Antimicrobial Penetration Research Articles

Antibacterial and antifungal drug concentrations in intra-abdominal abscesses: a prospective clinical study.

Secondary peritonitis with intra-abdominal abscesses (IAA) is difficult to treat because of the supposed low rate of penetration of antimicrobial drugs at the site of infection. However, clinical data about the actual bioavailability of antimicrobial drugs in IAA are scarce. This prospective observational study aimed at assessing the drug penetration in IAA of the antibiotics (piperacillin-tazobactam, carbapenems) and antifungals (fluconazole, echinocandins) that are usually recommended for the treatment of intra-abdominal infections. Patients with IAA who underwent a radiological or surgical drainage procedure were included. Antimicrobial drug concentrations were measured in IAA (CIAA) and in a simultaneous plasma sample (Cplasma) to assess the CIAA/Cplasma ratio. The pharmacodynamic target was defined as a CIAA equal or superior to the clinical breakpoints of susceptibility of the most relevant intra-abdominal pathogens. Clinical outcomes were assessed at hospital discharge. A total of 54 antimicrobial drug measurements were performed in 39 IAA samples originating from 36 patients. Despite important inter-individual variability, piperacillin-tazobactam exhibited the highest CIAA/Cplasma ratios (median 2). The rates of target achievement were 75%-80% for piperacillin-tazobactam and meropenem but 0% for imipenem and ertapenem. These results tended to correlate with clinical outcomes (96% success rate versus 73%, respectively, P = 0.07). Among antifungals, fluconazole exhibited higher CIAA/Cplasma ratios and rates of target achievement compared to echinocandins. However, no differences in clinical outcomes were observed. These results provide unique information about antimicrobial drug penetration in IAA in real clinical conditions and suggest that piperacillin-tazobactam and meropenem may have better efficacy compared to imipenem or ertapenem.

Microneedles for Enhanced Bacterial Pathogen Inactivation and Accelerated Wound Healing

AbstractBacterial wound infections are a significant socioeconomic concern in the modern healthcare industry owing to increased morbidity, prolonged hospital stay, and mortality. Bacterial infectious agents that colonize the wound bed develop biofilms, acting as a physical barrier that prevents the effective penetration of topical antimicrobials. Further, bacteria in such infectious wounds express a wide range of virulence factors promoting intercellular transmigration and host cell invasion complicating the treatment regimen. To address this need, a water‐dissolvable poly‐vinyl pyrrolidine (PVP), calcium peroxide (CPO) infused microneedle structure (denoted as PVP/CPO MN) for effective transdermal delivery of antimicrobial payload deep into the tissues is developed. Fluid exudate from the wound bed dissolves the PVP/CPO MN enabling the release of CPO deep into the infected wound bed. A slow catalytic decomposition of CPO results in the sustained release of reactive oxygen species (ROS) deep within the infected wound inhibiting the inter‐ and intracellular pathogens. Here, a systematic study of microneedle fabrication and sterilization after complete packaging is conducted to ensure scalability and safe applicability while maintaining mechanical and antibacterial properties. In vitro, antibacterial efficacy of the microneedles is validated against two common wound pathogens, Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). Moreover, the PVP/CPO MN exhibited significant efficacy in eradicating both extracellular and intracellular bacterial populations within an in vivo porcine wound model. Additionally, the microneedle technology facilitated a faster wound healing, with ≈30% increase compared to control and a 15% improvement over conventional silver dressing.

Mitigating candidiasis with acarbose by targeting Candida albicans α-glucosidase: in-silico, in-vitro and transcriptomic approaches

Biofilm-associated candidiasis poses a significant challenge in clinical settings due to the limited effectiveness of existing antifungal treatments. The challenges include increased pathogen virulence, multi-drug resistance, and inadequate penetration of antimicrobials into biofilm structures. One potential solution to this problem involves the development of novel drugs that can modulate fungal virulence and biofilm formation, which is essential for pathogenesis. Resistance in Candida albicans is initiated by morphological changes from yeast to hyphal form. This transition triggers a series of events such as cell wall elongation, increased adhesion, invasion of host tissues, pathogenicity, biofilm formation, and the initiation of an immune response. The cell wall is a critical interface for interactions with host cells, primarily through various cell wall proteins, particularly mannoproteins. Thus, cell wall proteins and enzymes are considered potential antifungal targets. In this regard, we explored α-glucosidase as our potential target which plays a crucial role in processing mannoproteins. Previous studies have shown that inhibition of α-glucosidase leads to defects in cell wall integrity, reduced adhesion, diminished secretion of hydrolytic enzymes, alterations in immune recognition, and reduced pathogenicity. Since α-glucosidase, primarily converts carbohydrates, our study focuses on FDA-approved carbohydrate mimic drugs (Glycomimetics) with well-documented applications in various biological contexts. Through virtual screening of 114 FDA-approved carbohydrate-based drugs, a pseudo-sugar Acarbose, emerged as a top hit. Acarbose is known for its pharmacological potential in managing type 2 diabetes mellitus by targeting α-glucosidase. Our preliminary investigations indicate that Acarbose effectively inhibits C. albicans biofilm formation, reduces virulence, impairs morphological switching, and hinders the adhesion and invasion of host cells, all at very low concentrations in the nanomolar range. Furthermore, transcriptomic analysis reveals the mechanism of action of Acarbose, highlighting its role in targeting α-glucosidase.

Fabrication of Eucalyptus Oil-loaded Ciprofloxacin Hydrochloride Topical Films for Enhanced Treatment of Post-Operative Wound Infection

Background: The efficacious penetration of antimicrobials at infectious sites and the reduction of microbial resistance development are critical in controlling the effective treatment of post-operative wound infection. Methods: To create the enhanced antimicrobial topical films, a solvent casting method for ciprofloxacin hydrochloride (CiproHCl) loaded eucalyptus oil (EO) containing low molecular weight chitosan films was used. Nine batches of CiproHCl with varying chitosan and glycerol concentrations were prepared and tested. Additionally, optimised CiproHCl films with EO were created and tested. The antimicrobial activity of CiproHCl-loaded EO containing low molecular weight chitosan films against S. Aureus, E. Coli, and B. Subtilus was tested. Results: The FT-IR spectroscopy and DSC analysis revealed no interaction between the drug and any of the other excipients, and the drug remained amorphous in chitosan film. The SEM analysis revealed that the prepared CiproHCl-loaded EO-containing films had smooth surfaces and large agglomerates. In vitro drug release testing revealed that the EO-loaded films have a sustained release profile of up to 16 hours with a cumulative drug release of 96.83%. In an ex vivo drug permeation study, CiproHCl-loaded EO-containing films demonstrated 2.44 times more permeation flux than CiproHCl-alone films. After six months, the stability study revealed that the CiproHCl-loaded EO-loaded EO-containing film showed no significant change in drug release profile or folding endurance. Conclusion: This present study highlights the possible usage of CiproHCl-loaded EO containing low molecular weight chitosan films in enhanced post-operative wound treatment.

Antimicrobial Drug Penetration Is Enhanced by Lung Tissue Inflammation and Injury.

Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into lung tissue.Objectives: To determine and compare tissue and BAL fluid concentrations of ceftaroline fosamil and linezolid in a model of unilateral acute lung injury in pigs and to evaluate whether dose adjustment is necessary to reach sufficient antimicrobial concentrations in injured lung tissue.Methods: After induction of unilateral acute lung injury, ceftaroline fosamil and linezolid were administered intravenously. Drug concentrations were measured in lung tissue through microdialysis and in blood and BAL fluid samples during the following 8 hours. The primary endpoint was the tissue concentration area under the concentration curve in the first 8 hours (AUC0-8 h) of the two antimicrobial drugs.Measurements and Main Results: In 10 pigs, antimicrobial drug concentrations were higher in inflamed and injured lung tissue compared with those in uninflamed and uninjured lung tissue (median ceftaroline fosamil AUC0-8 h [and interquartile range] = 26.7 mg ⋅ h ⋅ L-1 [19.7-39.0] vs. 16.0 mg ⋅ h ⋅ L-1 [13.6-19.9], P = 0.02; median linezolid AUC0-8 h 76.0 mg ⋅ h ⋅ L-1 [68.1-96.0] vs. 54.6 mg ⋅ h ⋅ L-1 [42.7-60.9], P = 0.01), resulting in a longer time above the minimal inhibitory concentration and in higher peak concentrations and dialysate/plasma ratios. Penetration into BAL fluid was excellent for both antimicrobials, but without left-to-right differences (ceftaroline fosamil, P = 0.78; linezolid, P = 1.00).Conclusions: Tissue penetration of two commonly used antimicrobial drugs for pneumonia is enhanced by early lung tissue inflammation and injury, resulting in longer times above the minimal inhibitory concentration. Thus, lung tissue inflammation ameliorates antimicrobial drug penetration during the acute phase.

2533. Cerebrospinal Fluid Penetration of Cefazolin and Flucloxacillin in Children

Abstract Background Effective treatment of methicillin-susceptible Staphylococcus aureus meningitis requires antimicrobial penetration into the CSF. Anti-staphylococcal penicillins, including flucloxacillin, are generally recommended as first-line treatment. However, some evidence suggests that the first-generation cephalosporin, cefazolin, may be an appropriate alternative. We investigated the CSF concentration of cefazolin and flucloxacillin in children. Methods CSF samples from children aged 0-18 years treated with cefazolin or flucloxacillin were collected when there was sample remaining after diagnostic tests were completed. Unbound antibiotic concentrations of cefazolin and flucloxacillin were measured. Results Overall, 222 CSF samples were collected from 163 children, median age 12 months (range 0.0-17.5 years). Of these, 157 were collected while the antibiotic was at steady state. For cefazolin, children ≤1 year had a higher median CSF concentration compared with those >1 year (1.8 versus 0.5 mg/L, p< 0.001), whereas for flucloxacillin the concentration was similar between the two age groups (0.2 versus 0.1 mg/L, p=0.9). In infants aged ≥ 1 month to 1 year, the CSF concentration of both antibiotics was higher in those with pleocytosis (WCC >5 x106/L) than those without (flucloxacillin 0.2 versus 0.065 mg/L, cefazolin 5.6 versus 1.06 mg/L). Notably, only those aged ≤1 year receiving cefazolin (7/12; 58%) achieved steady state CSF concentrations above the CLSI breakpoint for sensitive S. aureus (MIC ≤2 mg/L). Conclusion CSF penetration of cefazolin was higher in younger infants and for both antibiotics was higher in those with pleocytosis. In most children, the CSF concentrations in the CSF for either cefazolin or flucloxacillin were not above the S. aureus MIC. Disclosures All Authors: No reported disclosures

Polysaccharide-Targeting Lipid Nanoparticles to Kill Gram-Negative Bacteria.

The rapid increase and spread of Gram-negative bacteria resistant to many or all existing treatments threaten a return to the preantibiotic era. The presence of bacterial polysaccharides that impede the penetration of many antimicrobials and protect them from the innate immune system contributes to resistance and pathogenicity. No currently approved antibiotics target the polysaccharide regions of microbes. Here, describe monolaurin-based niosomes, the first lipid nanoparticles that can eliminate bacterial polysaccharides from hypervirulent Klebsiella pneumoniae, are described. Their combination with polymyxin B shows no cytotoxicity in vitro and is highly effective in combating K. pneumoniae infection in vivo. Comprehensive mechanistic studies have revealed that antimicrobial activity proceeds via a multimodal mechanism. Initially, lipid nanoparticles disrupt polysaccharides, then outer and inner membranes are destabilized and destroyed by polymyxin B, resulting in synergistic cell lysis. This novel lipidic nanoparticle system shows tremendous promise as a highly effective antimicrobial treatment targeting multidrug-resistant Gram-negative pathogens.

Carbonation inhibitor by polyethylene glycol encapsulation of calcium hydroxide fine particles to improve antimicrobial and root canal penetration properties

The carbonation of calcium hydroxide (Ca(OH)2) is affected by humidity and a saturated atmosphere. Ca(OH)2 from nature is easily carbonation and self-aggregates into calcium carbonate (CaCO3), resulting in larger particle size impairing the antimicrobial properties due to lack of penetration into the dentinal tubules and lower ion dissociation. To reduce the particle size, the wet beads milling process with distilled water as the medium is commonly used, but often results in great carbonation of the final product. Polyethylene Glycol (PEG) may inhibit the carbonation process as well as re-agglomeration. However, it requires intensive drying of the fine Ca(OH)2 particles. As an alternative, we used ethanol as a medium in the milling process, which is easily dried and compatible with PEG as a surfactant. This study aimed to evaluate PEG 400 as a dispersing agent in ethanol medium in the beads milling process to prevent carbonation of the fine Ca(OH)2 particles. The following groups were analysed CaP-PEG (Ca(OH)2-PEG) with ethanol as a medium, CaP-Eth (Ca(OH)2 with ethanol as a medium), CaP-DW (Ca(OH)2 with distilled water as a medium), CaPC (Ca(OH)2-carbonated) as the negative control and CaC (Ca(OH)2 analytical grade) as the positive control The final particle results were characterized to evaluate the crystal structure, functional groups, and particle size. The corresponding pH and antimicrobial activity against Enterococcus faecalis were assessed at 1, 3, 7, and 14 days. The penetration ability was evaluated by Scanning Electron Microscope. The data obtained were analysed by ANOVA with a significance level of 5%. PEG was able to inhibit carbonation and stabilize pH for up to 14 days, providing increased antimicrobial activity against E. faecalis. PEG also facilitates the ability of fine Ca(OH)2 particles to penetrate deeper into the dentine tubules by reducing particle size.

Side Chain Engineering of Amphiphilic Conjugated Polymer Nanoparticles for Biofilm Ablation

AbstractBiofilm recalcitrance, which enables bacteria to survive deep within the body under antimicrobial treatment, leading to persistent infections by reducing the penetration of antimicrobials, remains a major challenge in the antibacterial field. Conjugated polymer‐based nanoparticles with near‐infrared (NIR) photo responsiveness have emerged as a promising class of photothermal agents for biofilm ablation. However, the development of CPNs has been limited due to dissociation of the nanoparticles synthesized through nanoprecipitation. In this study, surface‐functionalized amphiphilic conjugated polymer‐based nanoparticles with photothermal conversion capacity for pH‐responsive targeting of bacteria are developed. The pH‐sensitive properties of the nanoparticles promote their adhesion to negatively charged bacterial surfaces, resulting in accumulation in biofilms. This accumulation enhances the ablation efficiency of biofilms under the synergistic photothermal effect. The method of constructing functional amphiphilic conjugated polymer‐based nanoparticles is simple to operate and can be used universally, providing a potential design option for biocompatible light‐responsive nanoparticles for in vivo applications.

Drug delivery strategies for antibiofilm therapy.

Although new antibiofilm agents have been developed to prevent and eliminate pathogenic biofilms, their widespread clinical use is hindered by poor biocompatibility and bioavailability, unspecific interactions and insufficient local concentrations. The development of innovative drugdelivery strategies can facilitate penetration of antimicrobials through biofilms, promote drug dispersal and synergistic bactericidal effects, and provide novel paradigms for clinical application. In this Review, we discuss the potential benefits of such emerging techniques for improving the clinical efficacy of antibiofilm agents, as well as highlighting the existing limitations and future prospects for these therapies in the clinic.

Ultrastructural Analysis of Differences in the Growth and Maturation of Staphylococcus pseudintermedius Biofilm on Biotic and Abiotic Surfaces.

Biofilms are extremely complex yet systematic microbial structures. Studies comparing the differences in their growth on living and nonliving surfaces by electron microscopy are limited. Therefore, the purpose of this study was to ultrastructurally investigate the differences in the growth and development of Staphylococcal biofilm on polycarbonate filters and canine skin explants. Using scanning and transmission electron microscopy (SEM and TEM), Staphylococcus pseudintermedius was incubated for 6, 12, 24, 48, and 72 h. It was observed that similar amounts of exopolymeric substance (EPS) were deposited on the biofilm on both surfaces, but the biofilm on the skin explants was primarily flat, whereas the biofilm on the membrane developed a multilayered plateaued look. Microcolony formation was only observed on the membrane filter during the early stages of biofilm development. On the membrane biofilms, EPS was observed to be deposited in a distinctive pattern. EPS deposition on the membrane surface was observed to peak before it declined, but on the explant, a constant increase was observed at all time points. Cell exposure to the environment on both the membrane filters and explants differed depending on the stage of biofilm formation. On both the membranes and the skin explants, there was a perceptible difference between the biofilm growth patterns and speeds. The results of this study suggest that data extrapolated from studies on biofilm bactericidal compounds performed on abiotic surfaces (such as polycarbonate filters) may not be entirely applicable to biofilm growing on biotic surfaces (e.g., skin) due to ultrastructural variations revealed in this study. IMPORTANCE Biofilm has been recognized as an important source of antimicrobial resistance. These sessile microbial colonies tend to attach and grow on every surface, biotic and abiotic, and they account for approximately 80% of chronic and recurrent infections. Biofilms are not all alike; they have different structures and microbial compositions. This high variability allows for differences in the production of exopolymer substances, affecting antimicrobial penetration. No studies have been published that simultaneously compare the structure of biofilms grown on abiotic (in vitro) and biotic (ex vivo) surfaces. To identify treatment alternatives, it is essential to understand the differences between biofilms. The results of the study show how biofilm structures and compositions are dependent on the substrate on which they grow.

Treatment for Multidrug Resistant Gram-Negative Infections With Cefiderocol (Fetroja)

Global concern regarding antimicrobial resistance has allowed for innovative antimicrobials to emerge specifically in the presence of infections caused by resistant gram-negative microorganisms. The outer membrane of gram-negative microorganisms can hinder antimicrobial penetration. A novel approach to infiltrate gram-negative microorganisms would be to use their own transport systems. Cefiderocol is the first approved intravenous siderophore cephalosporin to treat resistant gram-negative infections. Cefiderocol achieves direct entry into the bacteria’s periplasmic space, avoiding mechanisms of resistance encountered with antimicrobials in clinical practice. Cefiderocol can revolutionize clinical practice with its original mechanism of action and sustainable activity against resistant gram-negative microorganisms.

Hydrophobic modification improves the delivery of cell-penetrating peptides to eliminate intracellular pathogens in animals.

Infections induced by intracellular pathogens are difficult to eradicate due to poor penetration of antimicrobials into cell membranes. It is of great importance to develop a new generation of antibacterial agents with dual functions of efficient cell penetration and bacterial inhibition. In this study, the association between hydrophobicity and cell-penetrating peptide delivery efficiency was investigated by fragment interception and hydrophobicity modification of natural porcine antimicrobial peptide PR-39 and the combination of cationic cell-penetrating peptide (R6) with antimicrobial peptide fragments modified with hydrophobic residues. The chimeric peptides P3I7 and P3L7, obtained through biofunctional screening, exhibited potent broad-spectrum antibacterial activity and low cytotoxicity. Moreover, P3I7 and P3L7 can effectively penetrate cells to eliminate intracellular pathogens mainly through endocytosis. The membrane destruction mechanism makes the peptides fast sterilizers and less prone to developing drug resistance. Finally, their good biocompatibility and antibacterial infection effects were verified in mice and piglets. To conclude, the chimeric peptides P3I7 and P3L7 show great potential as affordable and effective antimicrobial agents and may serve as ideal candidates for the treatment of intracellular bacterial infections. STATEMENT OF SIGNIFICANCE: The low permeability of antibacterial drugs makes infections induced by intracellular bacteria extremely difficult to treat. To address this issue, we designed chimeric peptides with dual cell-penetrating and antibacterial functions. The active peptides P3I7 and P3L7, acquired through functional screening have strong broad-spectrum antibacterial activity and powerful bactericidal effects against intracellular Staphylococcus aureus. The membrane permeation mechanism of P3I7 and P3L7 against bacteria endows fast bactericidal activity with low drug resistance. The biosafety and antibacterial activity of P3I7 and P3L7 were also validated by in vivo trials. This study provides an ideal drug candidate against intracellular bacterial infections.

Spatial organisation of the E. coli outer membrane from multiscale computer simulations.

The cell envelope that surrounds Gram-negative bacteria is composed of two membranes (the inner and outer) which are separated by an aqueous region known as the periplasm. Together these three regions provide the bacterium with a formidable defence against unwanted incoming molecules, including antibiotics. The outer membrane contains a range of beta-barrel proteins of varying sizes and functions and in terms of its lipidic composition, it has lipopolysaccharides (LPS) in the outer leaflet and phospholipids in the inner leaflet. We are using multiscale simulations in combination with the experimental work (including native mass spectrometry, cross-linking studies and AFM) of our colleagues to develop a picture of the spatial organisation of the outer membrane of E. coli. Our work has shown that outer membrane proteins (OMPs) are not uniformly distributed throughout the membrane but occupy high protein density regions or ‘OMP islands’. These islands are separated by regions of high LPS (upper leaflet) and phospholipid (lower leaflet), in which there are hardly any proteins. We provide details of our current view of the organisation of OMP islands and briefly describe how this is being incorporated into our efforts to study antimicrobial penetration into the outer membrane. We also discuss the advancements in our computational models that are enabling us to expand the scope of our studies to larger systems by using ultra coarse-grained approaches. Overall, our studies are now revealing a very different picture of the E. coli surface than the one presented in textbooks.

Heterologous Assembly of the Type VI Secretion System Empowers Laboratory Escherichia coli with Antimicrobial and Cell Penetration Capabilities.

The synthetic biology toolbox has amassed a vast number of diverse functional modules, but protein translocation modules for cell penetration and cytosol-to-cytosol delivery remain relatively scarce. The type VI secretion system (T6SS), commonly found in many Gram-negative pathogens, functions as a contractile device to translocate protein toxins to prokaryotic and eukaryotic cells. Here, we have assembled the T6SS of Aeromonas dhakensis, an opportunistic waterborne pathogen, in the common laboratory strain Escherichia coli BL21(DE3). We constructed a series of plasmids (pT6S) carrying the T6SS structural and effector genes under native or tetracycline-inducible promoters, the latter for controlled expression. Using fluorescence microscopy and biochemical analyses, we demonstrate a functional T6SS in E. coli capable of secreting proteins directly into the cytosol of neighboring bacteria and outcompeting a number of drug-resistant pathogens. The heterologous assembly of T6SS not only confers the lab workhorse E. coli with the cytosol-to-cytosol protein delivery capability but also demonstrates the potential for harnessing the T6SS of various pathogens for general protein delivery and antibacterial applications. IMPORTANCE The T6SS is a powerful and versatile protein delivery system. However, the complexity of its macromolecular structure and gene regulation makes it not a trivial task to reconstitute the T6SSs of pathogens in a nonpathogenic host. In this study, we have assembled an inducible T6SS in E. coli BL21(DE3) and demonstrated its functions in protein delivery and antimicrobial activities. The engineered T6SS empowers E. coli to deliver protein cargos into a wide range of prokaryotic and eukaryotic cells.

Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review-Part II.

In patients that are admitted to intensive care units (ICUs), the clinical outcome of severe infections depends on several factors, as well as the early administration of chemotherapies and comorbidities. Antimicrobials may be used in off-label regimens to maximize the probability of therapeutic concentrations within infected tissues and to prevent the selection of resistant clones. Interestingly, the literature clearly shows that the rate of tissue penetration is variable among antibacterial drugs, and the correlation between plasma and tissue concentrations may be inconstant. The present review harvests data about tissue penetration of antibacterial drugs in ICU patients, limiting the search to those drugs that mainly act as protein synthesis inhibitors and disrupting DNA structure and function. As expected, fluoroquinolones, macrolides, linezolid, and tigecycline have an excellent diffusion into epithelial lining fluid. That high penetration is fundamental for the therapy of ventilator and healthcare-associated pneumonia. Some drugs also display a high penetration rate within cerebrospinal fluid, while other agents diffuse into the skin and soft tissues. Further studies are needed to improve our knowledge about drug tissue penetration, especially in the presence of factors that may affect drug pharmacokinetics.

Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review-Part I.

The challenging severity of some infections, especially in critically ill patients, makes the diffusion of antimicrobial drugs within tissues one of the cornerstones of chemotherapy. The knowledge of how antibacterial agents penetrate tissues may come from different sources: preclinical studies in animal models, phase I–III clinical trials and post-registration studies. However, the particular physiopathology of critically ill patients may significantly alter drug pharmacokinetics. Indeed, changes in interstitial volumes (the third space) and/or in glomerular filtration ratio may influence the achievement of bactericidal concentrations in peripheral compartments, while inflammation can alter the systemic distribution of some drugs. On the contrary, other antibacterial agents may reach high and effective concentrations thanks to the increased tissue accumulation of macrophages and neutrophils. Therefore, the present review explores the tissue distribution of beta-lactams and other antimicrobials acting on the cell wall and cytoplasmic membrane of bacteria in critically ill patients. A systematic search of articles was performed according to PRISMA guidelines, and tissue/plasma penetration ratios were collected. Results showed a highly variable passage of drugs within tissues, while large interindividual variability may represent a hurdle which must be overcome to achieve therapeutic concentrations in some compartments. To solve that issue, off-label dosing regimens could represent an effective solution in particular conditions.

Boosting Cosmeceutical Peptides: Coupling Imidazolium-Based Ionic Liquids to Pentapeptide-4 Originates New Leads with Antimicrobial and Collagenesis-Inducing Activities.

ABSTRACTFollowing our previous reports on dual-action antibacterial and collagenesis-inducing hybrid peptide constructs based on “pentapeptide-4” (PP4, with amino acid sequence KTTKS), whose N-palmitoyl derivative is the well-known cosmeceutical ingredient Matrixyl, herein we disclose novel ionic liquid/PP4 conjugates (IL-KTTKS). These conjugates present potent activity against either antibiotic-susceptible strains or multidrug resistant clinical isolates of both Gram-positive and Gram-negative bacterial species belonging to the so-called “ESKAPE” group of pathogens. Noteworthy, their antibacterial activity is preserved in simulated wound fluid, which anticipates an effective action in the setting of a real wound bed. Moreover, their collagenesis-inducing effects in vitro are comparable to or stronger than those of Matrixyl. Altogether, IL-KTTKS exert a triple antibacterial, antifungal, and collagenesis-inducing action in vitro. These findings provide solid grounds for us to advance IL-KTTKS conjugates as promising leads for future development of topical treatments for complicated skin and soft tissue infections (cSSTI). Further studies are envisaged to incorporate IL-conjugates into suitable nanoformulations, to reduce toxicity and/or improve resistance to proteolytic degradation.IMPORTANCE As life expectancy increases, diseases causing chronic wound infections become more prevalent. Diabetes, peripheral vascular diseases, and bedridden patients are often associated with non-healing wounds that become infected, resulting in high morbidity and mortality. This is exacerbated by the fact that microbes are becoming increasingly resistant to antibiotics, so efforts must converge toward finding efficient therapeutic alternatives. Recently, our team identified a new type of constructs that combine (i) peptides used in cosmetics to promote collagen formation with (ii) imidazolium-based ionic liquids, which have antimicrobial and skin penetration properties. These constructs have potent wide-spectrum antimicrobial action, including against multidrug-resistant Gram-positive and Gram-negative bacteria, and fungi. Moreover, they can boost collagen formation. Hence, this is an unprecedented class of lead molecules toward development of a new topical medicine for chronically infected wounds.

Insight to Pseudomonas aeruginosa biofilms

Pseudomonas aeruginosa is well known nosocomial pathogen. It is recognized for hospital-related infections in immuno-compromised patients. P. aeruginosa has a plastic genome known for developing faster multidrug-resistant strains. P. aeruginosa is identified for transiting lifestyle from free-swimming to encapsulated sessile biofilms. This bacterium is notorious to cause acute infection during free swimming lifestyle (planktonic). The infections may transit to chronic form which is difficult to treat. Chronic infections are generally represented by biofilm formation. P. aeruginosa causes device and non-device related biofilm-based infections. The problem arises when biofilm infection becomes antibiotic tolerant and resistant to immune response due to restricted penetration of antimicrobials. Thus, biofilm formation creates more problem during infection as it can become untreatable and more persistent. Therefore, a detailed study of biofilm biology is a necessity. In this review, we have described infections caused by P. aeruginosa biofilms, immune response against biofilms and antibiotic tolerance mechanisms. We have also discussed how in vitro biofilms are studied in lab. Further we have described composition of biofilm matrix and their sequential formation. In addition, P. aeruginosa biofilm formation is tightly regulated mainly by three ways- changing c-di-GMP level, two components signaling (GAC/RET/LAD) and quorum sensing (QS). This review gives insight to different aspect of P. aeruginosa biofilms, one of the topmost model organism studied in infection biology.

The Role of Antimicrobial Resistance in Refractory and Recurrent Bacterial Vaginosis and Current Recommendations for Treatment.

Bacterial vaginosis (BV), the most common cause of vaginal discharge, is characterized by a shift in the vaginal microbiota from Lactobacillus species dominance to a diverse array of facultative and strict anaerobic bacteria which form a multi-species biofilm on vaginal epithelial cells. The rate of BV recurrence after therapy is high, often >60%. The BV biofilm itself likely contributes to recurrent and refractory disease after treatment by reducing antimicrobial penetration. However, antimicrobial resistance in BV-associated bacteria, including those both within the biofilm and the vaginal canal, may be the result of independent, unrelated bacterial properties. In the absence of new, more potent antimicrobial agents to eradicate drug-resistant pathogenic vaginal microbiota, treatment advances in refractory and recurrent BV have employed new strategies incorporating combination therapy. Such strategies include the use of combination antimicrobial regimens as well as alternative approaches such as probiotics and vaginal fluid transfer. Our current recommendations for the treatment of refractory and recurrent BV are provided.