Pseudomonas aeruginosa Bloodstream Infections Presenting with Septic Shock in Neutropenic Cancer Patients: Impact of Empirical Antibiotic Therapy.

This large, multicenter, retrospective cohort study including onco-hematological neutropenic patients with Pseudomonas aeruginosa bloodstream infection (PABSI) found that among 1213 episodes, 411 (33%) presented with septic shock. The presence of solid tumors (33.3% vs. 20.2%, p < 0.001), a high-risk Multinational Association for Supportive Care in Cancer (MASCC) index score (92.6% vs. 57.4%; p < 0.001), pneumonia (38% vs. 19.2% p < 0.001), and infection due to multidrug-resistant P. aeruginosa (MDRPA) (33.8% vs. 21.1%, p < 0.001) were statistically significantly higher in patients with septic shock compared to those without. Patients with septic shock were more likely to receive inadequate empirical antibiotic therapy (IEAT) (21.7% vs. 16.2%, p = 0.020) and to present poorer outcomes, including a need for ICU admission (74% vs. 10.5%; p < 0.001), mechanical ventilation (49.1% vs. 5.6%; p < 0.001), and higher 7-day and 30-day case fatality rates (58.2% vs. 12%, p < 0.001, and 74% vs. 23.1%, p < 0.001, respectively). Risk factors for 30-day case fatality rate in patients with septic shock were orotracheal intubation, IEAT, infection due to MDRPA, and persistent PABSI. Therapy with granulocyte colony-stimulating factor and BSI from the urinary tract were associated with improved survival. Carbapenems were the most frequent IEAT in patients with septic shock, and the use of empirical combination therapy showed a tendency towards improved survival. Our findings emphasize the need for tailored management strategies in this high-risk population.

An Experimental Murine Model to Assess Biofilm Persistence on Commercial Breast Implant Surfaces.

Capsular contracture is the most frequently associated complication following breast implant placement. Biofilm formation on the surface of such implants could significantly influence the pathogenesis of this complication. The objective of this study was to design an experimental model of breast implant infection that allowed us to compare the in vivo S. epidermidis ability to form and perpetuate biofilms on commonly used types of breast implants (i.e., macrotexturized, microtexturized, and smooth). A biofilm forming S. epidermidis strain (ATCC 35984) was used for all experiments. Three different implant surface types were tested: McGhan BIOCELL® (i.e., macrotexturized); Mentor Siltex® (i.e., microtexturized); and Allergan Natrelle Smooth® (i.e., smooth). Two different infection scenarios were simulated. The ability to form biofilm on capsules and implants over time was evaluated by quantitative post-sonication culture of implants and capsules biopsies. This experimental model allows the generation of a subclinical staphylococcal infection associated with a breast implant placed in the subcutaneous tissue of Wistar rats. The probability of generating an infection was different according to the type of implant studied and to the time from implantation to implant removal. Infection was achieved in 88.9% of macrotextured implants (i.e., McGhan), 37.0% of microtexturized implants (i.e., Mentor), and 18.5% of smooth implants (i.e., Allergan Smooth) in the short-term (p < 0.001). Infection was achieved in 47.2% of macrotextured implants, 2.8% of microtexturized implants, and 2.8% of smooth implants (i.e., Allergan Smooth) in the long-term (p < 0.001). There was a clear positive correlation between biofilm formation on any type of implant and capsule colonization/infection. Uniformly, the capsules formed around the macro- or microtexturized implants were consistently macroscopically thicker than those formed around the smooth implants regardless of the time at which they were removed (i.e., 1−2 weeks or 3−5 weeks). We have shown that there is a difference in the ability of S epidermidis to develop in vivo biofilms on macrotextured, microtextured, and smooth implants. Smooth implants clearly thwart bacterial adherence and, consequently, biofilm formation and persistence are hindered.

Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19.

BACKGROUND: Excessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria, but have also been shown to mediate tissue damage in a number of diseases. RESEARCH QUESTION: Could NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in patients with severe COVID-19, and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocyte infiltrates? STUDY DESIGN AND METHODS: Sixteen lung biopsy samples obtained immediately after death were analyzed methodically as exploratory and validation cohorts. NETs were analyzed quantitatively by multiplexed immunofluorescence and were correlated with local levels of IL-8 messenger RNA (mRNA) and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by reverse-transcriptase polymerase chain reaction and immunohistochemistry analysis. RESULTS: NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one of eight liver tissues. NET focal presence correlated negatively with CD8+ T-cell infiltration in the lungs. INTERPRETATION: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation was found with viral loads. The strong association between NETs and IL-8 points to this chemokine as a potentially causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered with by the presence of NETs.

Novel treatment dynamics for biofilm-related infections.

Introduction: As a result of progress in medical care, a huge number of medical devices are used in the treatment of human diseases. In turn, biofilm-related infection has become a growing threat due to the tolerance of biofilms to antimicrobials, a problem magnified by the development of antimicrobial resistance worldwide. As a result, successful treatment of biofilm-disease using only antimicrobials is problematic.Areas covered: We summarize some alternative approaches to classic antimicrobials for the treatment of biofilm disease. This review is not intended to be exhaustive but to give a clinical picture of alternatives to antimicrobial agents to manage biofilm disease. We highlight those strategies that may be closer to application in clinical practice.Expert opinion: There are a number of outstanding challenges in the development of novel antibiofilm therapies. Screening for effective antibiofilm compounds requires models relevant to all clinical scenarios. Although in vitro research of anti-biofilm strategies has progressed significantly over the past decade, there is a lack of in vivo research. In addition, the complexity of biofilm biology makes it difficult to develop a compound that is likely to provide the single 'magic bullet'. The multifaceted nature of biofilms imposes the need for multi-targeted or combinatorial therapies.

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.

BACKGROUND: Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset. METHODS: Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022. FINDINGS: All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001). INTERPRETATION: Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials. FUNDING: ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.

High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection.

Long-term catheter-related bloodstream infections (CRBSIs) involving coagulase-negative staphylococci are associated with poor patient outcomes, increased hospitalization, and high treatment costs. The use of vancomycin lock therapy has been an important step forward in treatment of these biofilms, although failures occur in 20% of patients. In this study, we report that a high dose of daptomycin lock therapy may offer a therapeutic advantage for these CRBSIs in just 24 h of treatment.

Time-kill assays of amphotericin B plus anidulafungin against Candida tropicalis biofilms formed on two different biomaterials.

PURPOSE: To determine the fungicidal activity by time-killing assays of amphotericin B (AMB) combined with anidulafungin (ANF) against biofilms of 2 clinical isolates of Candida tropicalis and the reference strain ATCC® 750, developed on polytetrafluoroethylene (PTFE) and titanium, using the CDC Biofilm Reactor (CBR) as an in vitro model. METHODS: Biofilms were developed for 24 hours on the disk surfaces and then exposed to AMB (40 mg/L), ANF (8 mg/L), alone and combined. At predetermined time points after drug exposure, biofilms were removed from the disk surface by vortexing-sonication to quantify viable biofilm cells. RESULTS: Drug activity was dependent on strain and time. After exposure to AMB, the mean decrease in viable cells attached to PTFE was 2.23 ± 0.89 Log10 cfu/cm2 (range 0.6-3.56 Log10), and on titanium 2.91 ± 1.04 (range 1.49-4.51 Log10). The reduction with ANF was 0.78 ± 0.5 (0.03-1.58 Log10) on PTFE and 0.8 ± 2.26 (0.42-1.16 Log10) on titanium. The reduction obtained with the combination of AMB + ANF was 1.8 ± 1.07 (0.22-3.54 Log10) on PTFE and 1.97 ± 0.49 (1.36-2.84 Log10) on titanium. The interaction was classified as indifferent with a tendency to antagonism. CONCLUSIONS: The activity of antifungal agents depends on the biomaterial surfaces the biofilm forming capacity of the isolate. AMB + ANF is less effective than AMB alone on both surfaces. Thus, the combination of these antifungals does not seem to add additional benefits to the treatment of C. tropicalis biofilm-related infections.

Intracavitary and Systemic Daptomycin for Successful Treatment of a Postpneumonectomy Intrathoracic Infection.

Treatment of an infected postpneumonectomy cavity is very difficult. We present a patient with an infection of a postpneumonectomy cavity by Staphylococcus epidermidis treated with local daptomycin for different dwell times, maintaining high antibiotic levels above the MIC. Clinical and microbiological cure were achieved successfully.

[Activity of amphotericin B and anidulafungin, alone and combined, against Candida tropicalis biofilms developed on Teflon® and titanium]. / Actividad de la anfotericina B y la anidulafungina, solas y combinadas, frente a biopelículas de Candida tropicalis formadas sobre Teflon® y titanio.

BACKGROUND: Current therapeutic strategies have a limited efficacy against Candida biofilms that form on the surfaces of biomedical devices. Few studies have evaluated the activity of antifungal agents against Candida tropicalis biofilms. OBJECTIVES: To evaluate the activity of amphotericin B (AMB) and anidulafungin (AND), alone and in combination, against C. tropicalis biofilms developed on polytetrafluoroethylene (teflon -PTFE) and titanium surfaces using time-kill assays. METHODS: Assays were performed using the CDC Biofilm Reactor equipped with PTFE and titanium disks with C. tropicalis biofilms after 24h of maturation. The concentrations assayed were 40mg/l for AMB and 8mg/l for AND, both alone and combined. After 24, 48 and 72h of exposure to the antifungals, the cfu/cm2 was determined by a vortexing-sonication procedure. RESULTS: AMB reduced biofilm viable cells attached to PTFE and titanium by ≥99% and AND by 89.3% on PTFE and 96.8% on titanium. The AMB+AND combination was less active than AMB alone, both on PTFE (decrease of cfu/cm2 3.09 Log10vs. 1.08 when combined) and titanium (4.51 vs. 1.53 when combined), being the interaction irrelevant on both surfaces. CONCLUSIONS: AMB is more active than AND against C. tropicalis biofilms. Yeast killing rates are higher on titanium than on PTFE surfaces. The combination of AMB plus AND is less effective than AMB alone on both surfaces.

Activity of Amphotericin B and Anidulafungin Combined with Rifampicin, Clarithromycin, Ethylenediaminetetraacetic Acid, N-Acetylcysteine, and Farnesol against Candida tropicalis Biofilms.

We evaluated the activity of (1) amphotericin-B (AMB), combined with rifampicin (RIF), clarithromycin (CLA), N-acetylcysteine (NAC), ethylenediaminetetraacetic acid (EDTA), and farnesol (FAR) (1000, 1000, 1000, 4000, and 30,000 mg/L, and 300 µM, respectively), against Candida tropicalis biofilms formed on polytetrafluoroethylene (PTFE) and (2) anidulafungin (ANF) combined with the same compounds at 8, 10, 5, 40, and 30 mg/L, and 30 µM, respectively, against biofilms formed on titanium. Biofilm growth kinetics were performed in a CDC Biofilm Reactor (CBR). PTFE or titanium disks were removed from the CBR at 24, 48, 72, and 96 h to determine the Log10CFU/cm². Killing kinetics were performed by adding the drugs to 24-h-mature biofilms (time 0). Disks were removed after 24, 48, and 72 h of drug exposure to determine Log10CFU/cm². Viable cells in biofilms were 4.73 and 4.29 Log10CFU/cm² on PTFE and titanium, respectively. Maximum Log10 decreases in CFU/cm² depend on the combination and were: 3.53 (AMB + EDTA), 2.65 (AMB + RIF), 3.07 (AMB + NAC), 2.52 (AMB + CLA), 1.49 (AMB + FAR), 2.26 (ANF + EDTA), 2.45 (ANF + RIF), 2.47 (ANF + NAC), 1.52 (ANF + CLA), and 0.44 (ANF + FAR). In conclusion, EDTA, NAC, RIF, and CLA improve the activity of AMB and ANF against biofilms developed on both surfaces, which could be an effective strategy against C. tropicalis biofilm-related infections.

Prevention of Staphylococcus epidermidis biofilm formation using electrical current.

A technique for the prevention of staphylococcal adhesion by electrical current exposure was investigated. Teflon coupons were exposed to a continuous flow of 103 cfu/ml Staphylococcus epidermidis with or without 2000 microA DC electrical current delivered by electrodes on opposite sides of a coupon, touching neither each other nor the coupon. A mean 3.46 (SD, 0.20) and 5.70 (SD, 1.03) log10 cfu/cm2 were adhered to the non-electrical current exposed coupons after 4 h and 24 h, respectively. A mean 2.46 (SD, 0.31) and 1.47 (SD, 0.73) log10 cfu/cm2 were adhered after 4 h and 24 h with exposure to 2000 microA electrical current delivered by graphite electrodes. A mean 2.21 (SD, 0.14) and 0.55 (SD, 0.00) log10 cfu/cm2 were adhered after 4 h and 24 h with exposure to 2000 microA electrical current delivered by stainless steel electrodes. Electrical current may be useful in the prevention of staphylococcal adhesion to biomaterials.