In vitro activity of cefepime/taniborbactam and comparator agents against Gram-negative bacterial bloodstream pathogens recovered from patients with cancer.

Background: Taniborbactam is a ß-lactamase inhibitor that, when combined with cefepime, may offer a potential treatment option for patients with serious and resistant Gram-negative bacterial (GNB) pathogens. Objectives: This study evaluated in vitro activity of cefepime/taniborbactam and comparator agents against GNB pathogens isolated from patients with cancer at our institution. Methods: A total of 270 GNB pathogens (2019-23) isolated from patients with cancer were tested against cefepime/taniborbactam and comparator agents commonly used for these patients. CLSI-approved broth microdilution methods were used. MIC50, MIC90, MIC range and percentage of susceptibility calculations were made using FDA breakpoints when available. Results: Cefepime/taniborbactam showed highly potent activity against tested Enterobacterales, including isolates producing ESBLs and carbapenem-resistant Enterobacterales. At a provisional breakpoint of ≤16/4 mg/L, cefepime/taniborbactam inhibited most tested species of GNB pathogens, with overall 98.9% susceptibility, which was significantly (P < 0.0001) higher than the susceptibility of the GNB isolates to all other tested comparator agents, ranging from 39.6% for cefepime to 86.3% for ceftazidime/avibactam. Conclusions: Our results showed that taniborbactam in combination with cefepime improved in vitro activity against GNB pathogens isolated from patients with cancer, including MDR Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, ESBL-producing Enterobacterales and Stenotrophomonas maltophilia isolates, with highest activity compared with all tested comparator agents, including other ß-lactam/ß-lactamase inhibitor combinations. Further studies are warranted to explore the efficacy of cefepime/taniborbactam for empirical initial treatment of GNB infections in cancer patients with high rates of febrile neutropenia requiring hospitalization.

In vitro activity of tebipenem and comparator agents against bacterial pathogens isolated from patients with cancer.

Background: Tebipenem is a broad-spectrum orally administered carbapenem antibiotic that could be an alternative to IV carbapenems. The current study evaluated in vitro activity of tebipenem against bacterial isolates recovered from patients with cancer. Methods: A total of 611 bacterial pathogens recently isolated from patients with cancer were tested for susceptibility to tebipenem and comparators. CLSI-approved broth microdilution methods were used. MIC50, MIC90, MIC range and percentage susceptibility calculations were made using FDA breakpoints when available. Results: Tebipenem had a low MIC90 for most Gram-positive and Enterobacterales isolates. Tebipenem MIC90 ranged from 0.06 to 0.25 mg/L for all tested Enterobacterales. Conclusions: Oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from patients with cancer. Further clinical evaluation of tebipenem for the treatment of bacterial infections in patients with cancer is warranted.

The in vitro activity of delafloxacin and comparator agents against bacterial pathogens isolated from patients with cancer.

Background: Fluoroquinolones are used for infection prevention in high-risk patients with haematological malignancies. Fluoroquinolones are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms. We evaluated the in vitro activity of delafloxacin and selected comparators against 560 bacterial pathogens isolated exclusively from patients with cancer. Methods: Antimicrobial susceptibility testing and time-kill studies were performed using CLSI-approved methodology and interpretive criteria for 350 Gram-positive organisms and 210 GNB that had been recently isolated from patients with cancer. Results: Delafloxacin was more active than ciprofloxacin and levofloxacin against Staphylococcus aureus and CoNS. Overall, 63% of staphylococcal isolates were susceptible to delafloxacin, 37% to ciprofloxacin and 39% to levofloxacin. Activity of delafloxacin against most Enterobacterales was similar to that of ciprofloxacin and levofloxacin. Escherichia coli and MDR Pseudomonas aeruginosa isolates had low susceptibility rates to the three tested fluoroquinolones. In time-kill studies delafloxacin and levofloxacin decreased the bacterial load to 3.0 log10 in 8 and 13 h, respectively, using 8 × MIC. Conclusions: Delafloxacin is more active than ciprofloxacin and levofloxacin against S. aureus but has substantial gaps in coverage against GNB. Resistance to all three fluoroquinolones could be high among leading GNB such as E. coli and P. aeruginosa, particularly in cancer centres where these agents are widely used as prophylactic agents.

Review of allergic reactions from use of chlorhexidine on medical products in clinical settings over 40 years: Risks and mitigations.

Chlorhexidine is an antimicrobial agent widely used for infection prevention in medical settings. Nevertheless, allergic reactions ranging from mild to severe have been reported following its use. In this review, we analyzed all case reports published between the introduction of chlorhexidine and the end of 2019 for allergic responses associated with the use of medical devices and or other medical products containing chlorhexidine (CHX) to ascertain the prevalence of severe CHX allergic reactions and what practices might best mitigate those risks.In total, 77 publications containing 124 reported cases of allergic reactions were grouped into 3 product categories, catheters, semisolids, and fluid products. The country, type of reaction, route of sensitization, allergy confirmation, and intervention or mitigation was extracted for each case. Overall, 30 cases were associated with catheters, 46 cases were associated with semisolid products, and 48 cases were associated with the use of other medical products. Severe cases were managed with intravenous fluids, steroids, and epinephrine (adrenaline). None of the reported cases were fatal. The allergy risks can be mitigated by better warning and training clinicians and by recording and screening patient histories for CHX presensitization from prior exposure. For patients undergoing pre-use blood tests, IgE antibody screens can also be performed. Finally, as a precaution in the event a rare severe allergic reaction occurs, procedure carts and rooms can be prestocked with injectable epinephrine and other rapidly acting anti-inflammatory medications.

Novel antimicrobial ointment for infected wound healing in an in vitro and in vivo porcine model.

Microbial contamination of wounds is a significant problem that delays healing, particularly when bacterial biofilms are present. A novel combination of pectinic acid (PG) + caprylic acid (CAP) was previously found in vitro to be highly effective in eradicating various pathogens in biofilms with minimal cytotoxicity. In this study, a novel wound ointment was formulated with PG + CAP and first assessed in vitro using a well-established biofilm eradication model. In vitro, the PG + CAP ointment was shown to be efficacious in reducing the microbial biofilms. This ointment was then tested in vivo in two pilot porcine wound healing models, with and without Staphylococcus aureus microbial challenge. Ointments were applied to each wound daily, and healing by wound closure area measurement was assessed weekly over 4 weeks. After 4 weeks, pigs were sacrificed and wounds were scored for reepithelialization, inflammation, granulation tissue, and collagen deposition. We compared PG + CAP to hydroxyethylcellulose + glycerol ointment base (control) and MediHoney (comparator). In the porcine microbial challenge model, the novel antimicrobial PG + CAP wound ointment rapidly eradicated bacterial organisms embedded in wounds, was safe and well-tolerated, and was associated with enhanced healing compared to ointment base and MediHoney. Specifically, the cumulative histopathology, reepithelialization of epidermis, and mature granulation tissue in the wound bed was significantly better with PG + CAP than with control and MediHoney treatments. This ointment warrants further study as a non-antibiotic ointment for use in treating a wide array of infected wounds.

Enhanced Biofilm Eradication and Reduced Cytotoxicity of a Novel Polygalacturonic and Caprylic Acid Wound Ointment Compared with Common Antiseptic Ointments.

Antiseptic wound ointments are widely used to treat dermal wounds that are microbially contaminated. Polygalacturonic acid (PG)+caprylic acid (CAP) is a novel combination that has been shown to eradicate biofilms. We developed a novel PG+CAP ointment and compared the biofilm eradication capability and cytotoxicity of PG+CAP with that of commercially available antiseptic wound ointments. We used a well-established biofilm model to quantitatively assess the eradication of organisms following exposure to the wound ointments for 2 hours. PG+CAP ointment completely eradicated Candida albicans, multidrug-resistant Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus biofilms, whereas MediHoney, polyhexamethylene biguanide (PHMB), and benzalkonium chloride (BZK) ointments failed to eradicate all biofilms within 2 hours. We assessed cytotoxicity by exposing L-929 fibroblasts to extracts of each ointment; Trypan blue exclusion was used to assess cell viability, and Alamar blue conversion was used to assess metabolic function. After exposure to PG+CAP and MediHoney, fibroblast viability was 96.23% and 95.23%, respectively (Trypan blue), and was comparable to untreated cells (98.77%). PHMB and BZK showed reduced viability (83.25% and 77.83%, respectively, p < 0.05). Metabolic activity results followed a similar pattern. Cytotoxicity of PG+CAP ointment towards erythrocytes was comparable to saline. PG+CAP ointment seems to be safe and can rapidly eradicate microbial biofilm; thus, PG+CAP ointment merits further in vivo testing as a potential antimicrobial wound ointment.

Minocycline-EDTA-Ethanol Antimicrobial Catheter Lock Solution Is Highly Effective In Vitro for Eradication of Candida auris Biofilms.

Candida auris is an emerging pathogen that can cause virulent central-line-associated bloodstream infections. Catheter salvage through the eradication of biofilms is a desirable therapeutic option. We compared taurolidine and minocycline-EDTA-ethanol (MEE) catheter lock solutions in vitro for the eradication of biofilms of 10 C. auris strains. MEE fully eradicated all C. auris biofilms, while taurolidine lock partially eradicated all of the C. auris biofilms. The superiority was significant for all C. auris strains tested (P = 0.002).

The potential for developing new antimicrobial resistance from the use of medical devices containing chlorhexidine, minocycline, rifampicin and their combinations: a systematic review.

BACKGROUND: Catheter infections remain one of the most persistent adverse events causing significant morbidity, economic impact and mortality. Several strategies have been proposed to reduce these infections including the use of catheters embedded with antibiotics and/or antiseptics. One reoccurring challenge is the fear that antimicrobial medical devices will induce resistance. The aim of this systematic review is to evaluate the evidence for induced antimicrobial resistance caused by exposure to antimicrobial medical devices. METHODS: Four electronic databases [MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus] were screened for studies published between 1983 and 2019 regarding assessment of microbial resistance with use of medical devices containing chlorhexidine, minocycline, rifampicin or combinations thereof. Development of new resistance, selection for tolerant organisms and 'no change in resistance' were assessed. RESULTS: Forty-four publications, grouped by study type and stratified by drug assessed, were included for analyses. The majority of studies found no change in resistance after exposure to antimicrobial medical devices (13 in vitro, 2 in vivo, 20 clinical). Development of new resistance was commonly reported with the use of rifampicin as a single agent and only reported in one study assessing the minocycline/rifampicin combination (M/R); however, the increase in MIC was well below clinical relevance. CONCLUSIONS: Emergence of new resistance to combinations of M/R, minocycline/rifampicin/chlorhexidine (M/R/CH) and chlorhexidine/silver sulfadiazine (CHXSS) was rare. No clinical trials confirmed its occurrence and some refuted it. The risk of development of new resistance to these antimicrobial combinations appears more fear-based than substantiated by clinical and experimental evidence but warrants continued surveillance.

Advances in the prevention and management of central-line-associated bloodstream infections: The role of chelator-based catheter locks.

The proper functioning of central lines is imperative for the management of patients with cancer or on hemodialysis. However, these lifelines can become infected and can malfunction.Chelators such as citrate and EDTA have been widely studied alone or in combination with other antimicrobial agents in catheter lock solutions to prevent catheter-related bloodstream infections and to maintain catheter patency. Given their anticoagulation, antiplatelet aggregation, antibiofilm, antimicrobial activity, safety profile, as well as their low cost, chelators have long been considered alternatives to heparin and a vital component of catheter lock solutions. In this review, we present a detailed summary of the properties of chelators and in vitro and in vivo studies of chelator-containing lock solutions.

Epidemiology of Infectious and Noninfectious Catheter Complications in Patients Receiving Home Parenteral Nutrition: A Systematic Review and Meta-Analysis.

Patients receiving parenteral nutrition (PN) as their primary source of nutrition are at high risk for both infectious and noninfectious catheter complications (catheter-related infections, catheter occlusion, and venous thrombosis). The aim of this review was to synthesize and evaluate what is known about catheter complications and prevention strategies in the PN population. Three electronic databases (Medline, Embase, and CINAHL) were screened for studies published between January 2012 and February 2019 regarding infectious and noninfectious catheter complications in patients receiving PN. Rates of infectious and noninfectious catheter complications, prevalence of causative pathogens, potential risk factors, and prevention strategies via the use of antimicrobial lock therapy (ALT) were assessed. Fifty-three catheter complication studies and 12 ALT studies were included. Studies were grouped by definition of complication: catheter-related bloodstream infections (CRBSI) or central line-associated bloodstream infections (CLABSI). Random effects summary rates per 1000 catheter days were 0.85 CRBSI episodes (95% CI 0.27-2.64) and 1.65 CLABSI episodes (95% CI 1.09-2.48). Use of taurolidine or ethanol ALT was efficacious in reducing infectious catheter complications; however, several studies had concerns for adverse mechanical complications. Potential risk factors for catheter complications were highly varied and often contradictory between studies. The rates of catheter complications were higher among catheterized patients receiving PN compared with nationally reported rates of complications in all catheterized patients. Risk factors for catheter complications need to be better understood for targeted prophylactic use of ALT. Future studies are warranted; however, they should be conducted using more standardized definitions and criteria.

Nitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective for In Vitro Eradication of Candida auris Biofilm.

Candida auris poses emerging risks for causing severe central line-associated bloodstream infections. We tested in vitro the ability of antifungal lock solutions to rapidly eradicate C. auris biofilms. Liposomal amphotericin B, amphotericin B deoxycholate, fluconazole, voriconazole, micafungin, caspofungin, and anidulafungin failed to completely eradicate all 10 tested C. auris biofilms. Conversely, nitroglycerin-citrate-ethanol (NiCE) catheter lock solution completely eradicated all replicates for all of C. auris biofilms tested.

Assessment of the Potential for Inducing Resistance in Multidrug-Resistant Organisms from Exposure to Minocycline, Rifampin, and Chlorhexidine Used To Treat Intravascular Devices.

To assess the potential for the induction of antimicrobial resistance following repeated subinhibitory exposures to the combination minocycline (MIN), rifampin (RIF), and chlorhexidine (CHX), a total of 29 clinical microbial pathogenic isolates were repeatedly exposed to subinhibitory concentrations of MIN, RIF, and CHX for 20 passages. MICs of the MIN, RIF, and CHX combination were assessed at each passage to evaluate the potential for resistance to have been induced. The combination of MIN, RIF, and CHX showed significant antimicrobial efficacy and synergy against organisms resistant to all 3 individual components (MIC of ≥16 µg/ml for MIN or MIC of ≥4 µg/ml for RIF or CHX). Among the organisms originally resistant to 2 or more individual components and the organisms originally susceptible to 2 or more individual components, there was no evidence that organisms became resistant following 20 repeated subinhibitory exposure cycles to the triple combination. The risk of resistance developing to the triple combination is extremely low because microbes are inhibited or killed before resistance can simultaneously emerge to all three agents. Surveillance studies monitoring the development of resistance should be conducted in a clinical setting.

A Design-Based Stereologic Method to Quantify the Tissue Changes Associated with a Novel Drug-Eluting Tracheobronchial Stent.

BACKGROUND: Granulation tissue is a common complication of airway stenting, but no published methods can quantify the volume and type of tissue that develops. OBJECTIVE: To use design-based stereology to quantify changes in tissue volume and type associated with airway stenting. METHODS: We compared drug-eluting stents (DES) filled with gendine to standard silicone stents in pigs in an assessor-blinded randomized trial. Tracheal stents were placed via rigid bronchoscopy. After 1 month, animals were euthanized and necropsies were performed. Antimicrobial effects of the DES were assessed in trachea tissue samples, on the DES surface, and with residual gel from the DES reservoir. Tracheal thickness was measured using orthogonal intercepts. Design-based stereology was used to quantify the volume density of tissues using a point-counting method. The volume of each tissue was normalized to cartilage volume, which is unaffected by stenting. RESULTS: Pigs were randomized to DES (n = 36) or control stents (n = 9). The drug was successfully eluted from the DES, and the stent surface showed antibacterial activity. DES and controls did not differ in tissue microbiology, tracheal thickness, or granulation tissue volume. Compared to nonstented controls, stented airways demonstrated a 110% increase in soft-tissue volume (p = 0.005). Submucosal connective tissue (118%; p < 0.0001), epithelium (70%; p < 0.0001), submucosal glands (47%; p = 0.001), and smooth muscle (41%; p < 0.0001) increased in volume. CONCLUSION: Stenting doubles the volume of soft tissue in the trachea. Design-based stereology can quantify the tissue changes associated with airway stenting.

Pilot Ex Vivo and In Vitro Evaluation of a Novel Foley Catheter with Antimicrobial Periurethral Irrigation for Prevention of Extraluminal Biofilm Colonization Leading to Catheter-Associated Urinary Tract Infections (CAUTIs).

CAUTI remains a serious healthcare issue for incontinent patients whose urine drainage is managed by catheters. A novel double-balloon Foley catheter was developed which was capable of irrigating the extraluminal catheter surfaces within the periurethral space between the urethral-bladder junction and meatus. The catheter has a retention cuff that is inflated to secure the catheter in the bladder and a novel irrigation cuff proximal to the urethral-bladder junction capable of providing periurethral irrigation from the urethral-bladder junction to the meatus. Uniform periurethral irrigation was demonstrated in an ex vivo porcine model by adding a dye to the antimicrobial urethral irrigation solution. An in vitro biofilm colonization model was adapted to study the ability of periurethral irrigation with a newly developed antimicrobial combination consisting of polygalacturonic acid + caprylic acid (PG + CAP) to prevent axial colonization of the extraluminal urethral indwelling catheter shaft by common uropathogens. The extraluminal surface of control catheters that were not irrigated formed biofilms along the entire axial urethral tract after 24 hours. Significant (p < 0.001) inhibition of colonization was seen against multidrug-resistant Pseudomonas aeruginosa (PA), carbapenem-resistant Escherichia coli (EC), and carbapenem-resistant Klebsiella pneumoniae (KB). For other common uropathogens including Candida albicans (CA), Proteus mirabilis (PR), and Enterococcus faecalis (EF), a first irrigation treatment completely inhibited colonization of half of the indwelling catheter closest to the bladder and a second treatment largely disinfected the remaining intraurethral portion of the catheter towards the meatus. The novel Foley catheter and PG + CAP antimicrobial irrigant prevented biofilm colonization in an in vitro CAUTI model and merits further testing in an in vivo CAUTI prevention model.

Removal and insertion of central venous catheters in cancer patients is associated with high symptom burden.

OBJECTIVES: To assess the symptom burden associated with CVC removal and insertion in cancer patients. METHODS: We collected patient-reported symptom-burden outcomes for 60 consecutive cancer patients: 30 undergoing CVC removal and 30 undergoing CVC insertion. Cancer patients self-administered the MD Anderson Symptom Inventory to rate the severity of 21 different symptoms immediately after the procedure Results: Symptoms were present in up to 57% to 67% of patients undergoing CVC insertion and removal respectively. Nineteen patients (32%) were moderately symptomatic with a symptom burden of four or more: ten insertion and nine removal patients. Symptoms with a score of 4 or more clustered around physical symptoms (pain, pressure or burning) or more generalized symptoms (fatigue, sleep, distress, dry mouth, and drowsiness). Nine (15%) patients rated at least one symptom as eight or more, five (17%) being insertion patients. CONCLUSIONS: CVCs are essential for the management of cancer patients. However, they can become infected and may need to be removed. Catheter removal and insertion produced moderate to severe symptom burden in cancer patients. Safe interventions that would salvage the vascular access without worsening the infectious outcome should be explored to alleviate morbidity associated with the symptom burden of removal and re-insertion.

Sodium Mercaptoethane Sulfonate Reduces Collagenolytic Degradation and Synergistically Enhances Antimicrobial Durability in an Antibiotic-Loaded Biopolymer Film for Prevention of Surgical-Site Infections.

Implant-associated surgical-site infections can have significant clinical consequences. Previously we reported a method for prophylactically disinfecting implant surfaces in surgical pockets, where an antibiotic solution containing minocycline (M) and rifampin (R) was applied as a solid film in a crosslinked biopolymer matrix that partially liquefied in situ to provide extended prophylaxis. Here we studied the effect of adding sodium 2-mercaptoethane sulfonate (MeSNA) on durability of prophylaxis in an in vitro model of implant-associated surgical-site infection. Adding MeSNA to the M/R biopolymer, antimicrobial film extended the duration for which biofilm formation by multidrug-resistant Pseudomonas aeruginosa (MDR-PA) was prevented on silicone surfaces in the model. M/R films with and without MeSNA were effective in preventing colonization by methicillin-resistant Staphylococcus aureus. Independent experiments revealed that MeSNA directly inhibited proteolytic digestion of the biopolymer film and synergistically enhanced antimicrobial potency of M/R against MDR-PA. Incubation of the MeSNA containing films with L929 fibroblasts revealed no impairment of cellular metabolic activity or viability.

Caprylic and Polygalacturonic Acid Combinations for Eradication of Microbial Organisms Embedded in Biofilm.

There is a need for non-antibiotic, antimicrobial compositions with low toxicity capable of broad-spectrum eradication of pathogenic biofilms in food preparation and healthcare settings. In this study we demonstrated complete biofilm eradication within 60 min with synergistic combinations of caprylic and polygalacturonic (PG) acids in an in vitro biofilm eradication model against representative hospital and foodborne infectious pathogen biofilms (methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, Candida albicans, Escherichia coli, and Salmonella enteritidis). Antimicrobial synergy against biofilms was demonstrated by quantifying viable organisms remaining in biofilms exposed to caprylic acid alone, PG acid alone, or combinations of the two. The combinations also synergistically inhibited growth of planktonic organisms. Toxicity of the combination was assessed in vitro on L929 fibroblasts incubated with extracts of caprylic and PG acid combinations using the Alamar Blue metabolic activity assay and the Trypan Blue exclusion cell viability assay. The extracts did not produce cytotoxic responses relative to untreated control fibroblasts.