Ureteral stent-associated infection and sepsis: pathogenesis and prevention: a review.

Ureteral stents are commonly used devices in hospital settings. However, their usage is often complicated by associated urinary tract infections as a result of bacterial adhesion onto the indwelling implant surfaces, followed by the formation of layers of biofilm. Once formed, the biofilm is exceedingly difficult to remove, potentially leading to further morbidity and even urosepsis. Urosepsis, where pathogens from the urinary tract enter the bloodstream, has a mortality rate of up to 50% of severely infected patients. Hence, it is important to understand its pathogenesis. In this review, ureteral stent-associated urinary tract infection and urosepsis will be addressed. In particular, the bacterial mechanisms involved, as well as the prevention and treatment of these infections will be discussed.

A high throughput, minimally invasive, ultrasound guided model for the study of catheter associated urinary tract infections and device encrustation in mice.

PURPOSE: Catheter associated urinary tract infections are one of the most common health care associated infections. The condition is frequently complicated by encrustation, which blocks the catheter lumen. Preclinical research is limited by the lack of relevant high throughput and cost-effective animal models. Current models are restricted to female mice, associated with major transurethral loss of catheter materials during micturition, highly invasive and complex. We present an ultrasound guided, minimally invasive model that enables catheter associated urinary tract infection and catheter encrustation studies in each mouse gender. MATERIALS AND METHODS: Catheter segments (4 mm) were implanted in murine bladders percutaneously in 15 males and 5 females, and transurethrally in 15 females using the Seldinger technique under ultrasound guidance. Proteus mirabilis was instilled intraluminally. Catheter encrustation was monitored by ultrasound. Bacteria were quantified in urine, and catheters and encrustation were analyzed on day 6 or 21. RESULTS: Percutaneous and transurethral catheter implantations were performed in a mean ± SE 3.6 ± 0.8 vs 2.5 ± 0.5 minutes in all mice. Ultrasound confirmed that 100% and 66% of implanted catheters, respectively, remained indwelling during the study period. Catheter encrustation developed in P. mirabilis infected urine 48 hours after instillation and an increase with time was detected by ultrasound. Fourier transform spectroscopy of the encrustation confirmed a typical struvite spectrum. Control catheters remained sterile during 21 days. CONCLUSIONS: Our minimally invasive, reproducible percutaneous technique is suitable for studying catheter associated urinary tract infection in each gender. Infecting urine with P. mirabilis generates a preclinical model of catheter encrustation within 3 days. The progression of encrustation can be monitored in vivo by ultrasound, making this image based model suitable for assessing novel antibacterial and anti-encrustation therapies.

Understanding urinary conditioning film components on ureteral stents: profiling protein components and evaluating their role in bacterial colonization.

Ureteral stents are fraught with problems. A conditioning film attaches to the stent surface within hours of implantation; however, differences between stent types and their role in promoting encrustation and bacterial adhesion and colonization remain to be elucidated. The present work shows that the most common components do not differ between stent types or patients with the same indwelling stent, and contain components that may drive stent encrustation. Furthermore, unlike what was previously thought, the presence of a conditioning film does not increase bacterial adhesion and colonization of stents by uropathogens. Genitourinary cytokeratins are implicated in playing a significant role in conditioning film formation. Overall, stent biomaterial design to date has been unsuccessful in discovering an ideal coating to prevent encrustation and bacterial adhesion. This current study elucidates a more global understanding of urinary conditioning film components. It also supports specific focus on the importance of physical characteristics of the stent and how they can prevent encrustation and bacterial adhesion.

Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.

Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.

The Combined Use of Gentamicin and Silver Nitrate in Bone Cement for a Synergistic and Extended Antibiotic Action against Gram-Positive and Gram-Negative Bacteria.

Using bone cement as a carrier, gentamicin was for years the default drug to locally treat orthopedic infections but has lost favor due to increasing bacterial resistance to this drug. The objective of this study was to investigate the effect of combining gentamicin with silver nitrate in bone cement against S. aureus and P. aeruginosa. Antibacterial effects (CFU counts) of gentamicin and silver were initially studied followed by studies using subtherapeutic concentrations of each in combination. The release rates from cement were measured over 10 days and day 7 release samples were saved and analyzed for antibiotic activity. A strong synergistic effect of combining silver with gentamicin was found using both dissolved drugs and using day 7 bone cement release media for both Gram-positive and Gram-negative bacteria. The cement studies were extended to vancomycin and tobramycin, which are also used in bone cement, and similar synergistic effects were found for day 7 release media with P. aeruginosa but not S. aureus. These studies conclude that the combined use of low loadings of gentamicin and silver nitrate in bone cement may offer an economical and much improved synergistic method of providing anti-infective orthopedic treatments in the clinic.

Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer.

Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.

Polymer-Nanoparticle Interaction as a Design Principle in the Development of a Durable Ultrathin Universal Binary Antibiofilm Coating with Long-Term Activity.

Bacterial attachment and biofilm formation pose major challenges to the optimal performance of indwelling devices. Current coating methods have significant deficiencies including the lack of long-term activity, easy of application, and adaptability to diverse materials. Here we describe a coating method that could potentially overcome such limitations and yield an ultrathin coating with long-term antibiofilm activity. We utilized the interaction between polydopamine (PDA) nanoaggregates/nanoparticles and ultrahigh molecular weight (uHMW) hydrophilic polymers to generate stable coatings with broad spectrum antibiofilm activity. We used a short-term bacterial adhesion assay as an initial screening method to identify coating compositions that give superior performance and found that only selected polymers (out of 13 different types) and molecular weights gave promising antifouling activity. Optimization of PDA self-assembly, polymer-PDA interaction, and deposition on the surface using uHMW poly( N,N-dimethylacrylamide) (PDMA) (∼795 kDa) resulted in a stable ultrathin coating (∼19 nm) with excellent antifouling and antibiofilm properties (>4 weeks) against diverse bacteria (∼108 CFU/mL) in shaking and flow conditions. The ultrathin coating is effective on diverse substrates including metals and polymeric substrates. The uHMW PDMA is stabilized in the coating via supramolecular interactions with PDA and generated a surface that is highly enriched with PDMA in aqueous conditions. Based on the surface analyses data, we also propose a mechanism for the stable coating formation. The molecular weight of PDMA is a crucial factor, and only uHMW polymers generate this property. An attractive feature of the coating is that it does not contain any antimicrobial agents and has the potential to prevent biofilm formation for diverse applications both short- and long-term.

Anti-adhesive antimicrobial peptide coating prevents catheter associated infection in a mouse urinary infection model.

Catheter-associated urinary tract infections (CAUTIs) represent one of the most common hospital acquired infections with significant economic consequences and increased patient morbidity. CAUTIs often start with pathogen adhesion and colonization on the catheter surface followed by biofilm formation. Current strategies to prevent CAUTIs are insufficiently effective and antimicrobial coatings based on antimicrobial peptides (AMPs) hold promise in curbing CAUTIs. Here we report an effective surface tethering strategy to prepare AMP coatings on polyurethane (PU), a common biomedical plastic used for catheter manufacture, by using an anti-adhesive hydrophilic polymer coating. An optimized surface active AMP, labeled with cysteine at the C-terminus (RRWRIVVIRVRRC), was used. The coated PU surface was characterized using ATR-FTIR, XPS and atomic force microscopy analyses. The tethered peptides on the PU catheter surface displayed broad spectrum antimicrobial activity and showed long term activity in vitro. The surface coating prevented bacterial adhesion by up to 99.9% for both Gram-positive and -negative bacteria, and inhibited planktonic bacterial growth by up to 70%. In vivo, the coating was tested in a mouse urinary catheter infection model; the AMP-coated PU catheter was able to prevent infection with high efficiency by reducing the bacteria adhesion on catheter surface by more than 4 logs (from 1.2 × 106 CFU/mL to 5 × 101 CFU/mL) compared to the uncoated catheter surface, and inhibit planktonic bacterial growth in the urine by nearly 3 logs (1.1 × 107 CFU/mL to 1.47 × 104 CFU/mL). The AMP-brush coating also showed good biocompatibility with bladder epithelial cells and fibroblast cells in cell culture. The new coating might find clinical applications in preventing CAUTIs.

Current and potential applications of host-defense peptides and proteins in urology.

The use of antibiotics has become increasingly disfavored as more multidrug resistant pathogens are on the rise. A promising alternative to the use of these conventional drugs includes antimicrobial peptides or host-defense peptides. These peptides typically consist of short amino acid chains with a net cationic charge and a substantial portion of hydrophobic residues. They mainly target the bacterial cell membrane but are also capable of translocating through the membrane and target intracellular components, making it difficult for bacteria to gain resistance as multiple essential cellular processes are being targeted. The use of these peptides in the field of biomedical therapies has been examined, and the different approaches to using them under various settings are constantly being discovered. In this review, we discuss the current and potential applications of these host-defense peptides in the field of urology. Besides the use of these peptides as antimicrobial agents, the value of these biological molecules has recently been expanded to their use as antitumor and anti-kidney-stone agents.

Toward Infection-Resistant Surfaces: Achieving High Antimicrobial Peptide Potency by Modulating the Functionality of Polymer Brush and Peptide.

Bacterial infection associated with indwelling medical devices and implants is a major clinical issue, and the prevention or treatment of such infections is challenging. Antimicrobial coatings offer a significant step toward addressing this important clinical problem. Antimicrobial coatings based on tethered antimicrobial peptides (AMPs) on hydrophilic polymer brushes have been shown to be one of the most promising strategies to avoid bacterial colonization and have demonstrated broad spectrum activity. Optimal combinations of the functionality of the polymer-brush-tethered AMPs are essential to maintaining long-term AMP activity on the surface. However, there is limited knowledge currently available on this topic. Here we report the development of potent antimicrobial coatings on implant surfaces by elucidating the roles of polymer brush chemistry and peptide structure on the overall antimicrobial activity of the coatings. We screened several combinations of polymer brush coatings and AMPs constructed on nanoparticles, titanium surfaces, and quartz slides on their antimicrobial activity and bacterial adhesion against Gram-positive and Gram-negative bacteria. Highly efficient killing of planktonic bacteria by the antimicrobial coatings on nanoparticle surfaces, as well as potent killing of adhered bacteria in the case of coatings on titanium surfaces, was observed. Remarkably, the antimicrobial activity of AMP-conjugated brush coatings demonstrated a clear dependence on the polymer brush chemistry and peptide structure, and optimization of these parameters is critical to achieving infection-resistant surfaces. By analyzing the interaction of polymer-brush-tethered AMPs with model lipid membranes using circular dichroism spectroscopy, we determined that the polymer brush chemistry has an influence on the extent of secondary structure change of tethered peptides before and after interaction with biomembranes. The peptide structure also has an influence on the density of conjugated peptides on polymer brush coatings and the resultant wettability of the coatings, and both of these factors contributed to the antimicrobial activity and bacterial adhesion of the coatings. Overall, this work highlights the importance of optimizing the functionality of the polymer brush to achieve infection-resistant surfaces and presents important insight into the design criteria for the selection of polymers and AMPs toward the development of potent antimicrobial coating on implants.

Phytoremediation of petroleum hydrocarbons in tropical coastal soils. I. Selection of promising woody plants.

GOAL, SCOPE AND BACKGROUND: This glasshouse study is aimed at evaluating tropical plants for phytoremediation of petroleum hydrocarbon-contaminated saline sandy subsurface soils. Tropical plants were selected for their ability to tolerate high salinity and remove No. 2 diesel fuel in coastal topsoil prior to further investigation of the phytoremediation feasibility in deep contaminated soils. The residual petroleum-hydrocarbon contaminant at the John Rogers Tank Farm site, a former petroleum storage facility, at Hickam Air Force Base, Honolulu, Hawaii, is located in a coastal area. It lies below a layer of silt in the subsurface, in loamy sand characterized by moderate salinity and high pH. Little is known regarding the ability of tropical plants to remediate petroleum hydrocarbon-contaminated subsurface soil in Hawaiian and other Pacific Island ecosystems although suitable plants have been identified and utilized for bioremediation in surface soil or marine sediments. METHODS: The experiments were conducted in long narrow pots under glasshouse conditions in two phases. A preliminary experiment was done with nine tropical plants: kiawe (Prosopis pallida), milo (Thespesia populnea), common ironwood (Casuarina equisetifolia), kou (Cordia subcordata), tropical coral tree (Erythrina variegata), false sandalwood (Myoporum sandwicense), beach naupaka (Scaevola sericea), oleander (Nerium oleander), and buffelgrass (Cenchrus ciliaris). These plants were screened for resistance to high salinity treatment (2% NaCl) and two diesel fuel levels (5 and 10 g No. 2 diesel fuel/kg soil) in separate treatments. Plants that showed good tolerance of both factors were further evaluated in a second phase for their efficacy in the phytoremediation of diesel-fuel petroleum hydrocarbons under moderate salinity treatment (1% NaCl). RESULTS: Tropical coral tree and buffelgrass were susceptible to either 2% NaCl or diesel fuel at 10 g/kg soil, but tolerant of diesel fuel at 5 g/kg soil. Kiawe, milo, kou, common ironwood, N. oleander, beach naupaka and false sandalwood were tolerant of high salinity (2% NaCl) or high diesel fuel level (10 g/kg soil). These seven plants were also tolerant of the combined adverse effects of a moderate salinity (1% NaCl) and 10 g diesel fuel/kg soil. Three trees, kiawe, milo and kou significantly accelerated the degradation of petroleum hydrocarbons in the soil spiked with 10 g diesel fuel/kg soil under a moderate salinity treatment (1% NaCl). CONCLUSION: Thus the tropical woody plants, kiawe, milo and kou showed potential for use in phytoremediation of petroleum hydrocarbons in coastal tropical soils. RECOMMENDATIONS AND OUTLOOK: Two fast growing trees, milo and kou, appeared promising for further phytoremediation evaluation in experiments that simulate the soil profile at the field site.

Ureteral Stents and Foley Catheters-Associated Urinary Tract Infections: The Role of Coatings and Materials in Infection Prevention.

Urinary tract infections affect many patients, especially those who are admitted to hospital and receive a bladder catheter for drainage. Catheter associated urinary tract infections are some of the most common hospital infections and cost the health care system billions of dollars. Early removal is one of the mainstays of prevention as 100% of catheters become colonized. Patients with ureteral stents are also affected by infection and antibiotic therapy alone may not be the answer. We will review the current evidence on how to prevent infections of urinary biomaterials by using different coatings, new materials, and drug eluting technologies to decrease infection rates of ureteral stents and catheters.