Addressing the need for preclinical study of penile prosthesis infection: a new animal model and narrative review.

Background and Objective: Erectile dysfunction (ED) is a common condition in men, and many patients refractory to conservative treatment may undergo penile prostheses (PPs) placement. The primary concern following PP implantation is device infection. Although antibiotic and hydrophilic coatings have reduced the incidence of inflatable PP (IPP) infections, there remains room for improvement. Optimization of PP outcomes requires a practical in vivo model to better understand mechanisms of infection and to test new infection control strategies. We aimed to describe a new rabbit model which contains a functional IPP and review previously reported animal PP models. Methods: An IPP was placed into rabbit flanks and cycled for functionality testing. Rabbits were evaluated for signs of pain and distress over 14 days. Separately, narrative review methodology was utilized to search the PubMed and Scopus databases for all publications through March 21, 2023, which studied PP within an in vivo setting. Three independent reviewers ultimately selected 12 papers from 1992-2021 for inclusion. Key Content and Findings: Several animal studies highlighted the initial functionality or feasibility of devices for ED before their introduction in the clinical setting. There are several subsequent studies aimed at optimizing the type of antibiotic use or coating material using segments of PP material in an in vivo setting. However, the literature lacks a contemporary animal model containing a functional IPP. Our novel rabbit model offers a safe, practical way to implant a functioning IPP and investigate new perioperative infection prevention and treatment strategies before trials in the clinical setting. Conclusions: Animal models have played a key role in testing medical devices, including PPs, prior to their clinical introduction. Our review uncovered no modern animal studies involving placement of a functional PP. A new animal model can facilitate study of evolving microorganism profiles, novel methods to enhance antibiotic delivery, and proposed treatment options.

In Vitro and In Vivo Evaluation of Ultrasound-Triggered Release From Novel Spinal Device.

OBJECTIVES: Bacterial infection following spinal fusion is a major clinical concern with up to 20% incidence. An ultrasound-triggered bulk-release system to combat postsurgical bacterial survival was designed and evaluated. METHODS: Polylactic acid (PLA) clips were loaded with vancomycin (VAN) and microbubbles (Sonazoid, GE HealthCare) in vitro. Stability was determined over 14 days. VAN-loaded clips were submerged in water and insonated using a Logiq E10 scanner (GE HealthCare) with a curvilinear C6 probe. Doppler-induced VAN release was quantified using spectrophotometry. For in vivo testing, clips were loaded with methylene blue (MeB) solution and Sonazoid. These clips were implanted into a rabbit along the spine at L2 and L5, as well as a pig at L1 and L3, then insonated in Doppler mode using the C6 probe. RESULTS: Sonazoid microbubbles were better preserved when incubated in VAN compared with distilled water at 4°C, 25°C, and 37°C incubation temperatures (P = .0131). Contrast enhancement was observed from both solutions when incubated at 4°C storage conditions. Insonated clips achieved average cumulative VAN release of 101.8 ± 2.8% (81.4 ± 2.8 mg) after 72 hours. Uninsonated clips had only 0.3 ± 0.1% (0.3 ± 0.1 mg) average cumulative VAN release (P < .0001). Clips retrieved from the rabbit did not rupture with insonation nor produce MeB staining of surrounding tissues. In the pig, the PLA film was visibly ruptured and MeB tissue was observed following insonation, whereas the uninsonated clip was intact. CONCLUSION: These results demonstrate ultrasound-triggered release of an encapsulated prophylactic solution and provide an important proof-of-concept for continuing large animal evaluations for translational merit.

Berberine disrupts staphylococcal proton motive force to cause potent anti-staphylococcal effects in vitro.

The presence of antibiotic resistance has increased the urgency for more effective treatments of bacterial infections. Biofilm formation has complicated this issue as biofilm bacteria become tolerant to antibiotics due to environmental factors such as nutrient deprivation and adhesion. In septic arthritis, a disease with an 11% mortality rate, bacteria in synovial fluid organize into floating, protein-rich, bacterial aggregates (mm-cm) that display depressed metabolism and antibiotic tolerance. In this study, Staphylococcus aureus (S. aureus), which is the most common pathogen in septic arthritis, was tested against different inhibitors that modulate bacterial surface protein availability and that should decrease bacterial aggregation. One of these, berberine, a quaternary ammonium compound, was found to reduce bacterial counts by 3-7 logs in human synovial fluid (aggregating medium) with no effect in tryptic soy broth (TSB, non-aggregating). Unlike traditional antibiotics, the bactericidal activity of berberine appeared to be independent of bacterial metabolism. To elucidate the mechanism, we used synovial fluid fractionation, targeted MRSA transposon insertion mutants, dyes to assess changes in membrane potential (DiSC3(5)) and membrane permeability (propidium iodide (PI)), colony counting, and fluorescence spectroscopy. We showed that berberine's activity was dependent on an alkaline pH and berberine killed both methicillin-sensitive S. aureus and MRSA in alkaline media (pH 8.5-9.0; p < 0.0001 vs. same pH controls). Under these alkaline conditions, berberine localized to S. aureus where berberine was isolated in cytoplasmic (∼95%) and DNA (∼5%) fractions. Importantly, berberine increased bacterial cell membrane permeability, and disrupted the proton motive force, suggesting a mechanism whereby it may be able to synergize with other antibacterial compounds under less harsh conditions. We suggest that berberine, which is cheap and readily available, can be made into an effective treatment.

Microbubble cavitation restores Staphylococcus aureus antibiotic susceptibility in vitro and in a septic arthritis model.

Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does not increase antibiotic activity. Importantly, in the porcine model of septic arthritis, no bacteria are recovered from the SynF after treatment with amikacin and UTMD-ultrasound without UTMD is insufficient. Our data suggest that UTMD + antibiotics may serve as an important adjunct for the treatment of septic arthritis.

A scoping review of penile implant biofilms-what do we know and what remains unknown?

Background: Penile prosthesis (PP) is a gold standard for treatment of erectile dysfunction given its reliability and efficacy. Infection remains the most feared complication of prosthetic surgery, which usually results in device removal, and places a significant economic burden on the healthcare system. While biofilms have shown to support the persistence of microorganisms, the degree by which this matrix is truly pathogenic remains unknown given its high prevalence even in asymptomatic patients. We aim to review and summarize the current literature pertaining to biofilm formation in the setting of PP surgeries in clinically infected and non-infected cases. Methods: Searches were performed in the MEDLINE online database through PubMed using a combination of keywords "penile prosthetic" OR "penile prosthesis" OR "penile implant" AND "biofilm" OR "revision" OR "removal" OR "infection" OR "explant". Eleven articles met inclusion criteria. There were only three studies that explicitly listed the number of biofilms identified in their cohort, but we also included eight articles that mentioned swabbing and culturing of any bacterial biofilm during revision procedures for both clinically infected and non-infected implants. Results: Infected PP yielded a 11-100% rate of biofilm presence, while non-infected PP yielded a 3-70% rate of biofilm presence. Time to reoperation from initial PP placement were also largely variable, ranging from 2 weeks to over 2 years. Coagulase-negative staphylococcus (i.e., Staphylococcus epidermidis) were the most commonly reported organisms among non-infected implants, however, newer studies have identified a change towards more virulent organisms. Conclusions: Since the advent of PP surgery, diabetes control, revision washout protocols and antibiotic-impregnated devices have led to an overall decrease in biofilm formation and infectious complications. There is an overall paradigm shift in microbial profiles with more virulent organisms, such as Escherichia coli, Pseudomonas aeruginosa, Enterococcus species, and even fungal species beginning to replace the more common coagulase-negative staphylococcal species, especially in clinically infected implants. Additional studies are necessary to define the significance of bacterial presence in biofilms using impactful technologies such as next-generation sequencing. Currently, preliminary and experimental biofilm-control strategies are also underway to further address this clinical issue.

Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches.

Administration of drugs through oral and intravenous routes is a mainstay of modern medicine, but this approach suffers from limitations associated with off-target side effects and narrow therapeutic windows. It is often apparent that a controlled delivery of drugs, either localized to a specific site or during a specific time, can increase efficacy and bypass problems with systemic toxicity and insufficient local availability. To overcome some of these issues, local delivery systems have been devised, but most are still restricted in terms of elution kinetics, duration, and temporal control. Ultrasound-targeted drug delivery offers a powerful approach to increase delivery, therapeutic efficacy, and temporal release of drugs ranging from chemotherapeutics to antibiotics. The use of ultrasound can focus on increasing tissue sensitivity to the drug or actually be a critical component of the drug delivery. The high spatial and temporal resolution of ultrasound enables precise location, targeting, and timing of drug delivery and tissue sensitization. Thus, this noninvasive, non-ionizing, and relatively inexpensive modality makes the implementation of ultrasound-mediated drug delivery a powerful method that can be readily translated into the clinical arena. This review covers key concepts and areas applied in the design of different ultrasound-mediated drug delivery systems across a variety of clinical applications.

Minimizing Penile Prosthesis Implant Infection: What Can We Learn From Orthopedic Surgery?

The implantation of penile protheses for the surgical treatment of erectile dysfunction has risen in popularity over the past several decades. Considerable advances have been made in surgical protocol and device design, specifically targeting infection prevention. Despite these efforts, device infection remains a critical problem, which causes significant physical and emotional burden to the patient. The aim of this review is to broaden the discussion of best practices by not only examining practices in urology, but additionally delving into the field of orthopedic surgery to identify techniques and approaches that may be applied to penile prothesis surgery.

Plasma Monocyte Chemotactic Protein-1 Is Associated With Acute Kidney Injury and Death After Cardiac Operations.

BACKGROUND: Monocyte chemotactic protein-1 (MCP-1; chemokine C-C ligand-2 [CCL-2]) is upregulated in ischemia-reperfusion injury and is a promising biomarker of inflammation in cardiac operations. METHODS: We measured preoperative and postoperative plasma MCP-1 levels in adults undergoing cardiac operations to evaluate the association of perioperative MCP-1 levels with acute kidney injury (AKI) and death in Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI), a prospective, multicenter, observational cohort. RESULTS: Of the 972 participants in the study, AKI developed in 329 (34%), and severe AKI developed in 45 (5%). During a median follow-up of 2.9 years (interquartile range, 2.2 to 3.5 years), 119 participants (12%) died. MCP-1 levels were significantly higher in those who developed AKI and died than in those without AKI and death. Participants with a preoperative MCP-1 level in the highest tertile (>196 pg/mL) had an increased AKI risk than those in the lowest tertile (<147 pg/mL; odds ratio [OR], 1.43l; 95% confidence interval [CI], 1.00 to 2.05). The association appeared similar but was not significant for the severe AKI outcome (OR, 1.48; 95% CI, 0.62 to 3.54). Compared with participants with preoperative MCP-1 level in the lowest tertile, those in the highest tertile had higher adjusted risk of death (hazard ratio, 1.82; 95% CI, 1.40 to 2.38). Similarly, participants in the highest tertile had a higher adjusted risk of death (hazard ratio, 1.95; 95% CI, 1.09-3.49) than those with a postoperative MCP-1 level in the lowest tertile. CONCLUSIONS: Higher plasma MCP-1 is associated with increased AKI and risk of death after cardiac operations. MCP-1 could be used as a biomarker to identify high-risk patients for potential AKI prevention strategies in the setting of cardiac operations.