A chitosan-modified tea tree oil self-nanoemulsion improves antibacterial effects in vivo and in vitro and promotes wound healing by influencing metabolic processes against multidrug-resistant bacterial infections.

Infectious diseases, especially multidrug-resistant bacterial infections, have caused crises and majorly disrupted public health and economic stability worldwide. Many natural essential oils, especially tea tree oil, have potential to treat multidrug-resistant bacteria, such as H. pylori and P. aeruginosa. However, there are some problems need to be solved, such as poor stability upon light or oxygen exposure. Therefore, it is urgent to develop the ideal formation to tackle these difficulties. Herein, we reported the novel chitosan-modified self-nanoemulsion (TNE) encapsulating natural essential tea tree oil with strong antibacterial and stability characterize. In this study, we found that this self-nanoemulsion (size: 212 nm, PDI: 0.124, zeta potential: -20.5 mV, 6 % tea tree oil) not only had physical properties, good stability and tissue safety, but also had better antibacterial synergism (2-8 times) than that of water suspension against various multidrug-resistant bacterial (such as H. pylori, MRSA and P. aeruginosa). Additionally, TNE showed high antibacterial effectiveness in vivo, reduced inflammation, promoted ulcer healing after H. pylori infection and accelerated wound healing after P. aeruginosa infection. Importantly, this novel self-nanoemulsion can induce 274 protein down-regulated and 251 protein up-regulated, and disrupt H. pylori metabolic processes (glyoxylate, dicarboxylic acid, glutamate and tryptophan metabolism) and reduced its viability, leading to significant synergistic antibacterial effects. TNE is a potential treatment for skin wounds or ulcers caused by multidrug-resistant bacterial infections.

Venetoclax for an ATRA and ATO resistance acute promyelocytic leukemia patient with TNRC18::RARA fusion gene.

Variant acute promyelocytic leukemia (APL) poses diagnostic and therapeutic challenges primarily because of the absence of PML::RARA. This report presents the case of a patient diagnosed with all-trans retinoic acid (ATRA)-resistant APL harboring the TNRC18::RARA fusion gene. After treatment with venetoclax, azacitidine, and ATRA, the patient achieved complete remission. The patient also developed pulmonary tuberculosis and a multidrug-resistant infection, which improved considerably after antituberculosis treatment and carrimycin, respectively.

Patient Selection for Living Donor Liver Transplantation in Acute-on-chronic Liver Failure.

Background and objectives: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality without liver transplantation (LT). The selection criteria for LT in these patients are not well defined. The objective of this study was to determine factors associated with post-transplant survival in ACLF. Methods: This was a single-center retrospective study of patients who underwent living donor liver transplantation (LDLT) for ACLF between 2012 and 2022. Out of 1093 transplants, 110 patients had underlying ACLF, based on the European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) criteria. We looked at factors associated with 1-year posttransplant survival. Results: The median model for end-stage liver disease (MELD) score was 33.5 (31-38), and the 1-year posttransplant survival was 72%. Six risk factors were associated with posttransplant survival, namely, body mass index > 30 kg/m2 [HR, 4.4; 95% CI, 1.8-10.7], platelet count < 66,000/µl [HR, 2.91; CI,1.2-6.6], poor response to medical treatment [HR, 2.6; CI, 1.1-5.7], drug-resistant bacterial or fungal cultures [HR, 4.2; CI, 1.4-12.4], serum creatinine > 2.5 mg/dl [HR, 3.4; CI, 1.5-7.7], and graft-to-recipient weight ratio < 0.7 [HR, 4.8; CI, 1.4-16.3]. The 1-year post-transplant survival was 84% in patients with 0-2 risk factors (n = 89) and was 6% with 3 risk factors (n = 15) (P < 0.001). For 1-year posttransplant survival, the area under curve (AUC) for the current model was 0.8 (0.69-0.9). The AUC for CLIF-ACLF, Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), and EASL-CLIF ACLF grades was < 0.5. Conclusion: In LT for ACLF, acceptable survival can be achieved when less than three high-risk factors are present.

Clinical and microbiological profile of health care-associated infections in a tertiary hospital: Comparison between a cohort of hospitalized patients during prepandemic and COVID-19 pandemic periods.

BACKGROUND: During the COVID-19 pandemic, health service practices underwent significant changes, impacting the occurrence of health care-associated infections (HAIs). This study presents the epidemiology of bacterial infections and compares clinical data on nosocomial infections in hospitalized patients before and during the pandemic. METHODS: A unicentric, observational, retrospective cohort study was conducted with descriptive analyses on the microorganism identification and resistance profile. Patient's clinical data who had hospital-acquired infection (HAI), during their hospitalization in a tertiary hospital before and during the COVID-19 pandemic was compared by descriptive and inferential analyses. RESULTS: A total of 1,581 bacteria were isolated from 1,183 hospitalized patients. Among patients coinfected with COVID-19, there was a statistically significant increase in HAI-related deaths (P < .001) and HAI caused by multidrug-resistant organisms (P < .001), mainly by Acinetobacter baumannii and Staphylococcus aureus. A higher odds ratio of HAI-related deaths compared to the prepandemic period was observed (odds ratio 6.98 [95% confidence interval 3.97-12.64]). CONCLUSIONS: The higher incidence of multidrug-resistant bacteria and increased deaths due to HAI, especially in patients with COVID-19 coinfection, might be related to various factors such as increased workload, broad-spectrum antibiotic use, and limited resources. The pandemic has changed the profile of circulating bacteria and antimicrobial resistance. Prevention strategies should be considered to reduce the impact of these infections.

Conjugation of antimicrobial peptides to enhance therapeutic efficacy.

The growing prevalence of antimicrobial resistance (AMR) has brought with it a continual increase in the numbers of deaths from multidrug-resistant (MDR) infections. Since the current arsenal of antibiotics has become increasingly ineffective, there exists an urgent need for discovery and development of novel antimicrobials. Antimicrobial peptides (AMPs) are considered to be a promising class of molecules due to their broad-spectrum activities and low resistance rates compared with other types of antibiotics. Since AMPs also often play major roles in elevating the host immune response, the molecules may also be called "host defense peptides." Despite the great promise of AMPs, the majority remain unsuitable for clinical use due to issues of structural instability, degradation by proteases, and/or toxicity to host cells. Moreover, AMP activities in vivo can be influenced by many factors, such as interaction with blood and serum biomolecules, physiological salt concentrations or different pH values. To overcome these limitations, structural modifications can be made to the AMP. Among several modifications, physical and chemical conjugation of AMP to other biomolecules is widely considered an effective strategy. In this review, we discuss structural modification strategies related to conjugation of AMPs and their possible effects on mode of action. The conjugation of fatty acids, glycans, antibiotics, photosensitizers, polymers, nucleic acids, nanoparticles, and immobilization to biomaterials are highlighted.

Clinical Outcome of Cefiderocol for Infections with Carbapenem-Resistant Organisms.

Cefiderocol is a novel cephalosporin recently approved by the FDA to aid clinicians in the fight against multidrug-resistant (including carbapenem-resistant) gram-negative organisms. The primary objective of this study is to evaluate the 14- and 28-day mortality associated with cefiderocol. We performed a retrospective chart review of all adult patients admitted at Stony Brook University Hospital between October 2020 and December 2021 and received cefiderocol for at least 3 days. Patients were excluded if they received more than one course of cefiderocol therapy or remained hospitalized at the time of this study. A total of 22 patients met the inclusion criteria. The all-cause mortality on day 28 for all patients was 13.6%, whereas this rate for patients with BSI was 0%, with cUTI was 0% and with LRTI was 16.7%. The all-cause mortality on day 28 for patients who received the dual antibiotics (in conjunction with cefiderocol) was 0%, compared to 25% for patients who only received cefiderocol (p = 0.25). We noted treatment failure in two patients (9.1%). Our findings suggest that cefiderocol could possibly be associated with lower all-cause mortality than previously thought. In our study, we did not find any significant difference between cefiderocol's use in combination with another antibacterial agent and its use as a monotherapy.

Risk factors of sepsis and prevalence of multidrug-resistant organisms in pediatric cardiac surgery in tertiary care teaching rural hospital in India: A retrospective observational study.

Background and aims: Cardiac surgery and cardiopulmonary bypass result in an immunoparalyzed state in children making them susceptible to sepsis and other hospital-acquired infections. Therefore, identification of the risk factors of sepsis would lead to appropriate management. The current study seeks to evaluate the prevalence of sepsis and risk factors linked to sepsis in pediatric cardiac surgical patients and the subsequent prevalence of multidrug-resistant organisms. Methods: A retrospective, single-center observational study was conducted including 100 pediatric patients admitted to the pediatric intensive care unit (ICU) after cardiac surgery between January 2017 and February 2018. All patient data were obtained from the medical record department of the hospital. Patient case report form comprised demography, surgery details, preoperative and postoperative hematological reports, and clinical details. After collecting the data, chi-square test and logistic regression analysis were used to determine the risk factors linked to sepsis. Results: The prevalence of sepsis in our population was 27% and the mortality rate due to sepsis was 1%. The only statistically significant risk factor for sepsis we discovered in this analysis was prolonged ICU stay for more than 5 days. A total of eight patients had blood cultures positive for bacterial infection. The alarming finding was that all eight were infected with multidrug-resistant organisms, demanding the last line of antibacterials. Conclusion: Our study indicates that special clinical care is required when ICU stay is prolonged to lower the risk of sepsis. These new and upcoming infections not only promote high mortality and morbidity rates but also contribute to increased cost of care due to the use of newer broad-spectrum antibiotics and longer hospital stay. The high prevalence of multidrug-resistant organisms is unacceptable in the current scenario and hospital infection and prevention control play a crucial role in minimizing such infections.

Acute Kidney Injury (AKI) at Admission Predicts Mortality in Patients With Severe Alcoholic Hepatitis (SAH).

Background & aims: Severe alcoholic hepatitis (SAH) is a grave condition, and the presence of acute kidney injury (AKI) further jeopardizes patient survival. However, the impact of AKI on survival in SAH has not been assessed from this region of Asia. Materials and methods: This study was conducted on consecutive alcohol-associated liver disease (ALD) patients hospitalized in Gastroenterology Department, SCB Medical College, Cuttack, India, between October 2016 and December 2018. On diagnosis of SAH (mDF score ≥32), demographic, clinical, and laboratory parameters were recorded, and survival was compared between patients with and without AKI (AKIN criteria). In addition, survival was compared among SAH patients defined by other criteria and prognostic models in the presence and absence of AKI. Results: 309 (70.71%) of ALD patients had SAH, and 201 (65%) of them had AKI. SAH patients with AKI had higher total leucocyte count, total bilirubin, serum creatinine, serum urea, INR, MELD (UNOS), MELD (Na+), CTP score, mDF score, Glasgow score, ABIC score, and increased prevalence of acute on chronic liver failure (ACLF) as per EASL-CLIF Consortium criteria (P < 0.001). Further, they had prolonged hospital stay, and increased death during hospitalization, at 28 days as well as 90 days (P < 0.001). Significant differences in survival were also seen in SAH (as per MELD, ABIC, and GAHS criteria) patients above the marked cut offs in respect to AKI. Conclusions: Over two-thirds of ALD patients had SAH, and about two-thirds had AKI. Patients with SAH and AKI had an increased prevalence of ACLF, longer hospital stay, and increased mortality during hospitalization at 28 days and 90 days. Lay summary: SAH is a critical condition, and the presence of AKI negatively affects their survival. Hence, early identification of SAH and AKI, as well as early initiation of treatment, is crucial for better survival. Our study from the coastal part of eastern India is the first to demonstrate the prevalence of SAH among patients with ALD along with the prevalence of AKI among SAH patients in this region. This knowledge will be helpful in managing these patients from this region of world.

Development and internal validation of simplified predictive scoring (ICU-SEPSA score) for mortality in patients with multidrug resistant infection.

Background: Mortality from multidrug-resistant (MDR) pathogens is an urgent healthcare crisis worldwide. At present we do not have any simplified screening tools to predict the risk of mortality associated with MDR infections. The aim of this study was to develop a screening tool to predict mortality in patients with multidrug-resistant organisms. Methods: A retrospective cohort study to evaluate mortality risks in patients with MDR infections was conducted at Phrae Hospital. Univariable and multivariable analyses were used to classify possible risk factors. The model performance was internally validated utilizing the mean of three measures of discrimination corrected by the optimism using a 1000-bootstrap procedure. The coefficients were transformed into item scores by dividing each coefficient with the lowest coefficient and then rounding to the most adjacent number. The area under the receiver operating characteristic curve (AuROC) was used to determine the performance of the model. Results: Between 1 October 2018 and 30 September 2020, a total of 504 patients with MDR infections were enrolled. The ICU-SEPSA score composed of eight clinical risk factors: 1) immunocompromised host, 2) chronic obstructive pulmonary disease, 3) urinary tract infection, 4) sepsis, 5) placement of endotracheal tube, 6) pneumonia, 7) septic shock, and 8) use of antibiotics within the past 3 months. The model showed good calibration (Hosmer-Lemeshow χ2 = 19.27; p-value = 0.50) and good discrimination after optimism correction (AuROC 84.6%, 95% confidence interval [Cl]: 81.0%-88.0%). The positive likelihood ratio of low risk (score ≤ 5) and high risk (score ≥ 8) were 2.07 (95% CI: 1.74-2.46) and 12.35 (95% CI: 4.90-31.13), respectively. Conclusion: A simplified predictive scoring tool wad developed to predict mortality in patients with MDR infections. Due to a single-study design of this study, external validation of the results before applying in other clinical practice settings is warranted.

Quaternized Polysaccharide-Based Cationic Micelles as a Macromolecular Approach to Eradicate Multidrug-Resistant Bacterial Infections while Mitigating Antimicrobial Resistance.

Microbial infections and microbial resistance lead to a high demand for new antimicrobial agents. Quaternized polysaccharides are cationic antimicrobial candidates; however, the limitation of homogeneous synthesis solvents that affect the molecular structure and biological activities, as well as their drug resistance remains unclear. Therefore, the authors homogeneously synthesize a series of quaternized chitin (QC) and quaternized chitosan (QCS) derivatives via a green and effective KOH/urea system and investigate their structure-activity relationship and biological activity in vivo and in vitro. Their study reveals that a proper match of degree of quaternization (DQ) and degree of deacetylation (DD') of QC or QCS is key to balance antimicrobial property and cytotoxicity. They identify QCS-2 as the optimized antimicrobial agent with a DQ of 0.46 and DD' of 82%, which exhibits effective broad-spectrum antimicrobial properties, good hemocompatibility, excellent cytocompatibility, and effective inhibition of bacterial biofilm formation and eradication of mature bacterial biofilms. Moreover, QCS-2 exhibits a low propensity for development of drug resistance and significant anti-infective effects on MRSA in vivo comparable to that of vancomycin, avoiding excessive inflammation and promoting the formation of new blood vessels, hair follicles, and collagen deposition to thus expedite wound healing.

Impact of prior antibiotic therapy on severe necrotizing soft-tissue infections in ICU patients: results from a French retrospective and observational study.

Necrotizing soft-tissue infection (NSTI) is a life-threatening pathology that often requires management in intensive care unit (ICU). Therapies consist of early diagnosis, adequate surgical source control, and antimicrobial therapy. Whereas guidelines underline the need for appropriate routine microbiological cultures before starting antimicrobial therapy in patients with suspected sepsis or septic shock, delaying adequate therapy also strongly increases mortality. The aim of the present study was to compare the characteristics and outcomes of patients hospitalized in ICU for NSTI according to their antimicrobial therapy exposure > 24 h before surgery (called the exposed group) or not (called the unexposed group) before surgical microbiological sampling. We retrospectively included 100 consecutive patients admitted for severe NSTI. The exposed group consisted of 23(23%) patients, while 77(77%) patients belonged to the unexposed group. The demographic and underlying disease conditions were similar between the two groups. Microbiological cultures of surgical samples were positive in 84 patients and negative in 16 patients, including 3/23 (13%) patients and 13/77 (17%) patients in the exposed and unexposed groups, respectively (p = 0.70). The distribution of microorganisms was comparable between the two groups. The main antimicrobial regimens for empiric therapy were also similar, and the proportions of adequacy were comparable (n = 60 (84.5%) in the unexposed group vs. n = 19 (86.4%) in the exposed group, p = 0.482). ICU and hospital lengths of stay and mortality rates were similar between the two groups. In conclusion, in a population of severe ICU NSTI patients, antibiotic exposure before sampling did not impact either culture sample positivity or microbiological findings.

Impact of the COVID-19 pandemic on the incidence of multidrug-resistant bacterial infections in an acute care hospital in Brazil.

BACKGROUND: The impact of COVID-19 on healthcare- associated infections (HCAI) caused by multidrug-resistant (MDR) bacteria that contribute to higher mortality is a growing area of study METHODS: This retrospective observational study compares the incidence density (ID) of HCAI caused by MDR bacteria (CRE, CRAB, CRP, MRSA and VRE) pre-COVID (2017-2019) and during the COVID-19 pandemic (2020) in overall hospitalized patients and in intensive care (ICU) units. RESULTS: We identified 8,869 HCAI, of which 2,641 (29.7%) were caused by bacterial MDR, and 1,257 (14.1%) were from ICUs. The overall ID of MDR infections increased 23% (P < .005) during COVID-19. The overall per-pathogen analysis shows significant increases in infections by CRAB and MRSA (+108.1%, p<0.005; +94.7%, p<0.005, respectively), but not in CRE, CRP, or VRE. In the ICU, the overall ID of MDR infections decreased during COVID, but that decline was not significant (-6.5%, P = .26). The ICU per-pathogen analysis of ID of infection showed significant increases in CRAB and MRSA (+42.0%, P = .001; +46.2%, P = .04), significant decreases in CRE and CRP (-26.4%, P = .002; -44.2%, P = 0.003, respectively) and no change in VRE. CONCLUSIONS: The COVID-19 pandemic correlates to an increase in ID of CRAB and MRSA both in ICU and non-ICU setting, and a decrease in ID of CRE and CRP in the ICU setting. Infection control teams should be aware of possible outbreaks of CRAB and MRSA and promote rigorous adherence to infection control measures as practices change to accommodate changes in healthcare needs during and after the pandemic.

Management of Multidrug Resistant Infections in Lung Transplant Recipients with Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited multisystem disease characterised by bronchiectasis and chronic respiratory infections which eventually cause end stage lung disease. Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated lung disease, improving survival and quality of life. Navigating recurrent infections in the setting of LTx is often difficult, where immune suppression must be balanced against the constant threat of infection. Sepsis/infections are one of the major contributors to post-LTx mortality and multiresistant organisms (eg, Burkholderia cepacia complex, Mycobacterium abscessus complex, Scedosporium spp. and Lomentospora spp.) pose a significant threat to survival. This review will summarize current and novel therapies to assist with the management of multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort.

Predictors of mortality in acute pancreatitis complicated with multidrug-resistant Klebsiella pneumoniae infection.

BACKGROUND: Multidrug-resistant (MDR) Klebsiella pneumoniae infections, from pancreatic infections to bloodstream infections, influence the mortality of patients with acute pancreatitis (AP) on the condition of limited antibiotic choices. The aim of this study was to investigate the predictor of mortality among AP patients complicated with MDR-K. pneumoniae infections. METHODS: Seventy-one AP patients who occurred MDR-K. pneumoniae infections from August 1st, 2016 to August 1st, 2020 were enrolled. MDR-K. pneumoniae was defined as the K. pneumoniae strain non-susceptible to at least one agent in three or more antimicrobial categories. MDR-K. pneumoniae isolates were confirmed by Vitek-2 system. Antibiotic susceptibility test was carried out using a micro broth dilution method. Clinical characteristics and drug-resistance rates were retrospectively reviewed, and the predictors of mortality were evaluated by univariate and multivariate analyses. RESULTS: The mortality rate of AP patients complicated with MDR-K. pneumoniae infections reached 46.5% (33 of 71), and pancreas (n = 53) was the most common site of MDR-K pneumoniae strains. The drug resistance rates of MDR-K. pneumoniae were high to 11 of 12 common antibiotics (more than 50.0%) except of tigecycline (23.9%). The predictor independently associated with mortality was septic shock (hazard ratio 2.959, 95% confidence intervals 1.396 - 6.272, P = 0.005). CONCLUSIONS: More attention should be paid for pancreatic MDR-K. pneumoniae infections among AP patients The predictor for mortality of AP patients complicated with MDR-K. pneumoniae infection is septic shock. Therefore, further clinical investigations should focus on areas against septic shock.

In Vitro Antibacterial Activity of Cefiderocol against Multidrug-Resistant Acinetobacter baumannii.

Cefiderocol (CFDC), a novel siderophore cephalosporin, demonstrates strong activity against multidrug-resistant (MDR) Acinetobacter baumannii. Limited studies have evaluated CFDC alone and in combination with other Gram-negative antibiotics against MDR A. baumannii isolates. Susceptibility testing revealed lower CFDC MIC values (87% of MICs ≤ 4mg/liter) than the comparator Gram-negative agents. Six isolates, with elevated CFDC MICs (16 to 32 mg/liter) were selected for further experiments. Time-kill analyses presented with synergistic activity and beta-lactamase inhibitors increased CFDC susceptibility in each of the isolates.

Continuous infusion, therapeutic drug monitoring and outpatient parenteral antimicrobial therapy with ceftazidime/avibactam: a retrospective cohort study.

OBJECTIVES: Based on recent pharmacokinetic/pharmacodynamic (PK/PD) evidence, continuous-infusion (CI) ß-lactam administration is increasingly recommended for serious infections. Since 2016, the combination ceftazidime/avibactam (CAZ/AVI) is administered as per the manufacturer's instructions as an intermittent infusion of 2.5 g every 8 h. Thus, CI has not yet been evaluated in clinical trials. METHODS: We aimed to evaluate the use of CI of CAZ/AVI in a retrospective case series from December 2016 to October 2019. All isolates displayed in vitro susceptibility to CAZ/AVI according to EUCAST definitions. Patients were initially given CAZ/AVI as CI of 5 g every 12 h, and dosages were adjusted according to therapeutic drug monitoring of ceftazidime with a therapeutic goal of ≥4-5 × MIC in plasma and/or at the site of infection. RESULTS: CAZ/AVI was administered by CI in 10 patients with infections mainly caused by multidrug-resistant Pseudomonas aeruginosa (54.5%) and Klebsiella pneumoniae (36.4%). Bacteraemia occurred in 30% of cases. Sepsis or septic shock was present in 20% of cases. CAZ/AVI was used as monotherapy in 60% of cases. Clinical cure and microbiological eradication were achieved in 80% and 90% of cases, respectively. The 30-day mortality after CAZ/AVI treatment onset was 10%. The therapeutic goals of ≥4-5 × MIC in plasma and/or at the site of infection were achieved in 100% and 87.5% of cases, respectively, without adverse events. CONCLUSION: Despite a limited number of patients, CI of CAZ/AVI provided promising results after optimisation of PK/PD parameters both in plasma and at the site of infection.

Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins.

BACKGROUND: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.

Pharmacokinetics and Time-Kill Study of Inhaled Antipseudomonal Bacteriophage Therapy in Mice.

Inhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different from antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in immune-suppressed mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8, and 24 h posttreatment and various tissues (lungs, kidney, spleen, and liver), bronchoalveolar lavage fluid, and blood were collected for phage quantification. In a separate study combining phage with bacteria, mice (n = 4) were treated with PEV31 (109 PFU) or phosphate-buffered saline (PBS) at 2 h postinoculation with MDR P. aeruginosa Infective PEV31 and bacteria were enumerated from the lungs. In the phage-only study, the PEV31 titer gradually decreased in the lungs over 24 h, with a half-life of approximately 8 h for both doses. In the presence of bacteria, in contrast, the PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Of the 10 colonies tested, four phage-resistant isolates were observed from the lung homogenates sampled at 24 h after phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

Impact of prior antibiotics on infected pancreatic necrosis microbiology in ICU patients: a retrospective cohort study.

BACKGROUND: Recent guidelines advise against prophylactic antibiotics in patients with necrotizing pancreatitis, advocating instead a step-up drainage and necrosectomy strategy with antibiotics as dictated by microbiological findings. However, prompt antibiotic therapy is recommended in patients with sepsis or septic shock, a possible presentation of infected pancreatic necrosis (IPN). Consequently, in many critically ill patients with IPN, pancreatic samples are collected only after broad-spectrum antibiotic therapy initiation. Whether this prior antibiotic exposure alters the microbiological findings is unknown. The main objective was to determine whether prior antibiotic exposure sterilized the samples collected during procedures for suspected IPN in patients admitted to the intensive care unit (ICU) for acute pancreatitis with suspected IPN. We retrospectively studied 56 consecutive ICU patients admitted with suspected IPN. We collected details on the microbiological samples and antimicrobials used. A definite diagnosis of IPN was given when bacteria were identified in pancreatic samples. RESULTS: In all, 137 pancreatic samples were collected, including 91 (66.4%) after antibiotic therapy initiation. IPN was confirmed in 48 (86%) patients. The proportion of positive samples was 74 (81.3%) in antibiotic-exposed patients and 32/46 (69.5%) in unexposed patients (p = 0.58). Of the 74 positive samples from exposed patients, 62 (84%) had organisms susceptible to the antibiotics used. One-third of samples contained more than one organism. Among patients with IPN, 37.5% had positive blood cultures. Multidrug- or extensively drug-resistant bacteria were identified at some point in half the patients. Enterobacter cloacae complex was more frequent in the exposed group (p = 0.02), as were Gram-negative anaerobic bacteria (p = 0.03). CONCLUSION: Antibiotic exposure before sampling did not seem to affect culture positivity of pancreatic samples to confirm IPN, but may affect microbiological findings. Our results suggest that, in patients with sepsis and suspected IPN, antibiotics should be started immediately and pancreatic samples obtained as soon as possible thereafter. In other situations, antibiotics can be withheld until the microbiological results of pancreatic samples are available, to ensure accurate targeting of the spectrum to bacterial susceptibility patterns. ClinicalTrials.gov number NCT03253861.

A Severe Diabetic Foot Ulcer With Intermediate Cuneiform Displacement and Multidrug-Resistant Pseudomonas aeruginosa Infection: A Rare Case Report.

Diabetic foot ulcer (DFU) is considered as one of the most serious and prevailing complications of diabetes mellitus, while it is the major cause of amputations in diabetic patients. Herein, we reported an acquired severe traumatic DFU with an intermediate cuneiform hairline fracture and displacement in a 55-year old male (Grade IV of Wagner classification; Grade III of IWGDF classification). The Pseudomonas aeruginosa was identified in pus culture. Data of antibiotic susceptibility testing indicated that the isolates of Pseudomonas aeruginosa were multi-drug resistant. Routine debridement, clearing displaced intermediate cuneiform and drainage were performed to facilitate the outflow of pus and pressure mitigation. Dressing with Prontosan solution and gel was applied to the wound, and meropenem was systemically administrated in addition to effective glycemic control. The DFU has been fully healed after ~40-day treatment. For this case, clearing the displaced and fractured intermediate cuneiform is essential for the heal of the DFU in addition to the common strategy for DFU treatment, i.e., the combination of debridement, pressure mitigation, wound dressing with Prontosan, antibiotic selection and effective glycemic control. This case report might have value for the treatment of complex DFU with bone fracture and displacement, reducing the risk of amputation.