinogen binding. Genotypic comparisons of chromosomal DNA of strains ISP479 and ISP479R following restriction endonuclease digestion revealed indistinguishable pulsed-field gel electrophoretic patterns. The genotype exhibited by strain ISP479R was linked to the tPMP-resistant phenotype, as it was transducible into the initially tPMP-susceptible parental strain, ISP479. Southern hybridization verified the presence of a single copy of Tn551 in the same chromosomal restriction site of both ISP479R and tPMPr transductants of ISP479. The correlation of in vitro tPMP susceptibility phenotypes with the ability to induce experimental endocarditis (a prototypical endovascular infection) was evaluated. Despite equivalent rates of endocarditis induction, animals infected with strain ISP479R achieved significantly higher vegetation bacterial densities over a 7-day post-challenge period than did animals infected with strain ISP479. These data suggest that tPMPr microbial strains have a selective advantage in experimental staphylococcal endocarditis. Furthermore, the major impact of tPMP resistance upon endocarditis pathogenesis appears to involve a postvalvular adherence event(s), most probably by facilitating bacterial proliferation within vegetations.

Animals↗
PubMed1996

Rifabutin therapy for disseminated Mycobacterium avium complex infection.

Although numerous antimicrobial agents have been used to treat disseminated Mycobacterium avium complex (MAC) infection, the optimal therapy for this disease is unknown. One potentially effective agent is rifabutin, which has demonstrated activity against MAC both in vitro and in animal models of infection. In clinical trials, cultures of blood from 46% to 92% of patients become sterile after therapy with rifabutin combined with ethambutol, clofazimine, or amikacin. Moreover, the efficacy of ethambutol combined with clofazimine is markedly enhanced by rifabutin. In combination with clarithromycin, rifabutin at dosages of > or = 450 mg/d has been associated with a high incidence of uveitis, thus indicating that only 300 mg/d may be given with this macrolide. Although a definitive role for rifabutin in the treatment of MAC infection has not been established, this agent will likely be of value as an adjunct to macrolide-based therapy or in the treatment of macrolide-intolerant patients.

Anti-Bacterial Agents↗
PubMed1996

Diminished platelet binding in vitro by Staphylococcus aureus is associated with reduced virulence in a rabbit model of infective endocarditis.

The direct binding of platelets by bacteria is a postulated central mechanism in the pathogenesis of endocarditis. To address the role of binding more definitively, we employed Tn551 insertional mutagenesis of Staphylococcus aureus parental strain ISP479 to generate an isogenic variant (strain PS12) that bound platelets minimally. As compared with the binding of ISP479, the binding of PS12 to platelet monolayers was reduced by 67.2%. Similarly, the binding of PS12 to platelets in suspension was reduced by 71.3%, as measured by flow cytometry. The low-binding phenotype was transducible into both ISP479 and S. aureus Newman. Southern blotting indicated that a single copy of Tn551 was inserted within the chromosomes of PS12 and the transductants. When tested in a rabbit model, animals inoculated with PS12 were significantly less likely to develop endocarditis and had lower densities of organisms (CFU per gram) within vegetations and a decreased incidence of renal abscess formation, as compared with animals inoculated with the parental strain. The diminished virulence of PS12 was not attributable to a reduction in the initial attachment of organisms to the damaged endocardium, since 30 min after inoculation, PS12-infected animals had microbial densities on the valve surface comparable to those seen with the parental strain. These results indicate that the direct binding of Staphylococcus aureus to platelets is a major determinant of virulence in the pathogenesis of endocarditis. Staphylococcus-platelet binding appears to be critical for pathogenetic events occurring after the initial colonization of the valve surface, such as vegetation formation and septic embolization.

Animals↗
PubMed1995

The laminin alpha 1 chain Ile-Lys-Val-Ala-Val (IKVAV)-containing peptide promotes liver colonization by human colon cancer cells.

Laminin, a major basement membrane-specific glycoprotein, promotes the attachment, migration, and invasion of a variety of tumor cells. Since laminin is present in the perisinusoidal matrix of the liver, we studied its effects on liver colonization by human colon cancer cells (HM7, LiM6) previously shown to have liver-metastasizing ability in athymic mice. These malignant cells expressed high levels of a 32-kDa laminin-binding protein on Western blot analysis when compared to the low metastatic parental cell line. Coinjection of laminin alpha chain-derived peptides which contain the amino acid sequence Ile-Lys-Val-Ala-Val (IKVAV) significantly stimulated liver colonization as determined by liver weight (P < 0.005) and number of tumor nodules (P < 0.02) 3 weeks after splenic-portal inoculation into nude mice. No stimulation was seen with a control peptide containing the same amino acids but in a scrambled sequence. In contrast, the Tyr-Ile-Gly-Ser-Arg peptide from the laminin beta 1 chain significantly inhibited HM7 liver colonization. These differences were not due to alterations in the number of cells initially reaching the liver as determined by injection of [125I]iododeoxyuridine-labeled tumor cells, but retention in the liver was stimulated by the IKVAV-containing peptides. Flow analysis indicated that the IKVAV peptide may act, in part, by stimulating homotypic adhesion of tumor cells. These data suggest that interactions of colon cancer cells with the IKVAV site on laminin may play a role in the formation of metastatic foci in the liver through cell-cell or cell-substratum interactions which promote metastasis.

Adenocarcinoma↗
PubMed1995

Staphylococcus aureus induces platelet aggregation via a fibrinogen-dependent mechanism which is independent of principal platelet glycoprotein IIb/IIIa fibrinogen-binding domains.

Platelet aggregation by bacteria is felt to play an important role in the pathogenesis of infective endocarditis. However, the mechanisms involved in bacterium-induced platelet aggregation are not well-defined. In the present study, we examined the mechanisms by which Staphylococcus aureus causes rabbit platelet aggregation in vitro. In normal plasma, the kinetics of S. aureus-induced platelet aggregation were rapid and biphasic. The onset and magnitude of aggregation phase 1 varied with the bacterium-platelet ratio, with maximal aggregation observed at a ratio of 5:1. The onset of aggregation phase 2 was delayed in the presence of apyrase (an ADP hydrolase), suggesting that this later aggregation phase may be triggered by secreted ADP. The onset of aggregation phase 2 was delayed in the presence of prostaglandin I2-treated platelets, and this phase was absent when paraformaldehyde-fixed platelets were used, implicating platelet activation in this process. Platelet aggregation phase 2 was dependent on S. aureus viability and an intact bacterial cell wall, and it was mitigated by antibody directed against staphylococcal clumping factor (a fibrinogen-binding protein) and by the cyclooxygenase inhibitor indomethacin. Similarly, aggregation phase 2 was either delayed or absent in three distinct transposon-induced S. aureus mutants with reduced capacities to bind fibrinogen in vitro. In addition, a synthetic pentadecapeptide, corresponding to the staphylococcal binding domain in the C terminus of the fibrinogen delta-chain, blocked aggregation phase 2. However, phase 2 of aggregation was not inhibited by two synthetic peptides (alone or in combination) analogous to the two principal fibrinogen-binding domains on the platelet glycoprotein (GP) IIb/IIIa integrin receptor: (i) a recognition site on the IIIa molecule for the Arg-Gly-Asp (RGD) sequence of the fibrinogen alpha-chain and (ii) a recognition site on the IIb molecule for a dodecapeptide sequence of the fibrinogen delta-chain. This differs from ADP-induced platelet aggregation, which relies on an intact platelet GP IIb/IIIa receptor with an accessible RGD sequence and dodecapeptide recognition site for fibrinogen. Furthermore, a monoclonal antibody directed against the RGD recognition site on rabbit platelet GP IIb/IIIa receptors failed to inhibit rabbit platelet aggregation by S. aureus. Collectively, these data suggest that S. aureus-induced platelet aggregation requires bacterial binding to fibrinogen but is not principally dependent upon the two major fibrinogen-binding domains on the platelet GP IIb/IIIa integrin receptor, the RGD and dodecapeptide recognition sites.

Adenosine Triphosphate↗
PubMed1994

Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. The Rifabutin Treatment Group.

The incidence of infection with Mycobacterium avium complex (MAC) is increasing among patients with AIDS. Although numerous antimicrobial regimens have been proposed as treatment for this infection, it is unclear which therapy is most effective. For this reason, we prospectively evaluated rifabutin (600 mg/d) vs. a placebo, each in combination with clofazimine and ethambutol, for the treatment of MAC bacteremia. Patients in the rifabutin group had a significantly higher rate of microbiological response (defined as either sterilization of the blood or at least a 2-log10 reduction in mycobacterial titers). By week 4 of therapy, 7 of 11 patients receiving rifabutin, vs. 0 of 13 in the placebo group, had responded (P < .001). Similar results were seen at later time points (7 of 10 vs. 1 of 8 responded to rifabutin by week 8, and 6 of 9 vs. 1 of 7 responded to a placebo by week 12). These results indicate that, in combination with other antimicrobial agents, rifabutin may be effective in the treatment of disseminated MAC infection.

AIDS-Related Opportunistic Infections↗
PubMed1994

Fluconazole and platelet microbicidal protein inhibit Candida adherence to platelets in vitro.

Adherence to vascular endothelium is considered an essential step in the pathogenesis of hematogenously disseminated candidiasis. Platelets have been shown to promote Candida adherence to vascular endothelium in vitro. In contrast, recent studies indicate that platelets may also play a role in the primary host defense against endovascular infection by secretion of alpha granule-derived platelet microbicidal protein (PMP), which possesses both bactericidal and fungicidal activities as well as antiadherence properties. We examined the influences of PMP and the antifungal agent fluconazole on the adherence of Candida albicans to rabbit platelets, as measured by quantitative flow cytometry. In the absence of PMP and fluconazole, adherence of C. albicans to platelets was rapid (complete within 1 min), saturable, and reversible. Following 2 h of exposure to fluconazole at 10x the MIC, platelet binding of C. albicans was substantially reduced (mean reduction, 32.1%; P = 0.08). Similarly, exposure of C. albicans to PMP (range, 0.5 to 5 micrograms/ml) for 2 h (but not 30 min) significantly reduced candidal adherence to platelets 43.1 to 62.1%; (reduction range, P < 0.05). Moreover, exposure of C. albicans to PMP (5 micrograms/ml for 30 min) and then fluconazole (10x the MIC for 2 h) further decreased candidal adherence to platelets in comparison with the adherence after exposure to either agent alone (mean reduction, 57.2%; P = 0.02 and 0.05, respectively). These data demonstrate that PMP and fluconazole individually reduce the ability of C. albicans to bind to platelets in vitro and that the antiadherence activities of fluconazole are augmented by PMP.

Animals↗