Klebsiella pneumoniae Isolate from a New York City Hospital Belonging to Sequence Type 258 and Carrying blaKPC-2 and blaVIM-4.

Among 69 of 139 (49.6%) carbapenem-nonsusceptible Enterobacteriaceae carrying blaKPC, 1 Klebsiella pneumoniae was also positive for blaVIM. The isolate belonged to sequence type 258 (ST258) and carried blaKPC-2 on a copy of Tn4401a and blaVIM-4 on a class 1 integron. Genes were located on distinct plasmids belonging to Inc types A/C and FII. Elevated expression of the efflux pump AcrAB-TolC (acrA, 15.3 times) and reduced expression of outer membrane protein genes ompK35 and ompK37 (0.16 and 0.081 times, respectively) associated with various amino acid alterations on OmpK37 were observed. The presence of two carbapenemases in ST258 K. pneumoniae is of great concern due to the ability of this organism to widely disseminate.

Ceftazidime-avibactam activity tested against Enterobacteriaceae isolates from U.S. hospitals (2011 to 2013) and characterization of ß-lactamase-producing strains.

Ceftazidime-avibactam (MIC50/90, 0.12/0.25 µg/ml) inhibited 99.9% (20,698/20,709) of Enterobacteriaceae isolates at ≤8 µg/ml. This compound was active against resistant subsets, including ceftazidime-nonsusceptible Enterobacter cloacae (MIC50/90, 0.25/0.5 µg/ml) and extended-spectrum ß-lactamase (ESBL) phenotype isolates. An ESBL phenotype was noted among 12.4% (1,696/13,692 isolates from targeted species) of the isolates, including 776 Escherichia coli (12.0% for this species; MIC50/90, 0.12/0.25 µg/ml), 721 Klebsiella pneumoniae (16.3%; MIC50/90, 0.12/0.25 µg/ml), 119 Klebsiella oxytoca (10.3%; MIC50/90, 0.06/0.25 µg/ml), and 80 Proteus mirabilis (4.9%; MIC50/90, 0.06/0.12 µg/ml) isolates. The most common enzymes detected among ESBL phenotype isolates from 2013 (n = 743) screened using a microarray-based assay were CTX-M-15-like (n = 307), KPC (n = 120), SHV ESBLs (n = 118), and CTX-M-14-like (n = 110). KPC producers were highly resistant to comparators, and ceftazidime-avibactam (MIC50/90, 0.5/2 µg/ml) and tigecycline (MIC50/90, 0.5/1 µg/ml; 98.3% susceptible) were the most active agents against these strains. Meropenem (MIC50/90, ≤0.06/≤0.06 µg/ml) and ceftazidime-avibactam (MIC50/90, 0.12/0.25 µg/ml) were active against CTX-M-producing isolates. Other enzymes were also observed, and ceftazidime-avibactam displayed good activity against the isolates producing less common enzymes. Among 11 isolates displaying ceftazidime-avibactam MIC values of >8 µg/ml, three were K. pneumoniae strains producing metallo-ß-lactamases (all ceftazidime-avibactam MICs, >32 µg/ml), with two NDM-1 producers and one K. pneumoniae strain carrying the bla(KPC-2) and bla(VIM-4) genes. Therapeutic options for isolates producing ß-lactamases may be limited, and ceftazidime-avibactam, which displayed good activity against strains, including those producing KPC enzymes, merits further study in infections where such organisms occur.

Mutation-driven ß-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from U.S. hospitals.

OprD loss and hyperexpression of AmpC, MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM were evaluated among 120 Pseudomonas aeruginosa isolates collected during 2012 in U.S. hospitals and selected based on ceftazidime MIC values (1 to >32 µg/ml). AmpC derepression (10-fold greater than that with the control) and OprD loss (decreased/no band) were the most prevalent resistance mechanisms: 47.5 and 45.8% of the isolates were considered positive, respectively. Elevated expression of the efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was observed in 32.5, 8.3, 0.0, and 28.4% of the isolates, respectively. A total of 21 different combinations of resistance mechanisms were noted, and the most prevalent included AmpC derepression with OprD loss with and without efflux hyperexpression (38 and 10 isolates, respectively). A total of 26 isolates had no changes in the resistance mechanisms tested and had lower MIC values for all ß-lactams or ß-lactam/ß-lactamase inhibitor combinations analyzed. OprD loss had a strong correlation with elevated MIC results for imipenem and meropenem (median MIC values of 8 and 4 µg/ml, respectively), with all combinations displaying OprD loss also displaying elevated median MIC values for these carbapenems (4 to >8 µg/ml). AmpC expression levels were greater in isolates displaying elevated cefepime, ceftazidime, or piperacillin-tazobactam MIC values (≥4, ≥4, and ≥16 µg/ml, respectively). Isolates displaying derepressed AmpC had ceftolozane-tazobactam MIC values ranging from 1 to 16 µg/ml. No strong correlation was noticed with MIC values for this ß-lactam/ß-lactamase inhibitor combination and OprD loss or hyperexpression of efflux systems. Two KPC-producing isolates were detected among 16 isolates displaying ceftolozane-tazobactam MIC values of ≥8 µg/ml.

The randomised thoracoscopic talc poudrage+indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC): study protocol for a randomised controlled trial.

INTRODUCTION: Malignant pleural effusion (MPE) is common, with 50 000 new cases per year in the UK. MPE causes disabling breathlessness and indicates advanced disease with a poor prognosis. Treatment approaches focus on symptom relief and optimising quality of life (QoL). Patients who newly present with MPE commonly require procedural intervention for both diagnosis and therapeutic benefit.Thoracoscopic pleural biopsies are highly sensitive in diagnosing pleural malignancy. Talc poudrage may be delivered at thoracoscopy (TTP) to prevent effusion recurrence by effecting pleurodesis. Indwelling pleural catheters (IPCs) offer an alternative strategy for fluid control, enabling outpatient management and are often used as 'rescue' therapy following pleurodesis failure or in cases of 'trapped lung'. It is unknown whether combining a TTP with IPC insertion will improve patient symptoms or reduce time spent in the hospital.The randomised thoracoscopic talc poudrage + indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC) is the first randomised controlled trial (RCT) to examine the benefit of a combined TTP and IPC procedure, evaluating cost-effectiveness and patient-centred outcomes such as symptoms and QoL. The study remains in active recruitment and has the potential to radically transform the pathway for all patients presenting with MPE. METHODS AND ANALYSIS: TACTIC is an unblinded, multicentre, RCT comparing the combination of TTP with an IPC to TTP alone. Co-primary outcomes are time spent in the hospital and mean breathlessness score over 4 weeks postprocedure. The study will recruit 124 patients and aims to define the optimal pathway for patients presenting with symptomatic MPE. ETHICS AND DISSEMINATION: TACTIC is sponsored by North Bristol NHS Trust and has been granted ethical approval by the London-Brent Research Ethics Committee (REC ref: 21/LO/0495). Publication of results in a peer-reviewed journal and conference presentations are anticipated. TRIAL REGISTRATION: ISRCTN 11058680.

The importance of relationality: A note on co-determinism, multispecies relationships and implications for COVID-19.

The paper aims to highlight the importance of subjective, objective and intersubjective domains when engaging in public education and research on wicked problems such as violence, poverty, climate change, loss of habitat and pandemics. The case is made that critical systemic thinking and practice-underpinned by a meta Design of Inquiring Systems-could help to foster a more relational response to the convergent social, economic and environmental policy challenges that pose 'existential risks'. This paper explores the implications of 'mismeasuring our lives' by not understanding relationality. It reflects on the factors that are linked with the 'unravelling' of well-being, in order to prevent and restore the multispecies relationships that have been forgotten. This requires a bio-political approach to reframing not only economics but our relationships with one another and with nature. 'Power and knowledge are linked' and nowhere is Foucault's linkage more marked than in the biopolitical determination of what species are valued and why. Taxonomies are constructs based on values that need to be carefully considered in terms of the consequences of policy decisions.

Toward a big picture of COVID-19.

The paper aims to illustrate and explain the problems and opportunities for improvement in Covid management that become evident when taking a systems perspective. Critical time delays occurred in the regulation of the pandemic that the management cycle of political cybernetics makes explicit. In general, the executive management of the pandemic in global, regional, and national organizations was unprepared in detecting and responding to the onset of the waves and making appropriate decisions towards differential instead of general lockdowns based on available data. This was further complicated by the mutants of SARS-CoV2 that perpetuated the high dynamics of the pandemic. In addition, the diversity of medical specialisms, without appropriate big picture thinking, led to an imbalanced response that failed to appreciate the role of virology and epidemiology compared to clinical and public health-related issues. In consequence, laboratory experts suggested everyday regulations for the citizens without taking into account wider considerations for empirical research. There was an insufficient effort made for proposed treatment studies using existing agents based on the established understanding of essential physiology and the role of local and systemic chronic inflammation. In contrast, driven by media popularization, drugs that later proved beneficial were put in doubt and other drugs that lacked benefit and potentially caused harm were driven to clinical trials and utilization. Person-centered systems view backed by scientific knowledge and established data would have set better priorities. Finally, we need to take a step back and consider the Corona crisis pandemic in the context of the unidimensional utility-driven handling of natural ecosystems by the culture of industrialized countries. This ever-accelerating destruction of life spaces for species drives adaptations are the basis of zoonoses. There is strong evidence that future pandemics should be faced with a more systemic socio-ecological conceptual framework that also reflects the fatal impact of human civilization on natural ecosystems, no matter if SARS CoV2 is a zoonosis or a laboratory accident. It is critical for the future of our species that we collectively learn from this experience, address limitations in our perspectives, enhance our system-based science and bolster global, regional, and national crisis management. The impact of climate change and biodiversity loss has crossed the horizon and is now clearly in full sight.

The COVID-19 era: No longer business as usual.

The paper proposes an alternative cyclical economy based on eco-villages supporting urban hubs to regenerate rural-urban balance based on public education to support eco-facturing, to use Gunter Pauli's concept. The paper sketches an alternative cyclical economy based on eco-villages supporting urban hubs to regenerate rural-urban balance based on eco-facturing. Australia lost over 40 million acres of habitat and at least a billion creatures during the 2019-2020 bushfire season. Africa and Asia are also rapidly urbanizing and rapidly losing habitat. The paper outlines the way in which we could live differently by understanding that production, consumption and regeneration need to follow a natural ecological approach, rather than the current approach to extracting profit at the expense of future generations. Production and regeneration need to be conducted in ways that do not exploit people and the environment. Exchange practices need to ensure that the interests of the few are not expended at the expense of the many.

Randomized comparison of 2 different methods of intrabronchial lidocaine delivery during flexible bronchoscopy: a pilot study.

BACKGROUND: Adequate anesthesia during bronchoscopy is essential for patient comfort and tolerance, and for achieving a good sample yield. The Enk device was designed for use during anesthesia for awake intubations. The objective of this study was to compare patient tolerability and frequency of cough during flexible bronchoscopy according to the method of administration of local anesthetic. METHODS: Patients were randomized to receive topical lidocaine either nebulized through an Enk device or with conventional injection through the working channel of the bronchoscope. All patients, physicians, and the assisting nurse completed a questionnaire that included items on tolerability, ease of procedure, frequency of cough, etc. The response was marked on a 10-cm-long visual analog scale, with a higher score indicating better outcome. RESULTS: Fifty patients were divided into 2 groups of 25 patients each. The mean ± standard deviation duration of procedure was no different in the Enk group than in the syringe group (12.8 ± 7.5 and 10.8 ± 6.9 min, respectively). There was no statistically significant difference between the 2 groups in the scores of each of the questions. CONCLUSIONS: The Enk device showed a nonsignificant trend toward greater ease of procedure for the operator with no difference in the frequency of cough. For the patients, there was no significant difference. A further investigation through comparison with other methods, such as transtracheal installation, over a larger population may yield more significant results. TRIAL REGISTRATION: This trial was registered with the Local Research Ethics Committee and with International Standard Randomised Controlled Trial Number.

Diagnostic utility of endobronchial ultrasound guided transbronchial needle aspiration for mediastinal lesions: A prospective three year, single centre analysis.

BACKGROUND: The diagnostic yield of endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) over a 3-year period was analyzed. METHODS: Consecutive patients who underwent EBUS for the evaluation of pulmonary/mediastinal lesions were recruited. RESULTS: One hundred and ninety-one patients were studied (54% male, mean age, 65 years [standard deviation 11.1]). A final diagnosis of a malignant disorder was made in 151 patients (79%). Of these, EBUS-TBNA alone provided the diagnosis in 135 patients. The majority of the remaining 56 patients had reactive changes (n = 32). Nineteen patients, either because they did not respond to appropriate treatment or based on clinical indication, underwent a different procedure resulting in an additional diagnosis of malignancy in 16 patients, tuberculosis in one and indeterminate in two. The diagnostic yield of EBUS for malignant disorders was 70.7% (95% confidence interval (CI), 0.86, 0. 77). The overall ability of EBUS to achieve a definitive diagnosis (benign plus malignant) was 90.1% (95% CI, 0.85, 0. 94). Logistic regression and stepwise regression analysis revealed that older age, greater lymph node size, and the presence of intraprocedure complications significantly influenced EBUS yield for malignancy. CONCLUSION: EBUS-TBNA has a high diagnostic yield for mediastinal lesions, both benign and malignant. The yield depends on both lesion- and patient-related factors.

Performance characteristics of semirigid thoracoscopy in pleural effusions of undetermined etiology.

BACKGROUND: The utility of the recently introduced semirigid thoracoscopy in undiagnosed pleural effusions is still unclear. METHODS: A single-center, 4-year retrospective analysis of all semirigid medical thoracoscopy procedures was done. The diagnostic accuracy of thoracoscopy was calculated as the number of positive diagnoses achieved by thoracoscopy in relation to the end-diagnosis achieved in the patient group by any means. RESULTS: One hundred fifty procedures were analyzed. Ninety-two patients (62.3%) were diagnosed as having a malignant disorder, of which mesothelioma was the most common (26%). Pleural thickening and nodularity were the most common abnormalities noted. The combined presence of nodules and hemorrhagic fluid increased the likelihood of malignancy 9-fold. Thirteen patients with a high clinical suspicion of malignancy but negative by thoracoscopy underwent mediastinoscopy, computed tomography-guided biopsy, or open thoracotomy. A malignant etiology was confirmed in all of them. Overall, thoracoscopy provided a diagnostic accuracy of 91.3%, sensitivity of 87%, and specificity of 100%. The addition of a second procedure in selected patients improved the diagnostic accuracy for malignancy by 8.7%. The procedures were well tolerated and only 6 patients developed minor and transient complications such as pain, hypoxia, and bradycardia. CONCLUSION: Semirigid thoracoscopy is a safe, well-tolerated, and efficacious procedure for establishing the diagnosis in pleural effusions of undetermined etiology.