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This is the first case report of decubitus infection and bacteremia due to Veillonella parvula ( V. parvula ). A patient in his 70s with pre-existing diabetes mellitus was admitted with decubitus infection, and tazobactam/piperacillin treatment was initiated. Tazobactam/piperacillin-resistant V. parvula was detected in the blood and decubitus site cultures. The antimicrobial treatment was changed to clindamycin and cefmetazole. Antimicrobial therapy was administered for 28 days. The patient was transferred to a convalescent hospital. V. parvula occasionally causes infection in immunocompromised patients with underlying diseases, such as diabetes. An appropriate evaluation by culture test is important for diagnosis, treatment, and recurrence prevention. Tazobactam/piperacillin is often used in the treatment of multi-bacterial infections such as decubitus infections. V. parvula may be resistant to tazobactam/piperacillin, and this possibility should be taken into account when administering treatment., Competing Interests: None.

Background: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance., Methods: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties., Results: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04)., Conclusions: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials., Competing Interests: Potential conflicts of interest. D. L. P. has received research funding from Shionogi, Merck, Gilead, bioMérieux, BioVersys, and Pfizer; has received consulting fees from the AMR Action Fund, CARB-X, Aurobac, Innoviva, GSK, Pfizer, Merck, Cepheid, bioMérieux, and Spero; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Merck, bioMérieux, and Cepheid; reports receipt of consumables for use in clinical trial from bioMérieux and receipt of antibiotics for use in clinical trials from Pfizer and Shionogi; and reports an unpaid role on the board of the Australasian Society of Infectious Diseases. M. H. is an employee of Pfizer and holds Pfizer stock options. Y. M. has received honoraria from Pfizer. P. N. A. H. reports research grants from Gilead; served on an advisory board for Sandoz; received honoraria from OpGen, Gilead, and Pfizer; and received travel support and accommodation for a speaking event from Pfizer. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The standard treatment for an infected pressure ulcer (PU) with osteomyelitis is debridement, wound coverage and antibiotic administration. However, systemic administration of antibiotics in patients with osteomyelitis is controversial, and the optimal treatment duration for chronic osteomyelitis has not been standardised. We report a case of sudden severe thrombocytopenia induced by piperacillin/tazobactam (PIPC/TAZ) in a patient with PU-related osteomyelitis. A 57-year-old male patient with paraplegia, using a wheelchair full-time, presented to our plastic surgery department with infection of a stage IV hard-to-heal ischial PU. We surgically debrided the necrotising tissue and raised an ipsilateral biceps femoris musculocutaneous propeller flap for wound coverage. Polymicrobial infections, including Pseudomonas aeruginosa , were detected in the bone biopsy sample; therefore, systemic PIPC/TAZ was administered for the osteomyelitis. Unexpectedly, during the next 12 days of antibiotic administration, the patient's platelet count acutely dropped to 1×10 3 /μl over three days. Based on a series of examinations, PIPC/TAZ was suspected to be the most likely cause of the severe thrombocytopenia. After drug discontinuation, the thrombocytopenia gradually improved. PIPC/TAZ is one of the most widely used antibiotic combinations in the plastic surgery field; it is conventionally administered for hard-to-heal wounds such as PUs and diabetic foot. The present case suggests that surgeons must take special precautions for patients undergoing PIPC/TAZ treatment. In this report, PIPC/TAZ-induced thrombocytopenia and the efficacy of antibiotic treatment for PU-related osteomyelitis are discussed in light of the available literature.

Objectives: WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam., Methods: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination., Results: We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required., Conclusions: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Antibiotic treatment is crucial for patients with chronic bacterial infections. Suspected drug allergies often lead to inconsistent therapies and challenging clinical management for patients and caregivers. The objective of this study was to evaluate the value of lymphocyte transformation tests in comparison to skin tests for the prediction of delayed-type allergic reactions., Methods: This prospective, observational study tested the diagnostic value of skin prick tests, intradermal tests (reading: 15 min and 72 h) and lymphocyte transformations tests for the prediction of allergic reactions in CF patients with physician reported allergy to piperacillin/tazobactam, meropenem and ceftazidime. The tests were performed directly before a 14d intravenous drug challenge., Results: We performed 33 drug challenges in 29 subjects. 21 drug challenges were negative (63 %); 12 lead to a reaction (37 %), of those 2 were immediate and 10 were delayed-type. 100 % of the skin prick tests were negative. 97 % (33/34) of the intradermal tests with early reading and 100 % of the intradermal tests with late reading yielded negative results. 5/11 patients who experienced a delayed-type reaction during the drug challenge had a positive lymphocyte transformations test. All 17 patients who did not react had a negative lymphocyte transformations test. For piperacillin/tazobactam, 4/5 patients who experienced a delayed-type reaction during the drug challenge had positive lymphocyte transformations tests. Hence, for piperacillin/tazobactam, the sensitivity of the lymphocyte transformation test for prediction of reactions was 80.0 % and the specificity 100 %., Conclusion: We demonstrate that the lymphocyte transformation test predicts delayed-type allergy to piperacillin/tazobactam in contrast to skin tests., Competing Interests: Declaration of Competing Interest JR has received payments for lectures from Vertex Pharmaceuticals outside of the submitted work. MAM received grants from Vertex Pharmaceuticals; and personal fees for participation in advisory boards, consultancy and lectures from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. DJN has received research grants from Merck, AstraZeneca, GSK, and Janssen Pharmaceuticals to study mechanisms of drug hypersensitivity. However, this funding does not directly relate to the research described in this manuscript. Other authors have no conflicts to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: The problem of resistance to beta-lactam antibiotics, which is caused by ESBL and AmpC β-lactamases, is getting worse globally. Infections caused by bacterial isolates harboring these enzymes are difficult to treat with carbapenems being the sole effective treatment option for such infections. The objective of this study was to determine the frequency of ESBLs and AmpC-producing Gram-negative bacilli isolated from clinical specimens and to evaluate the sensitivity of cefepime-tazobactam combination against them., Methods: This is an observational cross-sectional study carried out on 100 Gram-negative bacilli at Theodor Bilharz Research Institute Hospital during the period from February 2015 to January 2016. ESBL production was screened by using the disc diffusion test followed by confirmation by the combined disc confirmatory test, the screening for AmpC production was conducted using the cefoxitin disc test, which was subsequently confirmed by the AmpC disc test. Isolates confirmed positive for ESBL and/ or AmpC production were investigated for their susceptibility to antibiotics., Results: Among 100 Gram-negative bacilli, 44 isolates were confirmed as ESBL producers by the combined disc confirmatory test out of 56 isolates that tested positive for ESBL production through the disc diffusion test. The presence of AmpC production was assessed using the cefoxitin disc test, 32 isolates were screened to be AmpC producers, and the AmpC disc test confirmed AmpC production in 9 isolates of them. Using the Mast® D68C set, 32 isolates were ESBL producers, 3 were AmpC producers, and 4 isolates were ESBL/AmpC co-producers. The highest sensitivity was to cefepime-tazobactam (91.48%) followed by the carbapenems., Conclusion: Cefepime-tazobactam showed remarkable activity against ESBL and/or AmpC-producing Gram-negative bacilli and may be considered as a therapeutic alternative to carbapenems., (© 2024. The Author(s).)

Objectives: To assess the agreement between clinical cardiovascular adrenergic function and cardiac adrenergic innervation in type 2 diabetes patients (T2D)., Methods: Thirty-three patients with T2D were investigated bimodally through (1) a standardized clinical cardiovascular adrenergic assessment, evaluating adequacy of blood pressure responses to the Valsalva maneuver and (2) 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy assessing myocardial adrenergic innervation measured as early and delayed heart heart/mediastinum (H/M) ratio, and washout rate (WR)., Results: T2D patients had significantly lower early and delayed H/M-ratios, and lower WR, compared to laboratory specific reference values. Thirteen patients had an abnormal adrenergic composite autonomic severity score (CASS > 0). Patients with abnormal CASS scores had significantly higher early H/M ratios (1.76 [1.66-1.88] vs. 1.57 [1.49-1.63], p < 0.001), higher delayed H/M ratios (1.64 [1.51:1.73] vs. 1.51 [1.40:1.61] (p = 0.02)), and lower WR (-0.13(0.10) vs -0.05(0.07), p = 0.01). Lower Total Recovery and shorter Pressure Recovery Time responses from the Valsalva maneuver was significantly correlated to lower H/M early (r = 0.55, p = 0.001 and r = 0.5, p = 0.003, respectively) and lower WR for Total Recovery (r = -0.44, p = 0.01)., Conclusion: The present study found impairment of sympathetic innervation in T2D patients based on parameters derived from MIBG cardiac scintigraphy (low early H/M, delayed H/M, and WR). These results confirm prior studies. We found a mechanistically inverted relationship with favourable adrenergic cardiovascular responses being significantly associated unfavourable MIBG indices for H/M early and delayed. This paradoxical relationship needs to be further explored but could indicate adrenergic hypersensitivity in cardiac sympathetic denervated T2D patients., Competing Interests: Declaration of competing interest We report no potential conflicts of interest in relation to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Classification of vibrational spectra is often challenging for biological substances containing similar molecular bonds, interfering with spectral outputs. To address this, various approaches are widely studied. However, whilst providing powerful estimations, these techniques are computationally extensive and frequently overfit the data. Shrinkage priors, which favour models with relatively few predictor variables, are often applied in Bayesian penalisation techniques to avoid overfitting., Methods: Using the logit-normal continuous analogue of the spike-and-slab (LN-CASS) as the shrinkage prior and modelling, we have established classification for accurate analysis, with the established system found to be faster than conventional least absolute shrinkage and selection operator, horseshoe or spike-and-slab. These were examined versus coefficient data based on a linear regression model and vibrational spectra produced via density functional theory calculations. Then applied to Raman spectra from saliva to classify the sample sex., Results: Subsequently applied to the acquired spectra from saliva, the evaluated models exhibited high accuracy (AUC>90 %) even when number of parameters was higher than the number of observations. Analyses of spectra for all Bayesian models yielded high-classification accuracy upon cross-validation. Further, for saliva sensing, LN-CASS was found to be the only classifier with 100 %-accuracy in predicting the output based on a leave-one-out cross validation., Conclusions: With potential applications in aiding diagnosis from small spectroscopic datasets and are compatible with a range of spectroscopic data formats. As seen with the classification of IR and Raman spectra. These results are highly promising for emerging developments of spectroscopic platforms for biomedical diagnostic sensing systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We evaluated the performance of automated susceptibility testing for piperacillin/tazobactam (PTZ) MICs against the reference microbroth dilution method. The Minimum Inhibitory Concentration of PTZ against a clinical isolate of Klebsiella pneumoniae was determined by reference broth micro-dilution method in 10 replicates which yielded a modal MIC of 16 mg/L (susceptible dose-dependent). Out of 434 laboratories who obtained MIC of 16 mg/L correctly, only 301 interpreted the result as susceptible dose dependent as per 2022 revised CLSI criteria. Educating the clinical laboratories in validating AST methods as per latest CLSI guidelines is of utmost important., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Electricity consumption and anaerobic reactions cause direct and indirect greenhouse gas (GHG) emissions within domestic sewage treatment systems (DSTSs). GHG emissions in DSTSs were influenced by the sewage quantity and the efficacy of treatment technologies. To address combined effects of these variables, this study presented an approach for identifying pathways for GHG mitigation within the DSTSs of cities under climate change and socio-economic development, through combining life cycle analysis (LCA) and the Hierarchical Archimedean copula (HAC) methods. The approach was innovative in the following aspects: 1) quantifying the GHG emissions of the DSTSs; 2) identifying the correlations among temperature changes, socioeconomic development, and domestic sewage quantity, and 3) predicting the future fluctuations in GHG emissions from the DSTSs. The effectiveness of the proposed approach was validated through its application to an urban agglomeration in the Pearl River Delta (PRD), China. To identify the potentials of GHG mitigation in the DSTSs, two pathways (i.e., general and optimized) were proposed according to the different technical choices for establishing facilities from 2021 to 2030. The results indicated that GHG emissions from the DSTS in the PRD were [3.01, 4.96] Mt CO 2 eq in 2021, with substantial contributions from Shenzhen and Guangzhou. Moreover, GHG emissions from the sewage treatment facilities based on Anaerobic-Anoxic-Axic (AAO) technology were higher than those based on other technologies. Under the optimized pathway, GHG emissions, contributed by the technologies of Continuous Cycle Aeration System (CASS) and Oxidation Ditch (OD), were the lowest. Through the results of correlation analysis, the impact of socioeconomic development on domestic sewage quantities was more significant than that of climate change. Domestic sewage quantities in the cities of the PRD would increase by 4.10%-28.38%, 17.14%-26.01%, and 18.15%-26.50% from 2022 to 2030 under three Representative Concentration Pathways (RCPs) 2.6, 4.5, and 8.5. These findings demonstrated that the capacities of domestic sewage treatment facilities in most cities of the PRD should be substantially improved from 0.12 to 2.99 times between 2022 and 2030. Under the optimized pathway, the future GHG emissions of the CASS method would be the lowest, followed by the OD method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: The study was a methodological conducted to evaluate the validity and reliability of the Turkish version of the Diabetes Caregiver Activity and Support Scale (D-CASS)., Methods: This study was included on 272 individuals who cared for patients diagnosed with type 2 diabetes at least one year ago. Language, content, internal criterion, construct-concept validity were used to test the validity of the scale, and cronbach alpha, item-scale correlation, and test-retest were used to test the reliability., Results: The CVI was 0.95. The study was conducted with 272(60.3% female, 39.7% male) caregivers of individuals with type 2 diabetes. The study was found four week test-retest reliability with r = 0.70, p < 0001. The factor loadings of the scale items are between 0.77 and 0.95. The single factor obtained explains 75% of the total variance. The scale was found to have a high degree of reliability (Cronbach alpha=0.95)., Conclusion: The activities and supportive behaviours scale of caregivers of individuals with type 2 diabetes(D-CASS) is a valid and reliable measurement tool that can be used for the Turkish population., Competing Interests: Declaration of Competing Interest There was no conflict of interest among the authors involved in this study and with the caregivers participating in the study., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended., (© 2024. The Author(s).)

Importance: Treatment satisfaction is important to achieving therapeutic success in patients with inflammatory dermatological diseases, such as acne., Objective: To evaluate the structural validity, internal consistency, and construct validity of the DermSat-7, a questionnaire-based measure of treatment satisfaction, in patients with acne seen in routine clinical practice., Design, Setting, and Participants: This cross-sectional study included adults with acne who were fluent in English and treated at an outpatient clinic at Brigham and Women's Hospital between July 2022 and May 2023. At each visit, patients completed a self-administered, patient-reported outcome questionnaire, including a patient global assessment (PGA) of their acne severity and the DermSat-7. The DermSat-7 consists of 7 items assessing 3 domains of treatment: effectiveness (3 items), convenience (3 items), and overall satisfaction (1 item). At subsequent visits, patients were asked an anchor item related to change in disease severity ("How has your acne changed compared to your last visit?") that was scored on a 7-point scale (-3 = much worse to 3 = much better). Also at each visit, a dermatologist completed the Comprehensive Acne Severity Scale (CASS)., Main Outcomes and Measures: The main outcomes were structural validity (assessed by factor analysis), internal consistency (assessed by Cronbach α), and construct validity (assessed using linear regression models and Pearson correlation coefficients)., Results: The analysis included 142 patients with acne (mean [SD] age, 25.1 [5.1] years; 96 females [67.6%]) taking acne medication who completed the DermSat-7. Exploratory factor and confirmatory factor analysis supported the unidimensionality of the 3 DermSat-7 domains. Cronbach α values of 0.89 and 0.80 supported good internal consistency in the effectiveness and convenience domains, respectively. Known-groups validity was supported by increasing DermSat-7 effectiveness and overall satisfaction scores with increasing levels of positive change in disease severity (linear regression coefficient, 7.51; 95% CI, 4.94-10.08; P < .001). Construct validity was further supported by moderate correlations with the anchor, PGA, and CASS scores (effectiveness domain: anchor r = 0.567, PGA r = -0.538, and CASS r = -0.485; overall satisfaction domain: anchor r = 0.467, PGA r = -0.486, and CASS r = -0.489)., Conclusion and Relevance: This cross-sectional study found that the DermSat-7 may be an effective tool for measuring treatment satisfaction, particularly effectiveness and overall satisfaction domains, among patients with acne. Further research is needed to examine additional measurement properties of the DermSat-7, such as content validity and interpretability, as well as to validate the DermSat-7 in other populations of patients with acne.

In recent years, carbonaceous aerosols (CA) have been recognized as a significant contributor to the concentration of particles smaller than 2.5 μm (i.e., PM 2.5 ), with a negative impact on public health and Earth's radiative balance. In this study, we present a method for CA apportionment based on high-time-resolution measurements of total carbon (TC), black carbon (BC), and spectral dependence of absorption coefficient using a recently developed Carbonaceous Aerosol Speciation System (CASS). Two-year-long CA measurements at two different locations within California's Los Angeles Basin are presented. CA was apportioned based on its optical absorption properties, organic or elemental carbon composition, and primary or secondary origin. We found that the secondary organic aerosols (SOA), on average, represent >50 % of CA in the study area, presumably resulting from the oxidation of anthropogenic and biogenic volatile organic components. Remarkable peaks of SOA in summer afternoons were observed, with a fractional contribution of up to 90 %. On the other hand, the peak of primary emitted CA, consisting of BC and primary organic aerosol (POA), contributed >80 % to the CA during morning rush hours on winter working days. The light absorption of BC dominated over the brown carbon (BrC), which contributed to 20 % and 10 % of optical absorption at the lower wavelength of 370 nm during winter nights and summer afternoons, respectively. The highest contribution of BrC, up to 50 %, was observed during the wildfire periods. Although the uncertainty levels can be high for some CA components (such as split between primary emitted and secondary formed BrC during winter nights), further research focused on the optical properties of CA at different locations may help to better constrain the parameters used in CA apportionment studies. We believe that the CASS system combined with the apportionment method presented in this study can offer simplified and cost-effective insights into the composition of carbonaceous aerosols., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: At the time of the research, Matic Ivančič, Asta Gregorič, Gašper Lavrič, Bálint Alföldy, Irena Ježek, and Martin Rigler were also employed by the manufacturer of the Aethalometer and Total carbon analyzer instruments. Other authors declare no conflict of interest. The views expressed in this document are solely those of the authors and do not necessarily reflect those of the South Coast AQMD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We explored the differences in baseline characteristics, pathogens, complications, outcomes, and risk factors between children with hospital-acquired septic shock (HASS) and community-acquired septic shock (CASS) in the pediatric intensive care unit (PICU)., Methods: This retrospective study enrolled children with septic shock at the PICU of Beijing Children's Hospital from January 1, 2016, to December 31, 2019. The patients were followed up until 28 days after shock or death and were divided into the HASS and CASS group. Logistic regression analysis was used to identify risk factors for mortality., Results: A total of 298 children were enrolled. Among them, 65.9% (n = 91) of HASS patients had hematologic/oncologic diseases, mainly with Gram-negative bacterial bloodstream infections (47.3%). Additionally, 67.7% (n = 207) of CASS patients had no obvious underlying disease, and most experienced Gram-positive bacterial infections (30.9%) of the respiratory or central nervous system. The 28-day mortality was 62.6% and 32.7% in the HASS and CASS groups, respectively (P < 0.001). Platelet [odds ratio (OR) = 0.996, 95% confidence interval (CI) = 0.992-1.000, P = 0.028], positive pathogen detection (OR = 3.557, 95% CI = 1.307-9.684, P = 0.013), and multiple organ dysfunction syndrome (OR = 10.953, 95% CI = 1.974-60.775, P = 0.006) were risk factors for 28-day mortality in HASS patients. Lactate (OR = 1.104, 95% CI = 1.022-1.192, P = 0.012) and mechanical ventilation (OR = 8.114, 95% CI = 1.806-36.465, P = 0.006) were risk factors for 28-day mortality in patients with CASS., Conclusions: The underlying diseases, pathogens, complications, prognosis, and mortality rates varied widely between the HASS and CASS groups. The predictors of 28-day mortality were different between HASS and CASS pediatric patients with septic shock., (© 2022. The Author(s).)

Competing Interests: Conflict of interest: Olivier Varenne reports grants from Abbott Vascular and Boston Scientific, lecture fees from Abbott Vascular, Astra Zeneca, Servier, Boston Scientific and transport from Astra Zeneca. Fabien Picard reports research, consulting and speaking fees from from Astra-Zeneca, Bayer, BBraun, Biotronik, BMS-Pfizer Alliance, Boston Scientific, and Sanofi, outside the submitted work. Alain Cariou reports lecture fees from Bard. Vincent Pham has nothing to disclose.

The present study deals with developing vermiculite (VMT)-alginate (Alg) composites with different cross-linker concentrations (CaCl 2 ) to deliver the controlled 6-aminopenicillin acid (6-APA). The Characterization of synthesized composites was conducted by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analyses. Optimization attempts were explored via the response surface method (RSM) to best predict the actual amount of compound. The adsorption capacity of 6-APA onto this adsorbent was found to be 208.33 mg/g, which was higher than that for other clays. The equilibrium and Kinetic studies (chemical reaction and diffusion-based models) indicated that drug absorption on VMT-Alg is homogeneous with chemical interaction. An increase in cross-linker (CaCl 2 ) concentration leads to improvement in the drug encapsulation efficiency while having no significant effect on loading efficiency. The in-vitro release of the pure drug shows a rapid burst release followed by 100% cumulative release within 6 h. Whereas, the synthesized drug with Alg substantially showed less release of 43% after 8 h. Release experiments revealed that the presence of the CaCl 2 delayed the release of the 6-APA less than 35% after 12 h. The kinetic release of 6-APA is followed by the Korsmeyer-Peppas model based on Fick's law mechanism due to the kinetic exponent ( n  < 0.5). All studied composites antibacterial activity after 24 h exposure against E. Coli and S. aureus . The antibacterial activities of composites were evaluated by the halo of no growth. The results showed that the VMT-Alg-6APA composite had strong activity against Gram-positive and Gram-negative bacteria.

Processes employed in separations of products of enzyme reactions are often driven by diffusion, and their efficiency can be limited. Here, we exploit the effect of a direct current (DC) electric field that intensifies mass transfer through a semipermeable membrane for fast, continuous, and selective separation of electrically charged molecules. Specifically, we separate low-molecular-weight reaction products (phenylacetic acid, 6-aminopenicillanic acid) from the original reaction mixture containing a free enzyme (penicillin acylase). The developed microfluidic dialysis-membrane contactor allows a stable counter-current arrangement of the retentate and permeates liquid streams on which DC electric field is perpendicularly applied. The applied electric field significantly accelerates the transport of electrically charged products through the semipermeable membrane yielding high separation efficiencies at short residence times. The residence time of 5 min is sufficient to reach 100% separation yield in the electric field. The same residence time provides only a 50% yield in the diffusion-controlled experiments. We experimentally demonstrated that a combined microreactor-microextractor with a recycle of the soluble penicillin acylase can continuously produce both the reaction products at high concentrations. The developed membrane-contactor is a versatile platform allowing to tune its characteristics, such as selectivity given by the membrane, or the type of the retentate phase, for a specific application., (© 2020 Wiley Periodicals LLC.)

Substantial concentrations of penicillin V potassium (PVK) have been found in livestock manure, soil, and wastewater effluents, which may pose potential threats to human health and contribute to the emergence of penicillin-resistant bacterial strains. In this study, bacterial strains capable of degrading PVK were isolated from sludge and characterized. Strain X-2 was selected for biodegradation of PVK. Based on morphological observations and 16S rRNA gene sequencing, strain X-2 was identified as an Ochrobactrum tritici strain. To enhance the PVK degradation ability of PVK, a whole-cell biodegradation process of Ochrobactrum tritici X-2 was established and optimized. In the whole-cell biodegradation process, the optimal temperature and pH were 30°C and 7.0, respectively. Under the optimized conditions, the degradation rate using 0.5 mg/ml PVK reached 100% within 3 h. During biodegradation, two major metabolites were detected: penicilloic acid and phenolic acid. The present study provides a novel method for the biodegradation of PVK using Ochrobactrum tritici strains, which represent promising candidates for the industrial biodegradation of PVK. IMPORTANCE Substantial concentrations of penicillin V potassium (PVK) have been found in the environment, which may pose potential threats to human health and contribute to the emergence of penicillin-resistant bacterial strains. In this study, antibiotic-degrading bacterial strains for PVK were isolated from sludge and characterized. Ochrobactrum tritici was selected for the biodegradation of PVK with high efficiency. To enhance its PVK degradation ability, a whole-cell biodegradation process was established and optimized using Ochrobactrum tritici The degradation rate with 0.5 mg/ml PVK reached 100% within 3 h. The potential biodegradation pathway was also investigated. To the best of our knowledge, the present study provides new insights into the biodegradation of PVK using an Ochrobactrum tritici strain, a promising candidate strain for the industrial biodegradation of β-lactam antibiotics., (Copyright © 2020 Wang et al.)

Piperacillin is a broad spectrum beta-lactam antibiotic used in combination with tazobactam for hospital-related bacterial infections. The reconstituted solutions must respect the sub-visible and visible particles specifications. It was claimed that the reformulation containing EDTA/sodium citrate was able to control the formation of an insoluble impurity responsible for the formation of particulate matter observed using Ringer Lactate as diluent. The nature of the impurities formed during the degradative process of piperacillin/tazobactam combination has been herein investigated, by exploring the effect of added excipients and pH variations. The exact structure of the isolated dimeric impurity, the penicilloic acid-piperacillin dimer, was determined through complete characterization, allowing to propose a novel degradative general pathway for beta-lactam antibiotics. The presence of EDTA resulted unnecessary to contain the formation of the insoluble impurity, since the use of sodium citrate alone allowed to avoid this drawback. Finally, the proposed mechanism was successfully applied to the design of a novel, easy and high purity procedure for the synthesis of the acetylated penicilloic acid, known related substance of piperacillin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aqueous two-phase systems (ATPSs) were screened for the production of 6-aminopenicillanic acid (6-APA) catalyzed by penicillin acylase, followed by the extractive separation of 6-APA from the reaction mixture. The key point of this study was to find an ATPS exhibiting a large difference in the partition coefficients of the biocatalyst and reaction products. Several ATPSs based on polyethylene glycol (PEG)/phosphate, PEG/citrate, and PEG/dextran were tested. We found that an ATPS consisting of 15 wt% of PEG 4000, 10 wt% of phosphates, 75 wt% of water (pH value 8.0 after dissolution) provided optimal separation of 6-APA from the enzyme. While the 6-APA was mainly found in the top PEG phase, the free enzyme favored the bottom salt-rich phase. This ATPS also fulfils other important requirements: (i) high buffering capacity, reducing an undesirable pH decrease due to the dissociation of phenylacetic acid (the side product of the reaction), (ii) a relatively low cost of the ATPS components, (iii) the possibility of electrophoretic transport of fine droplets as well as the reaction products for both the acceleration of phase separation and the enhancement of 6-APA concentration in the product stream. Extraction experiments in microcapillary and batch systems showed that the transport of 6-APA formed in the salt-rich phase to the corresponding PEG phase could occur within 30 s. The experimental results described form a base of knowledge for the development of continuously operating integrated microfluidic reactors-separators driven by an electric field for the efficient production of 6-APA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Penicillin acylase is commonly used to produce the medical intermediates of 6-Aminopenicillanic acid (6-APA) and 7-Aminodesacetoxycephalosporanic acid (7-ADCA) in industrial process. Nowadays, Penicillin G acylase (PGA) has been widely applied for making pharmaceutical intermediates, while penicillin V acylase (PVA) has been less used for that due to its low activity and poor conversion. In this study, a PVA from Bacillus sphaericus (BspPVA) was employed for directed evolution study with hoping to increase its catalytic efficiency. Finally, a triple mutant BspPVA-3 (T63S/N198Y/S110C) was obtained with 12.4-fold specific activity and 11.3-fold catalytic efficiency higher than BspPVA-wt (wild type of BspPVA). Moreover, the conversion yields of 6-APA catalyzed by BspPVA-3 reached 98% with 20% (w/v) penicillin V as substrate, which was significantly higher than that of the BspPVA-wt (85%). Based on the analysis of modeling, the enhancement of specific activity of mutant BspPVA-3 was probably attributed to the changes in the number of hydrogen bonds within the molecules. The triple mutant PVA developed in this study has a potential for large-scale industrial application for 6-APA production., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers., Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae., Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study., Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician., Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used., Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group., Conclusions and Relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting., Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Purpose: The development of surgical site infection (SSI) after biliary reconstruction is highly influenced by the presence of preoperative bacteria in the bile juice. We selected vancomycin and piperacillin/tazobactam (VCM + PIPC/TAZ) as perioperative prophylactic antibiotics for patients undergoing pancreaticoduodenectomy. This study aimed to retrospectively analyze the effectiveness of VCM + PIPC/TAZ compared to cefmetazole., Methods: Seventy-two patients who underwent pancreaticoduodenectomy between April 2015 and March 2017 at our department were evaluated. Forty patients were administered cefmetazole as the perioperative prophylactic antibiotic, and 32 were administered VCM + PIPC/TAZ. The intraoperative VCM blood concentration (incision, biliary reconstruction, and wound closure) was measured during surgery to confirm the hemodynamics., Results: The frequency of SSIs was significantly lower in the VCM + PIPC/TAZ group (8/32 patients) than in the cefmetazole group (20/40 patients, P = 0.031). Postoperatively, significantly fewer patients in the VCM + PIPC/TAZ group (4/32 patients) required ≥ 15 days of additional antibiotic administration compared to those in the cefmetazole group (14/40 patients, P = 0.033). Six of 32 patients in the VCM + PIPC/TAZ group showed redneck syndrome symptoms. There was no significant difference in the VCM blood concentration between patients with and without SSIs., Conclusions: The use of VCM + PIPC/TAZ can reduce the incidence of SSI after pancreaticoduodenectomy and also reduce the need for the additional administration of antibiotics for ≥ 15 days after surgery.

A total of 18,656 Enterobacteriaceae and 4,175 Pseudomonas aeruginosa were consecutively collected from 85 US hospitals and tested for susceptibility by broth microdilution methods in a central monitoring laboratory (JMI Laboratories). The antimicrobial susceptibility and frequency of key resistance phenotypes were assessed and stratified by infection type as follows: bloodstream (BSI; 3,434 isolates; 15.0%), pneumonia (6,439; 28.2%), skin and skin structure (SSSI; 4,134; 18.1%), intra-abdominal (IAI; 951; 4.2%), and urinary tract (UTI; 7,873; 34.5%). Ceftazidime-avibactam was active against 99.9% to 100.0% of Enterobacteriaceae and 97.0% (pneumonia) to 99.4% (UTI) of P. aeruginosa isolates. Susceptibility rates were consistently lower for β-lactams, such as ceftazidime (82.3% vs. 87.1-90.8%), piperacillin-tazobactam (87.5% vs. 90.2-95.6%), and meropenem (96.8% vs. 98.4-99.4%) among Enterobacteriaceae from pneumonia compared to other infection types. Susceptibility to gentamicin was also generally lower among isolates from pneumonia, whereas susceptibility to levofloxacin and colistin were lowest among BSI and SSSI isolates, respectively. The occurrence of multidrug-resistance (MDR; 8.2% overall), extensively drug-resistance (XDR; 1.1% overall), and carbapenem-resistant Enterobacteriaceae (CRE; 1.3% overall) phenotypes were markedly higher among isolates from patients with pneumonia compared to other infection types. Among P. aeruginosa, susceptibility rates for ceftazidime, piperacillin-tazobactam, and gentamicin were lowest among isolates from pneumonia, whereas susceptibility to meropenem was similar among isolates from BSI, pneumonia, and IAI (77.3-77.9%), and susceptibility to levofloxacin was markedly lower among UTI isolates (67.1%). The frequencies of P. aeruginosa isolates with MDR and XDR phenotypes were highest among isolates from patients with pneumonia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ceftolozane/tazobactam is a combination intravenous antibiotic with potentially important activity against drug-resistant Gram-negative organisms. Ceftolozane/tazobactam's in vitro activity was evaluated in 30 samples collected from 23 adult cystic fibrosis patients with extended and pan-resistant Pseudomonas aeruginosa in 2015. Testing results demonstrated that 30% of the isolates were susceptible,13% were intermediate, and 57% were resistant. This suggests that ceftolozane/tazobactam may be a useful antibiotic in carefully selected, multidrug-resistant Pseudomonas isolates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pipercillin-tazobactam is a frequently used antibiotic that has a broad spectrum of antibacterial activity. The development of severe thrombocytopenia following the use of piperacillin-tazobactam is unusual. Several mechanisms have been proposed for the pathogenesis of thrombocytopenia in this setting which include immune and non-immune causes. Multiple case reports have shown the ability of piperacillin-tazobactam to cause drug-induced immune thrombocytopenia, likely through formation of antibodies that recognize platelets in the presence of soluble piperacillin. However, severe and rapid development of thrombocytopenia that occurs in association with reexposure to piperacillin-tazobactam has not been clearly demonstrated in the literature. We present two cases in whom severe and rapid development of thrombocytopenia has occurred subsequent to administration of piperacillin-tazobactam with a prior history of recent exposure to the drug. In both cases, thrombocytopenia improved immediately and dramatically following withdrawal of piperacillin-tazobactam with initiation of steroids and intravenous immunoglubulins, suggesting and immune related drug-induced thrombocytopenia.

CME: Fusobacterium nucleatum/naviforme - a Rare but Serious Cause for Pyogenic Liver Abscesses Abstract. Pyogenic liver abscesses belong to the most common abdominal infections. Beside the most common pathogens, also rare forms like Fusobacteria, which can also be part of the natural oropharyngeal and enteral microbiome, may be considered to cause severe forms of abscesses of the liver. Since they may be more difficult to detect, they could become a challenge during diagnosis and therapy.

The combination of piperacillin/tazobactam (TZP) and vancomycin (VAN) provides a wide spectrum of activity against many pathogens acquired in healthcare settings. However, there have been reports of increased potential for nephrotoxicity with this combination. The aim of this study was to evaluate the nephrotoxic effect of TZP+VAN and to compare it with that of TZP and VAN monotherapies as well as VAN + meropenem (MEM), another broad-spectrum combination. A total of 402 patients receiving any of the antimicrobial regimens for >48 h were evaluated retrospectively over a 2-year period (2012-2013). Patients admitted to the intensive care unit, those with a baseline serum creatinine >2.0 mg/dL, patients on haemodialysis or peritoneal dialysis, pregnant women and those in septic shock were excluded. The presence and severity of acute kidney injury (AKI) was assessed according to the AKIN criteria. The incidence of AKI was significantly higher in the TZP+VAN group (41.3%) compared with the TZP (16.0%), VAN (15.7%) and VAN+MEM (10.1%) groups (P < 0.001). In the multivariate analysis, the risk of AKI increased 3.5-fold in patients treated with TZP+VAN and 1.7-fold in those who were receiving a potentially nephrotoxic drug when the antibiotic regimen was started compared with patients treated with VAN alone. Combined use of TZP+VAN carries a much higher risk of AKI than either antibiotic monotherapy regimen. Therefore, this broad-spectrum combination should be used cautiously in patients with a high likelihood of developing kidney injury., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Acute appendicitis in children requires early surgery and short-course antibiotics active against Enterobacteriaceae and anaerobes. Although an aminoglycoside-containing three-drug regimen has been used successfully for decades, simpler regimens with similar efficacy are increasingly used. This study evaluated the impact of a switch from the combination of cefotaxime, metronidazole and gentamicin (regimen 1) to piperacillin/tazobactam (regimen 2) as first-line regimen for complicated acute appendicitis in children. In total, 171 children were enrolled [median (IQR) age, 10 (6-13) years], treated with regimen 1 (n = 80) or regimen 2 (n = 91) following surgery for complicated acute appendicitis. The two groups were comparable except for surgical approach (through laparoscopy in 46% vs. 88% for regimens 1 and 2, respectively; P < 0.001). Post-operative complications and duration of hospital stay were similar. Deviations from antibacterial treatment protocol decreased from 36% (29/80) to 14% (13/91) (P < 0.001), with a dramatic reduction in antibacterial treatment duration from median (IQR) of 15 (12-16) days to 5 (5-8) days (P < 0.001). Post-operative intra-abdominal abscess developed in 32 children (18.7%). Female sex (OR = 2.76, 95% CI 1.18-6.48; P = 0.02) and sepsis/septic shock on admission (OR = 4.72, 95% CI 1.12-19.97; P = 0.035) were independently associated with post-operative intra-abdominal abscess, but not antibacterial regimen. This study shows that simplification of first-line antibacterial regimen for complicated appendicitis in children was associated with reduced protocol deviation, reduced duration of antibiotics, and similar outcomes (post-operative complications and duration of hospital stay)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to evaluate the effectiveness of ceftolozane/tazobactam (C/T) for treating extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) infections, and to analyze whether high C/T dosing (2 g ceftolozane and 1 g tazobactam every 8 h) and infection source control have an impact on outcome., Methods: Retrospective study of all consecutive patients treated with C/T for XDR-PA infection at a tertiary referral hospital (November 2015-July 2017). Main clinical and microbiological variables were analyzed., Results: Thirty-eight patients were included. Median age was 59.5 years and Charlson Comorbidity Index was 3.5. Fourteen (36.8%) patients had respiratory tract infection, six (15.8%) soft tissue, and six (15.8%) urinary tract infection. Twenty-three (60.5%) received high-dose C/T and in 24 (63.2%) C/T was combined with other antibiotics. At completion of treatment, 33 (86.8%) patients showed clinical response. At 90 days of follow-up, 26 (68.4%) achieved clinical cure, and 12 (31.6%) had clinical failure because of persistent infection in one patient, death attributable to the XDR-PA infection in four, and clinical recurrence in seven. All-cause mortality was 5 (13.2%). Lower C/T MIC and adequate infection source control were the only variables significantly associated with clinical cure., Conclusions: C/T should be considered for treating XDR-PA infections, with infection source control being an important factor to avoid failure and resistance.

Predictors of mortality and the impact of multidrug resistance and virulence on patients with Pseudomonas aeruginosa (PA) bacteraemia were evaluated. Patients with PA bacteraemia in a 12-month period were retrospectively analysed. Carbapenemase production, molecular typing and identification of virulence factor ExoU were carried out. The activity of ceftolozane-tazobactam and ceftazidime-avibactam was also investigated. The primary endpoint was 30-day crude mortality. Of 64 patients with bacteraemia, 24 (37.5%) were caused by extensively drug-resistant PA (XDR-PA): 10 (41.7%) cases involved the VIM-2 carbapenemase-producing ST175 clone, 11 (45.8%) the GES-5 carbapenemase-producing ST235 clone, and 3 (12.5%) were non-carbapenemase producers. The exoU genotype was detected in all ST235 strains and in 6 (15%) of the non-XDR isolates. Ceftazidime-avibactam (58.3%) showed greater activity than ceftolozane-tazobactam (12.5%) against XDR-PA isolates, particularly in GES-5 producers (100%). The 30-day crude mortality rate in patients with XDR-PA bacteraemia was higher than in cases caused by susceptible strains (62.5% vs. 30%; P=0.02). Multivariate analysis showed that independent risk factors associated with 30-day crude mortality were Pitt score ≥2 (OR, 42.31; 95% CI, 4.88-366.7; P=0.001) and respiratory source of bacteraemia (OR, 49.13; 95% CI 3.89-620.5; P=0.003). Stratified analysis adjusting for respiratory source revealed a non-significant trend towards higher mortality in patients with bacteraemia caused by the ST235 clone and exoU-producing isolates. These data support the notion that the XDR phenotype associated with the GES-5 carbapenemase-producing ST235 clone and the exoU-positive genotype adversely affects the outcome of patients with PA bacteraemia, particularly those with respiratory tract infections and a severe clinical presentation., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: Although survival of children with hematological diseases and cancer has increased dramatically, life-threatening complications due to bacterial infections occur in 5-10% of febrile episodes in pediatric cancer patients. A prospective randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) with or without intravenous immunoglobulin (IVIG) as second-line therapy for pediatric patients with febrile neutropenia (FN)., Procedure: As first-line therapy for FN, 105 patients with 434 episodes were randomly assigned to receive MEPM or PIPC/TAZ. A total of 71 pediatric patients and 144 episodes were judged as failures and enrolled for second-line treatment. In second-line treatment, patients were randomized to a group of MEPM and PIPC/TAZ with or without IVIG. MEPM was given to patients who received PIPC/TAZ as first-line treatment, and PIPC/TAZ was given to patients who received MEPM as first-line treatment., Results: The total success rate of second-line therapy was 49.3%. MEPM with or without IVIG was effective in 44.3% of cases, and PIPC/TAZ with or without IVIG was effective in 55.3%; this difference was not significant. The success rate in patients with serum IgG under 1000 mg/dl was 41.3% in the MEPM or PIPC/TAZ group and 64.3% in the MEPM + IVIG or PIPC/TAZ + IVIG group (p = 0.028)., Conclusions: The present results suggest that PIPC/TAZ is as effective as MEPM and safe for second-line treatment of FN in pediatric patients. Furthermore, IVIG appears very effective for patients with low serum IgG levels., (Copyright © 2017. Published by Elsevier B.V.)

Background: Sepsis is a common diagnosis in critical care with inpatient mortality rates up to 50%. Sepsis care is organized around source control, antibiotics, and supportive care. Drug disposition is deranged by changes in volume of distribution and regional blood flow, as well as multiple organ failure. Thus, assuring that each patient with sepsis attains pharmacokinetic targets is challenging. There is currently no commercially available FDA-approved assay to measure piperacillin-tazobactam, very commonly used as a beta-lactam/beta-lactamase inhibitor combination antibiotic in the intensive care unit (ICU)., Methods: Samples were prepared by ultrafiltration of plasma collected in lithium heparin Vacutainers. Separation was achieved by gradient elution on a C-18 column followed by UV detection at 214 nm. The method is validated in residual blood samples allowing investigators to exploit a waste product to develop insight into beta-lactam pharmacokinetics in the ICU., Results: Accuracy and precision were within the 25% CLIA error standard for other antibiotic assays. Free piperacillin concentrations were also in good agreement with total piperacillin concentrations measured in the same plasma by an assay in clinical use outside the United States., Conclusion: We describe a method for measuring piperacillin and tazobactam that meets clinical validation standards. Quick turnaround time and excellent accuracy on a low-cost platform make this method more than adequate for use as a routine therapeutic drug monitoring tool., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this study, the activity of 18 non-carbapenem antibiotics was evaluated against 100 extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-Ec) and 50 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) isolated from urinary tract infections and bacteraemia in 2016. Minimum inhibitory concentrations (MICs) were determined using reference methods and the susceptibility profiles were defined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2017 recommendations. All of the ESBL-Ec isolates were susceptible to ceftazidime/avibactam and a great majority of them were susceptible to fosfomycin (98%), piperacillin/tazobactam (97%), amikacin (97%) and nitrofurantoin (96%). Mecillinam, cefoxitin and ceftolozane/tazobactam remained active against 92%, 83% and 78% of the ESBL-Ec isolates, respectively. Moreover, 100%, 94% and 90% of the ESBL-Kp tested were susceptible to ceftazidime/avibactam, amikacin and mecillinam, respectively. This study showed that there are non-carbapenem options (including orally administrable drugs) for the treatment of all of the situations of ESBL-Ec or ESBL-Kp infections, with ceftazidime/avibactam being the most efficient alternative., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The appropriate use of broad-spectrum antibiotics, including appropriate de-escalation, is essential to reduce the emergence of antibiotic resistance. In surgical floors antibiotics are prescribed for prophylaxis (mostly, single dose), empirical treatment (started if infection is suspected till bacteria are identified with its sensitivity to antibiotics), or treatment of well-defined infection of previously isolated bacteria with its sensitivity to antibiotics. In this study, we aimed to evaluate the use of broad-spectrum antibiotics based on requests for cultures and de-escalation based on sensitivity results of culture tests at tertiary care hospital., Method: A retrospective cohort study was conducted to evaluate the utilization of broad-spectrum antibiotics on surgical floors at a tertiary care center in Jeddah, Saudi Arabia. Patients who are admitted to surgical floors were included if they received any of three broad-spectrum antibiotics (piperacillin-tazobactam, imipenem-cilastatin or meropenem) from 1 June 2014 to 31 August 2014. Data were collected on whether culture and sensitivity test requests were made within 24h of starting antibiotics, the duration of antibiotic therapy and the number of days to de-escalation after receiving culture and sensitivity results., Results: Of the 163 patients who received broad-spectrum antibiotics, culture tests were requested in 112. Before receiving culture results, one patient was discharged and one died. The results of culture tests justified continuation of broad-spectrum antibiotics in only 22 patients, whereas 24 showed no microbial growth in any culture. De-escalation was delayed >24h after culture results became available in 33 out of 64 eligible patients. On the other hand, 51 patients continued receiving broad spectrum antibiotics without any culture test during the whole treatment course., Conclusion: The use of broad-spectrum antibiotics in surgical floors at a tertiary care hospital in Saudi Arabia was largely unjustified by culture-test result. Interventions are needed to enforce culture and sensitivity test requests within 24h of starting the broad spectrum antibiotics therapy with further follow up to ensure appropriate de-escalation and discontinuation whenever indicated., (Copyright © 2017. Published by Elsevier Ltd.)

A 66-year-old woman presented with 2 days of fever and severe diarrhoea. She has a history of ulcerative colitis (UC), well controlled with medication. She also has a history of Ehlers-Danlos syndrome, infective endocarditis following aortic valve replacement and pulmonary embolism. She had complained of passing stool with traces of blood about 30 times per day. Stool testing for Clostridium difficile, routine culture and microscopy was done. She was started on ceftriaxone. CT scan revealed thick-walled colon consistent with UC flare. Flexible sigmoidoscopy showed active continuous colitis extending from the rectum to the proximal descending colon. Campylobacter jejuni was isolated from the stool and blood cultures yielded Pseudomonas aeruginosa. The antibiotic was transitioned to intravenous piperacillin/tazobactam and azithromycin followed by 2 weeks of intravenous cefepime. Her diarrhoea was controlled, and she was discharged for follow-up in 2 months., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Rationale: Superior mesenteric venous thrombosis (SMVT) is a rare condition that carries high mortality. Very few cases have been reported of SMVT, complicating acute appendicitis. Early recognition requires a high index of suspicion and is crucial in successful treatment of such a life-threatening condition., Patient Concerns: A 33-year-old male presents with a 4-day history of right lower abdominal pain, nausea and subjective fever. CT scan showed acute appendicitis and a central filling defect in the superior mesenteric vein., Diagnoses: Acute appendicitis complicated by SMVT., Interventions: Intravenous antibiotics, appendectomy, and anticoagulation., Outcomes: Repeat CT scan showed successful resolution of the SMVT at a 3-month follow up., Lessons: Clinical awareness and high index of suspicion are essential to diagnose and manage SMVT, a serious complication of acute appendicitis.

This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from hospitalized patients in the United States. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 18,960 organisms (15,223 Enterobacteriaceae and 3,737 P. aeruginosa) were consecutively collected from 32 medical centers located in all nine U.S. census divisions from 2013 to 2016. Organisms were tested for susceptibility by broth microdilution. CLSI and EUCAST interpretive criteria were used. Ceftolozane-tazobactam (94.4% susceptible), amikacin (99.0% susceptible), and meropenem (98.0% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 1.9% (n = 286) were carbapenem-resistant Enterobacteriaceae (CRE) and 9.5% (n = 1,450) exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Although ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (87.5% susceptible), it lacked useful activity against CRE. Ceftolozane-tazobactam was the most potent β-lactam agent tested against P. aeruginosa isolates, with 97.3% susceptible. Only colistin was more active, inhibiting 99.5% of isolates. Ceftolozane-tazobactam also maintained good activity against multidrug-resistant P. aeruginosa, with 88.6% susceptible. Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and was more active than available cephalosporins and piperacillin-tazobactam against Enterobacteriaceae.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infection causes significant mortality among patients with hematologic malignancies and hematopoietic-cell transplant recipients. Ceftolozane-tazobactam (C-T) is a novel therapeutic option for MDR-P. aeruginosa infections but clinical experience in these patients is limited. We report favorable clinical outcomes and lack of limiting toxicities using C-T monotherapy to treat invasive MDR-P. aeruginosa infections in these patient populations.

Gram negative anaerobic organisms are important pathogens in a range of clinical infections, and susceptibility testing is not commonly performed in the microbiology laboratory. We performed anaerobic susceptibility testing on 70 clinically relevant Gram negative anaerobes isolated from routine cultures in a busy diagnostic laboratory which were identified by MALDI-TOF mass spectrometry (MALDI-TOF MS). The susceptibility testing was performed by two methods: Sensititre trays (ThermoFisher Scientific) against 15 different antibiotics, and Etests (bioMérieux) against five clinically relevant antibiotics (metronidazole, piperacillin-tazobactam, amoxicillin-clavulanate, meropenem and clindamycin). We found that all isolates were susceptible to metronidazole, and overall susceptibility to commonly used antibiotics such as piperacillin-tazobactam and amoxicillin-clavulanate was high (93-100% and 89-100%, respectively). Two isolates of Bacteroides fragilis were resistant to both broad spectrum β-lactams and carbapenems. Comparing the two methods, using Sensititre broth microdilution as gold standard, there was high categorical agreement (92-100%). Antibiograms provide useful information for clinicians when choosing antimicrobials for infections caused by anaerobic organisms. This study has shown that in our area, use of metronidazole as a broad spectrum anti-anaerobic agent remains appropriate. Anaerobic susceptibility testing is also important to perform in individual clinical isolates, especially from sterile sites or in pure culture. The emergence of broad spectrum β-lactam and carbapenem resistance in clinical isolates of Bacteroides fragilis is of concern and will require further monitoring. The Etest method was considered superior to Sensititre trays given that the higher inoculum used may allow demonstration of heteroresistance, anaerobiasis can be maintained during setup, lower failure rates, and the ability to select only the antibiotics required., (Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Piperacillin-tazobactam is common empiric antibiotic therapy. Hematologic laboratory test abnormalities were documented but rare in premarketing studies, and whether these alterations are of clinical significance has been studied little. Very few cases of piperacillin-induced bleeding, thrombocytopenia, or both have been reported; aberrations in platelet function have not been implicated., Case Description: A 55-year old Vietnamese man with hypertension presented for treatment of an Intracranial hemorrhage. Platelet function assays (PFAs) at the time of external ventricular drain and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. The patient was later started on empiric piperacillin-tazobactam due to high suspicion for aspiration pneumonia. After removal of the quad-lumen bolt and external ventricular drain on separate days, both follow-up computed tomography scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. Repeat PFAs were abnormally prolonged, representing a distinct change from baseline. A trend toward normalization of PFAs was observed 6 hours after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter., Conclusions: This is unique in that the significant bleeding that occurred was attributable to platelet dysfunction rather than thrombocytopenia. This is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)