Beneficial Influence of Platelets on Antibiotic Efficacy in an In Vitro Model of<i>Staphylococcus aureus</i>-Induced Endocarditis

Mercier, Renée-Claude; Dietz, Robert M.; Mazzola, Jory L.; Bayer, Arnold S.; Yeaman, Michael R.

doi:10.1128/aac.48.7.2551-2557.2004

Cited by 27 publications

(15 citation statements)

References 33 publications

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“…First, an important factor in the pathogenesis of S. aureus infection is the ability of the microbe to circumvent clearance by platelet-mediated mechanisms, principally via resistance to killing by platelet HDPs (e.g., tPMPs) secreted in response to agonists generated at endovascular infection sites (58). Reduced killing by tPMPs in vitro has been correlated with enhanced in vivo virulence and less efficacy of antibiotic therapy (including vancomycin) in a rabbit endocarditis (IE) model in several previous studies from our laboratory (9,10,40). In addition, S. aureus bloodstream strains isolated from endovascular infections were significantly less susceptible to killing by tPMPs in vitro than bacteremia strains from other clinical syndromes (e.g., soft tissue abscesses), demonstrating the potential importance of relative tPMP resistance in clinical settings (1,55).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Phenotypic Signatures Distinguish Persistent from Resolving Methicillin-Resistant Staphylococcus aureus Bacteremia Isolates

Seidl

Bayer

Fowler

et al. 2011

Antimicrob Agents Chemother

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Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) (positive blood cultures after >7 days of therapy) represents a clinically challenging subset of invasive MRSA infections. In this investigation, we examined the potential correlation of specific virulence signatures with PB versus resolving MRSA bacteremia (RB) (negative blood cultures within 2 to 4 days of therapy) strains. Thirty-six MRSA isolates from patients enrolled in a recent multinational clinical trial were studied for (i) susceptibility to host defense cationic peptides (HDPs) (i.e., thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide 1 [hNP-1]); (ii) adherence to host endovascular ligands (fibronectin) and cells (endothelial cells); and (iii) biofilm formation. We found that PB isolates exhibited significantly reduced susceptibilities to tPMPs and hNP-1 (P < 0.001 and P ‫؍‬ 0.023, respectively). There was no significant association between the PB outcome and fibronectin binding, endothelial cell binding, or biofilm formation (P ‫؍‬ 0.25, 0.97, and 0.064 versus RB strains, respectively). However, multiple logistic regression analysis revealed that the PB outcome was significantly associated with the combination of reduced susceptibilities to HDPs and extent of biofilm formation (P < 0.0001). Similar results were obtained in a second analysis using days of bacteremia as a continuous outcome, showing that reduced HDP susceptibilities and increased biofilm formation cocontributed to predict the duration of bacteremia. Our data indicate that PB isolates have specific pathogenic signatures independent of conventional antimicrobial susceptibility. These combinatorial mosaics can be defined and used to prospectively distinguish PB from RB strains in advance and potentially to predict ultimate clinical outcomes.Staphylococcus aureus is a leading cause of bacteremia and infective endocarditis (IE) throughout the industrialized world (18,22,42,54). A growing proportion of these bloodstream infections are due to methicillin-resistant Staphylococcus aureus (MRSA), which is associated with worse clinical outcome, longer hospitalization, and higher net cost than similar infections caused by methicillin-susceptible S. aureus (MSSA) (3,6,14,15,26,49,52,60). Persistent-bacteremia (PB) outcomes comprise 20 to 30% of all episodes of MRSA bacteremia and are especially relevant to endovascular infections (13,22,23,31). Why some MRSA bacteremia strains persist while others resolve (RB) despite similar baseline clinical and microbiologic characteristics and identical medical and surgical therapeutic strategies is poorly understood.In two recent studies, we investigated S. aureus virulence factors that could potentially differentiate PB from RB strains in the context of endovascular infections (23, 56). We initially studied PB or RB isolates from the Duke University Medical Center and delineated several in vitro parameters that appeared to distinguish these two strain cohorts, including enhanced matrix ligand and e...

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Section: Discussionmentioning

confidence: 99%

Combinatorial Phenotypic Signatures Distinguish Persistent from Resolving Methicillin-Resistant Staphylococcus aureus Bacteremia Isolates

Seidl

Bayer

Fowler

et al. 2011

Antimicrob Agents Chemother

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“…A one-compartment infection model (250 ml) was utilized in duplicate (19). The models were filled with YNB-2% dextrose, and both reservoirs contained YNB-2% dextrose to supplement the models.…”

Section: Methodsmentioning

confidence: 99%

Activities and Ultrastructural Effects of Antifungal Combinations against Simulated Candida Endocardial Vegetations

Pai¹,

Samples²,

Mercier³

et al. 2008

Antimicrob Agents Chemother

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In vitro pharmacodynamic model (PDM) simulation of serum antifungal concentrations may predict the value of combination antifungal regimens against Candida sp. endocarditis. We investigated the effects of combinations of flucytosine (5FC), micafungin (Mica), and voriconazole (Vor) against Candida-infected human platelet-fibrin clots, used as simulated endocardial vegetations (SEVs). Single clinical bloodstream isolates of Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis were used. All four isolates were susceptible to 5FC, while C. glabrata was resistant to Vor and C. tropicalis had a paradoxical resistance phenotype to Mica. The SEVs were prepared with an initial inoculum of 1 x 10(6) CFU/g of SEV and added to a PDM, which utilized yeast nitrogen broth-2% glucose and incubation at 35 degrees C and simulated antifungal pharmacokinetic profiles. Fungal densities in the SEVs were determined in quadruplicate over 72 h. Scanning electron microscopy (SEM) was used to evaluate treatment and control SEVs. Vor was the least active single agent against all Candida spp. except for C. parapsilosis, where it was comparable to Mica. In contrast, 5FC was the most active against all Candida spp. except for C. tropicalis, where it was comparable to Mica. The combination of 5FC plus Vor was superior to either agent alone against C. parapsilosis. The combination of Vor plus Mica was inferior to the use of Mica alone against C. tropicalis. The triple combination of 5FC plus Vor plus Mica was no better than single or dual agents against any of the Candida spp. The ultrastructural features of infected SEVs were unique for each Candida sp., with C. parapsilosis in particular manifesting friable biofilm clusters. In general, 5FC and Mica were superior in their rates and extents of fungal burden reduction compared to Vor against Candida-infected SEVs. Evaluation of 5FC and Mica in animal models of Candida endocarditis is warranted.

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“…Several of these peptides are either structurally similar to, or identical to, known chemokines [77]. Studies of peptides have demonstrated in vitro , and in some cases in vivo , activity against a few bacterial species and fungal species [44,77–79]. However, there are as yet no studies of the direct antiviral activities of thrombocidins.…”

Section: Innate Immune Systemmentioning

confidence: 99%

Implications of the Innate Immune Response to Adenovirus and Adenoviral Vectors

Gregory

Nazir

Metcalf³

2011

Future Virol.

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Adenovirus (AdV) is a common cause of respiratory illness in both children and adults. Respiratory symptoms can range from those of the common cold to severe pneumonia. Infection can also cause significant disease in the immunocompromised and among immunocompetent subjects in close quarters. Fortunately, infection with AdV in the normal host is generally mild. This is one reason why its initial use as a gene-therapy vector appeared to be so promising. Unfortunately, both innate and adaptive responses to the virus have limited the development of AdV vectors as a tool of gene therapy by increasing toxicity and limiting duration of transgene expression. This article will focus on the innate immune response to infection with wild-type AdV and exposure to AdV gene-therapy vectors. As much of the known information relates to the pulmonary inflammatory response, this organ system will be emphasized. This article will also discuss how that understanding has led to the creation of new vectors for use in gene therapy.

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Beneficial Influence of Platelets on Antibiotic Efficacy in an In Vitro Model ofStaphylococcus aureus-Induced Endocarditis

Abstract: Platelets contribute to antimicrobial host defense against infective endocarditis (IE) by releasing platelet microbicidal proteins (PMPs).

Cited by 27 publications

References 33 publications

Combinatorial Phenotypic Signatures Distinguish Persistent from Resolving Methicillin-Resistant Staphylococcus aureus Bacteremia Isolates

Combinatorial Phenotypic Signatures Distinguish Persistent from Resolving Methicillin-Resistant Staphylococcus aureus Bacteremia Isolates

Activities and Ultrastructural Effects of Antifungal Combinations against Simulated Candida Endocardial Vegetations

Implications of the Innate Immune Response to Adenovirus and Adenoviral Vectors

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