Clinical Challenges in Addressing Resistance to Antimicrobial Drugs in the Twenty-First Century

Septimus, Edward; Kuper, Kristi

doi:10.1038/clpt.2009.122

Cited by 26 publications

(17 citation statements)

References 31 publications

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“…Once a patient becomes chronically infected by P. aeruginosa, the current guidelines recommend long-term antibiotic therapy. This has led to the development of antibiotic resistance due to selective pressure and subtherapeutic local drug concentrations (1,3,6,36,37). In addition, P. aeruginosa can grow as a biofilm, which can result in further reduced susceptibility to certain antibiotics (1,2,6,38).…”

Section: Discussionmentioning

confidence: 99%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 g/ml). Cytotoxic effects on CFBE41o-cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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Section: Discussionmentioning

confidence: 99%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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“…Rapid detection and identification of the causative pathogen(s) in BSIs and subsequent initiation of appropriate targeted therapy are also critical in an era of increasing emergence of microbial and multidrug resistance in both Gram-positive and Gram-negative bacteria [8][9][10]. Among Gram-positive bacteria, the occurrence of meticillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.…”

Section: Introductionmentioning

confidence: 99%

Verigene® Gram-Positive Blood Culture Nucleic Acid Test

Scott¹

2013

Mol Diagn Ther

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Bloodstream infections (BSIs) are a major cause of morbidity and mortality worldwide, and impose considerable costs on healthcare systems. A key predictor of clinical outcomes in patients with BSIs is the early initiation of appropriate targeted antimicrobial therapy. However, with conventional blood culture methods, the gold standard, there is a significant time delay of approximately 2-3 days before clinical results are available, with many patients receiving inappropriate and/or unnecessary antimicrobial therapy in the interim. During the past two decades, the use of in vitro assays that utilize nucleic acid amplification-based detection of pathogen-associated molecular patterns has led to a significant reduction in the time (hours vs. days with blood culture) to detection and identification of several of the causative pathogens of BSIs and, potentially, earlier initiation of targeted antimicrobial therapy. This review focuses on the properties and clinical use of one of these molecular diagnostic assays, the Verigene(®) Gram-Positive Blood Culture Nucleic Acid Test (BC-GP), which detects many of the potentially pathogenic Gram-positive bacteria associated with BSIs, including Staphylococcus spp., Streptococcus spp., Listeria spp., and Enterococcus spp., and specific resistance markers (mecA, vanA, and vanB). Based on more than 1,600 samples, there was a high degree of agreement between BC-GP test results and those obtained using conventional blood culture and assay methods, irrespective of whether samples were fresh or frozen, and a high degree of agreement for identification of mecA-mediated meticillin resistance in S. aureus and S. epidermidis organisms and vanA- or vanB-mediated vancomycin resistance in E. faecalis and E. faecium organisms.

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“…Penicillin was considered the drug of choice for the therapy of most URTI because of the susceptibility of most oral pathogens. The growing resistance of oral pathogens, however, has limited the use of this drug [24,25].…”

Section: Clinical Studiesmentioning

confidence: 99%

β-Lactamase–Producing Bacteria in Upper Respiratory Tract Infections

Brook

2010

Curr Infect Dis Rep

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β-Lactamase-producing bacteria (BLPB) can play an important role in respiratory infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme β-lactamase. BLPB not only may survive penicillin therapy, but as demonstrated by in vitro and in vivo studies, can also protect other penicillin-susceptible bacteria from penicillin by releasing the free enzyme into their environment. The clinical in vitro and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed.

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Clinical Challenges in Addressing Resistance to Antimicrobial Drugs in the Twenty-First Century

Cited by 26 publications

References 31 publications

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Verigene® Gram-Positive Blood Culture Nucleic Acid Test

β-Lactamase–Producing Bacteria in Upper Respiratory Tract Infections

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