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Background: Pseudomonas aeruginosa with difficult-to-treat resistance is a clinical burden. Ceftolozane/tazobactam is recommended for difficult-to-treat P. aeruginosa although cefiderocol represents an option due to its in vitro potency against isolates with ceftolozane/tazobactam-resistance. Head-to-head data assessing these compounds against difficult-to-treat P. aeruginosa are lacking., Objectives: To assess the efficacy and resistance development of cefiderocol and ceftolozane/tazobactam in a 72-h murine thigh infection model against five clinical difficult-to-treat P. aeruginosa isolates susceptible for both agents and previously developed resistance to ceftolozane/tazobactam in patients., Methods: Human-simulating regimens of ceftolozane/tazobactam (2/1 g IV q8h) and cefiderocol (2 g IV q8h) were utilized. Efficacy was assessed as the change in bacterial density from starting inoculum and compared to translational endpoints of 1- and 2-log 10 -kill. Development of resistance was defined as a post-exposure MIC increase greater than 4-fold dilutions., Results: Cefiderocol reached the 24h 1-log 10 -kill endpoint in all isolates; however, ceftolozane/tazobactam reached same endpoint in 3/5 isolates. Cefiderocol reached 2-log 10 -kill in all isolates by 48 h. Conversely, ceftolozane/tazobactam achieved same endpoint in four isolates by 72 h. In the cefiderocol and ceftolozane/tazobactam-treated groups 17% and 8% of the cultures displayed bacterial eradication after exposure to the human-simulating regimens which hinder MIC testing for those samples. Resistance was not detected for either antibiotic postexposure., Conclusion: Despite susceptibility to both cefiderocol and ceftolozane/tazobactam, cefiderocol provided a more rapid kill profile and achieved a greater magnitude of bactericidal activity relative to ceftolozane/tazobactam. While frank resistance did not develop to either compound, differences in the rate and extent of kill were observed. more...

Carbapenemases have had increasing prevalence within the United States and worldwide. Here, we present a case of carbapenem-resistant Klebsiella pneumoniae (CRKP) which is unique due to the rarity of multiple mechanisms of resistance within the Klebsiella pneumoniae harboring New Delhi metallo- β -lactamases (NDM), oxacillinase-48 (OXA-48)-like, and cefotaximase (CTX-M) resistance genes, detected in a patient following an international travel. This case demonstrates the need for a multidisciplinary approach to optimize the treatment of multidrug-resistant Gram-negative organisms., Competing Interests: C.M.G. has received research funding from Cepheid, Everest Medicines, Shionogi, and Entasis. The other authors declare no conflicts of interest., (Copyright © 2025 Christopher Phan et al. Case Reports in Infectious Diseases published by John Wiley & Sons Ltd.) more...

Background: Patients post hematopoietic stem cell transplant (HSCT) are highly susceptible to Clostridioides difficile infection (CDI). Exposure to antibiotic treatment, chemotherapeutic disruption to bacterial microbiome, immunosuppressive therapy, and prolonged hospitalizations synergistically contribute to the risk of CDI and its recurrence. The purpose of this study is to assess if the adjunctive administration of bezlotoxumab decreases the rate of recurrent CDI in patients post-HSCT., Study Design: This retrospective cohort study included patients post allogeneic or autologous HSCT with CDI who were 18 years of age or older. The first cohort included patients who received standard-of-care (SOC) treatment for CDI. The second cohort included patients who received standard of care treatment for CDI in addition to bezlotoxumab. The primary objective was the proportion of patients with recurrence of CDI within 12 weeks of initial diagnosis after treatment with bezlotoxumab plus SOC compared with controls receiving SOC alone., Results: The primary outcome occurred in 2.7% of patients in the bezlotoxumab plus SOC group, and 7.1% of patients in the SOC alone group. Results of the primary outcome were not statistically significant between groups. No difference in CDI recurrence occurred between the two groups (5.4% vs 7.1%) at 6 months. Bezlotoxumab administration was well-tolerated with no documented adverse reactions., Conclusion: In conclusion, the use of bezlotoxumab did not lead to statistically significant decreases in CDI recurrence in patients post-HSCT. Future studies should be conducted with a larger number of HSCT patients receiving bezlotoxumab to provide supporting evidence of its role in reducing CDI recurrence., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. more...

Study Design: Qualitative analysis of focus group data., Objective: Identifying barriers to and facilitators of learning to direct one's own care as a person with tetraplegia due to spinal cord injury (SCI)., Setting: Community, in New Jersey and Georgia, USA., Methods: Three focus groups of veterans and civilians with SCI, involving 26 people with chronic (≥1 year) tetraplegia due to SCI who provided direction to caregivers on a daily basis. Content analysis was used to identify barriers and facilitators., Results: Challenges to learning to direct one's care included: (1) lack of acceptance of lasting effects of SCI; (2) not yet understanding one's body post-SCI; (3) embarrassment; (4) being overwhelmed with information; (5) differences between the inpatient rehabilitation setting and the "real world"; (6) lack of capable and willing assistants; and (7) hesitance to criticize caregivers. Factors that helped participants become successful directors of care included: (1) experience living with SCI; (2) being observant; (3) communicating effectively; (4) developing confidence to advocate for one's own needs; (5) learning when to "let go" and when to speak up; and (6) learning from peers., Conclusions: Direction of care is a complex skill that is developed over time, and requires awareness of one's needs and preferences, self-confidence, and strong communication skills. Rehabilitation clinicians' efforts to prepare people with SCI to direct their own care effectively should cultivate awareness of one's body, identify strategies for communicating successfully with caregivers, and provide opportunities for practice of care direction skills and discussion with experienced peers., Competing Interests: Competing interests: The authors have no competing interests in relation to the work described. The authors have received research funding from the following components of the US government: Department of Defense, National Institute on Disability, Independent Living, and Rehabilitation Research, Patient-Centered Outcomes Research Institute, Centers for Disease Control, and Department of Veterans Affairs. They also received grants from the Craig H. Neilsen Foundation, Paralyzed Veterans of America, and New Jersey Commission on Spinal Cord Research. Ethics approval: This project was reviewed by the Institutional Review Boards of the Kessler Foundation (Reference # E-772-13), the VA New Jersey Health Care System (Reference # 01276), and Shepherd Center (Reference # 587). Activities taking place at Mount Sinai and Wayne State University did not involve identifiable data and were determined by the IRB to be exempt from further review. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.) more...

Introduction: Although CRPA may test susceptible to other β-lactams such as ceftazidime (CAZ), cefepime (FEP), and piperacillin/tazobactam (TZP), reduced potency has been observed. We assessed the adequacy of EUCAST Susceptible (S) or Susceptible Increased Exposure (SIE)/(I) doses for CAZ, FEP, and TZP against CRPA clinical isolates., Methods: CRPA isolates were collected from patients at three Turkish hospitals. CAZ, FEP, and TZP MICs were determined using broth microdilution. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for a free time above the MIC (fT > MIC) targets for various doses of each agent against isolates defined as susceptible. fT > MIC targets were 70% for CAZ or FEP and 50% for TZP. Cumulative fraction of response (CFR) was calculated. Optimal PTA and CFR was 90% target achievement., Results: The percentages of isolates SIE/I to CAZ, FEP, and TZP were 49,8%, 47%, and 31,8% respectively. Reduced potency was noted with 54,1% of CAZ-S isolates having MICs of 4 or 8 mg/L. Of the FEP and TZP-S isolates, MICs at the breakpoint (8 and 16 mg/L, respectively) were the mode with 45,2 and 53,9% of isolates for each, respectively. At an MIC of 8 mg/L for CAZ, the EUCAST standard dose was insufficient (CFR of 85%). 3 h infusions of EUCAST SIE doses were required for 90% PTA at MIC of 8 mg/L and an optimized CFR of 100%. For FEP, the SIE dose of 2 g q8h 0.5 h infusion of was effective (CFR 96%), utilization of an extended 3 h infusion further optimized the PTA at 8 mg/L (CFR 99%). For TZP, the standard dose of 4.5 q6h administered as a 0.5 h infusion was inadequate (CFR 86%). A standard TZP dose with an extended infusion (4.5 g q8h over 4 h) and the SIE dose 4.5 g q6h 3 h infusion resulted in CFRs > 95%., Conclusion: These data support the EUCAST SIE breakpoints for FEP and TZP. To optimize PTA at the SIE breakpoint for CAZ, prolonged infusion is required., Competing Interests: Declarations. Ethics approval and consent to participate: Human Ethics and Consent to Participate declarations: not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...

Background: Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections., Methods: Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters., Results: Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation., Conclusions: Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure., (© 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.) more...

Background: Acute kidney injury (AKI) remains a common sequela of sepsis necessitating use of continuous renal replacement therapy (CRRT). In the setting of AKI, renally adjusted antimicrobials (eg, β-lactams) are dose reduced to prevent toxicity; however, the extracorporeal clearance of CRRT may lead to subtherapeutic exposures of dose reduced antimicrobials. The present study sought to evaluate the time to dose adjustment to CRRT appropriate doses of antimicrobials after initiation of CRRT. Methods: A retrospective cohort study of patients on CRRT and anti-pseudomonal β-lactams was conducted. CRRT was conducted as continuous veno-venous hemodialysis (CVVHD) per institutional standards. Baseline characteristics were collected including dialysate flow rate. The primary outcome was time to CRRT appropriate dose adjustment. Secondary outcomes included the pharmacist shift (ie, day, evening, or night shift) that CRRT was ordered and initiated. Continuous data were reported as median (IQR). Results: Forty-four patients were included in the analysis. The median dialysate flow rate was 2.3 L/hour (2, 3.1). Of included patients, 75% received cefepime therapy while 25% received meropenem. The median time to CRRT appropriate dosing was 13 hours (6, 20). CRRT was most commonly ordered during day shift (68%) but not started until evening (59%). The observed delay in appropriate dose adjustment may predispose patients to suboptimal antimicrobial exposure and subsequently therapeutic failure. CRRT was often ordered during the day shift but not initiated until evening which led to identification of potential procedural improvements. Conclusions: These data led to the initiation of a pharmacy in basket consult to alert pharmacists in real time of CRRT orders so that once CRRT was started, doses could be appropriately adjusted. Future studies to assess the impact of this process change on both time to appropriate dose and clinical outcomes are warranted., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CMG has received research funding from Cepheid, Everest Medicines, Shionogi, and Entasis. MF and RS, none to declare., (© The Author(s) 2024.) more...

Background: Patients infected with difficult-to-treat Pseudomonas aeruginosa are likely to receive meropenem (MEM) empirically before escalation to ceftolozane/tazobactam (C/T). We assessed whether pre-exposure to MEM affected C/T resistance development on C/T exposure., Materials and Methods: Nine clinical P. aeruginosa isolates were exposed to MEM 16 mg/L for 72 h. Then, isolates were serially passaged in the presence of C/T (concentration of 10 mg/L) for 72 h as two groups: an MEM-exposed group inoculated with MEM pre-exposed isolates and a non-MEM control group. At 24 h intervals, samples were plated on drug-free and drug-containing agar (C/T concentration 16/8 mg/L) and incubated to quantify bacterial densities (log10 cfu/mL). Growth on C/T agar indicated resistance development, and resistant population was calculated by dividing the cfu/mL on C/T plates by the cfu/mL on drug-free agar., Results: At 72 h, resistant populations were detected in 6/9 isolates. In five isolates, MEM exposure significantly increased the prevalence of ceftolozane/tazobactam-resistance development; the percentages of resistance population were 100%, 100%, 53.5%, 31% and 3% for the MEM-exposed versus 0%, 0%, 2%, 0.35% and ≤0.0003% in the unexposed groups. One isolate had a similar resistant population at 72 h between the two groups. The remaining isolates showed no development of resistance, regardless of previous MEM exposure., Conclusions: MEM exposure may pre-dispose to C/T resistance development and thus limit the therapeutic utility of this β-lactam/β-lactamase inhibitor. Resistance may be a result of stress exposure or molecular-level mutations conferring cross-resistance. Further in vivo studies are needed to assess clinical implications of these findings., (© 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.) more...

Stenotrophomonas maltophilia (SM) bloodstream infections (BSIs) contribute to significant mortality in hematologic malignancy (HM) and hematopoietic stem cell transplantation (HSCT) patients. A risk score to predict SM BSI could reduce time to appropriate antimicrobial therapy (TTAT) and improve patient outcomes. A single center cohort study of hospitalized adults with HM/HSCT was conducted. Patients had ≥ 1 blood culture with a Gram-negative (GN) organism. A StenoSCORE was calculated for each patient. The StenoSCORE2 was developed using risk factors for SM BSI identified via logistic regression. Receiver operating characteristic (ROC) curves were plotted. Sensitivity and specificity for the StenoSCORE and StenoSCORE2 were calculated. Thirty-six SM patients and 534 non-SM patients were assessed. A StenoSCORE ≥ 33 points was 80% sensitive, 68% specific, and accurately classified 69% of GN BSIs. StenoSCORE2 variables included acute leukemia, prolonged neutropenia, mucositis, ICU admission, recent meropenem and/or cefepime exposure. The StenoSCORE2 performed better than the StenoSCORE (ROC AUC 0.84 vs. 0.77). A StenoSCORE2 ≥ 4 points was 86% sensitive, 76% specific, and accurately classified 77% of GN BSIs. TTAT was significantly longer for patients with SM BSI compared with non-SM BSI (45.16 h vs. 0.57 h; p < 0.0001). In-hospital and 28-day mortality were significantly higher for patients with SM BSI compared to non-SM BSI (58.3% vs. 18.5% and 66.7% vs. 26.4%; p-value < 0.0001). The StenoSCORE and StenoSCORE2 performed well in predicting SM BSIs in patients with HM/HSCT and GN BSI. Clinical studies evaluating whether StenoSCORE and/or StenoSCORE2 implementation improves TTAT and clinical outcomes are warranted., (© 2024. The Author(s).) more...

Background: In vitro-in vivo discordance in β-lactams' activities against metallo-ß-lactamase (MBL)-producing Enterobacterales has been described. We aimed to assess whether this discordance is attributed to the supra-physiologic zinc concentration in in vitro testing media., Methods: A clinical and microbiological observational study of patients with bloodstream infections due to New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae was performed. Outcomes of patients treated empirically with non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam + aztreonam) were documented. The patients' isolates were used to induce septicemia in mice, and survival upon meropenem treatment was recorded. Meropenem minimum inhibitory concentrations (MICs) were determined in standard media and in the presence of physiological zinc concentrations., Results: Twenty-nine patients receiving empiric non-MBL-active β-lactams (median duration, 4 days) were compared with 29 receiving MBL-active β-lactams. The 14-day mortality rates were 21% and 14%, respectively. In the murine septicemia model, meropenem treatment resulted in protection from mortality ( P < .0001). Meropenem MICs in the physiologic zinc concentration broth were 1- to >16-fold lower vs MICs in zinc-unadjusted broth (≥64 mg/L)., Conclusions: Our data provide foundational support to establish pharmacokinetic/pharmacodynamic relationships using MICs derived in physiologic zinc concentration, which may better predict β-lactam therapy outcome., Competing Interests: Potential conflict of interest. K.A. has received research grants from the FDA, Evopoint Biosciences, Venatorx Pharmaceuticals, and Toscana Life Sciences Foundation. C.M.G. received research funding from Cepheid, Everest Medicines, Shionogi, and Entasis. M.F. received unconditional grants from MSD and grants or speaker honoraria from Angelini, Shionogi, Pfizer, Menarini, Gilead, and Nordic Pharma. G.T. received honoraria for educational meetings for Shionogi. D.P.N. is a consultant, speaker bureau member, and has received other research grants from AbbVie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, and Shionogi. All other authors report no potential conflicts. Declared conflicts of interest are outside the submitted work and did not affect the scientific objectivity of this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.) more...

Charcot's neuroarthropathy and osteomyelitis can have similar initial presentations. The ability to differentiate between the two pathologic conditions is essential, as each requires different treatment. We present a case of a 53-year-old woman with pain, swelling, and warmth in her left first metatarsophalangeal joint and first tarsometatarsal joint. Radiographs showed comminuted fractures at the base of the first metatarsal. Osteomyelitis was suspected by the primary team based on physical findings and a history of previous first metatarsophalangeal joint arthrodesis. A triphasic bone scan and an indium white blood cell scan were positive for osteomyelitis. The podiatric medical team was suspicious for possible Charcot's neuroarthropathy based on physical findings and uncontrolled blood glucose levels at the time of her previous arthrodesis. A sulfur colloid scan was performed and compared with an indium scan, which showed no evidence of osteomyelitis. This case demonstrates the usefulness of sulfur colloid imaging compared with an indium white blood cell scan to differentiate osteomyelitis from Charcot's neuroarthropathy. This case also highlights the importance of using clinical judgment to make the correct diagnosis. more...

Objectives: To evaluate the efficacy of human-simulated regimens (HSRs) of ceftazidime, ceftazidime/avibactam, imipenem, imipenem/relebactam, meropenem and meropenem/vaborbactam in a murine thigh infection model against serine carbapenemase-producing Pseudomonas aeruginosa., Methods: Nine P. aeruginosa clinical isolates harbouring GES-5 (n = 1), GES-20 (n = 1), GES-5/20 (n = 1), GES-19, GES-20 (n = 3) and KPC (n = 3) were evaluated. Six mice were administered HSRs of ceftazidime 2 g q8h (2 h infusion), ceftazidime/avibactam 2.5 g q8h (2 h infusion), meropenem 2 g q8h (3 h infusion), imipenem 0.5 g q6h (0.5 h infusion), imipenem/relebactam 1.25 g q6h (0.5 h infusion) and meropenem/vaborbactam 4 g q8h (3 h infusion). Change in bacterial burden relative to baseline and the percent of isolates meeting the 1 log10 kill endpoint were assessed., Results: The addition of avibactam to ceftazidime increased the percentage of isolates meeting 1 log10 kill from 33% to 100% of GES- or KPC-harbouring isolates. Imipenem/relebactam HSR produced ≥1 log10 of kill against 83% and 100% of GES- and KPC-harbouring isolates, respectively, while imipenem alone failed to reach 1 log10 kill for any isolates. Vaborbactam resulted in variable restoration of meropenem activity as 1 log10 kill was achieved in only 33% and 66% of GES- and KPC-harbouring isolates, respectively, compared with no isolates for meropenem alone., Conclusions: Ceftazidime/avibactam and imipenem/relebactam were active against 100% and 89% of KPC- or GES-harbouring isolates tested in vivo. The activity of meropenem/vaborbactam was variable, suggesting this may be an inferior treatment option in this setting. Further studies to evaluate clinical outcomes in GES- and KPC-producing P. aeruginosa are warranted given their increasing prevalence worldwide., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Objectives: To determine the in vitro activity of cefiderocol in a global collection of carbapenem-resistant Pseudomonas aeruginosa including >200 carbapenemase-producing isolates., Methods: Isolates (n = 806) from the ERACE-PA Surveillance Program were assessed. Broth microdilution MICs were determined for cefiderocol (iron-depleted CAMHB) and comparators (CAMHB). Susceptibility was interpreted by CLSI and EUCAST breakpoints and reported as percent of isolates. The MIC distribution of cefiderocol in the entire cohort and by carbapenemase status was assessed., Results: In the entire cohort, cefiderocol was the most active agent (CLSI 98% susceptible; EUCAST 95% susceptible; MIC50/90, 0.25/2 mg/L). Amikacin (urinary only breakpoint) was the second most active, with 70% of isolates testing as susceptible. The percentage of isolates susceptible to all other agents was low (<50%) including meropenem/vaborbactam, imipenem/relebactam, piperacillin/tazobactam and levofloxacin. Cefiderocol maintained significant activity against the most commonly encountered carbapenemases including VIM- (CLSI 97% susceptible; EUCAST 92% susceptible) and GES (CLSI 100% susceptible; EUCAST 97% susceptible)-harbouring isolates. The cefiderocol MIC distribution was similar regardless of carbapenemase status, with MIC50/90 values of 0.5/4 mg/L, 0.5/2 mg/L and 0.25/1 mg/L for MBL, serine carbapenemase and molecular carbapenemase-negative isolates, respectively., Conclusions: Cefiderocol displayed potent in vitro activity in this global cohort of carbapenem-resistant P. aeruginosa including >200 carbapenemase-harbouring isolates. Cefiderocol was highly active against MBL-producing isolates, where treatment options are limited. These data can help guide empirical therapy guidelines based on local prevalence of carbapenemase-producing P. aeruginosa or in response to rapid molecular diagnostics., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Background: Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLIs) avibactam, relebactam and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL)/BLI combinations against serine carbapenemase-producing P. aeruginosa is unknown., Objectives: To compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam and meropenem against serine β-lactamase-producing P. aeruginosa., Methods: Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. MICs were determined by broth microdilution to each novel BL/BLI and BL alone., Results: GES was the most common carbapenemase identified (n = 59) followed by KPC (n = 8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/>16 mg/L and 13% of all isolates were defined as susceptible. Of the KPC-producing isolates, 38% were susceptible to imipenem/relebactam, compared with 0% to imipenem. The meropenem/vaborbactam MIC50/MIC90 were >16/>16 mg/L, and 6% of isolates were susceptible, which was similar to meropenem alone (MIC50/90, >8/>8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms., Conclusions: Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine carbapenemase-harbouring P. aeruginosa. While imipenem/relebactam displayed some activity, particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity, with MICs similar to meropenem alone., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Background: Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens., Methods: Static time-kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n = 4; P. aeruginosa, n = 4; Escherichia coli, n = 3; Klebsiella pneumoniae, n = 3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients., Results: Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain., Conclusions: Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic/pharmacodynamics data and clinical correlation are necessary to support our findings., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Molecular carbapenem-resistance testing, such as for the presence of carbapenemases genes, is commonly implemented for the detection of carbapenemase-producing Enterobacterales. Carbapenemase-producing P. aeruginosa is also associated with significant morbidity and mortality, although; prevalence may be underappreciated in the United States due to a lack of carbapenemase testing. The present study sought to compare hands-on time, cost and workflow implementation of carbapenemase gene testing in Enterobacterales and P. aeruginosa isolates versus sending out isolates to a public health laboratory (PHL) for testing to assess if in-house can provide actionable results. The time to carbapenemase gene results were compared. Differences in cost for infection prevention measures were extrapolated from the time of positive carbapenemase gene detection in-house versus PHL. The median time to perform carbapenemase gene testing was 7.5 min (range 5-14) versus 10 min (range 8-22) for preparation to send isolates to the PHL. In-house testing produced same day results compared with a median of 6 days (range 3-14) to receive results from PHL. Cost of in-house testing and send outs were similar ($46.92 versus $40.53, respectively). If contact precautions for patients are implemented until carbapenemase genes are ruled out, in-house testing can save an estimated $76,836.60 annually. Extension of in-house carbapenemase testing to include P. aeruginosa provides actionable results 3-14 days earlier than PHL Standard Pathway testing, facilitating guided therapeutic decisions and infection prevention measures. Supplemental phenotypic algorithms can be implemented to curb the cost of P. aeruginosa carbapenemases testing by identifying isolates most likely to harbour carbapenemases. more...

Background: Carbapenem-resistant Enterobacterales (CRE) are a public health concern. Among these isolates, there are reports of isolates that test as cefepime susceptible or susceptible-dose dependent (SDD) in vitro despite presence of a carbapenemase. This study aimed to evaluate the pharmacokinetic/pharmacodynamic profile of cefepime against carbapenemase-producing (CP-CRE) and non-producing (non-CP-CRE) isolates with a range of cefepime MICs., Methods: Reference broth microdilution and modified carbapenem inactivation method (mCIM) were performed on genotypically characterized clinical CRE isolates. Ultimately, CP-CRE (n = 21; blaKPC) and non-CP-CRE (n = 19) isolates with a distribution of cefepime MICs (≤0.5 to >256 mg/L) were utilized in the murine thigh infection model. Mice were treated with cefepime human-simulated regimens (HSRs) representative of a standard dose (1 g q12h 0.5 h infusion) or the SDD dose (2 g q8h 0.5 h infusion). Efficacy was assessed as the change in bacterial growth at 24 h compared with 0 h control, where ≥1 log bacterial reduction is considered translational value for clinical efficacy., Results: Among both cohorts of CRE isolates, i.e. CP-CRE and non-CP-CRE, that tested as SDD to cefepime in vitro, 1 log bacterial reduction was not attainable with cefepime. Further blunting of cefepime efficacy was observed among CP-CRE isolates compared with non-CP-CRE across both susceptible and SDD categories., Conclusions: Data indicate to avoid cefepime for the treatment of serious infections caused by CRE isolates that test as cefepime susceptible or SDD. Data also provide evidence that isolates with the same antibiotic MIC may have different pharmacokinetic/pharmacodynamic profiles due to their antimicrobial resistance mechanism., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Objectives: We evaluated the in vivo efficacy of human-simulated regimens (HSRs) of cefiderocol, ceftazidime/avibactam, meropenem and ceftazidime/avibactam/meropenem combination against Guiana-extended spectrum (GES)-producing Pseudomonas aeruginosa isolates., Methods: Eighteen P. aeruginosa isolates producing GES-1 (n = 5), GES-5 (n = 5) or miscellaneous GESs (combinations of GES-19, GES-20 and/or GES-26; n = 8) were evaluated. In vitro MIC testing was determined using broth microdilution. In a validated murine thigh infection model, HSRs of cefiderocol 2 g q8h as a 3 h IV infusion, ceftazidime/avibactam 2.5 g q8h as a 2 h IV infusion, meropenem 2 g q8h as a 3 h IV infusion or ceftazidime/avibactam/meropenem were administered. Change in bacterial burden relative to baseline and the proportion of isolates in each genotypic group meeting 1-log10 kill endpoint were assessed., Results: Modal MICs (mg/L) ranged from 0.125 to 1 for cefiderocol, 4 to >64 for ceftazidime/avibactam and 2 to >64 for meropenem. Cefiderocol produced >1-log10 of kill against all 18 tested isolates. Meropenem was active against all GES-1 isolates whereas activity against GES-5 and miscellaneous GESs was lacking, consistent with the MICs. Ceftazidime/avibactam was active against all GES-1 and GES-5 isolates and retained activity against 62.5% of miscellaneous GESs including isolates with elevated MICs. For isolates where ceftazidime/avibactam failed, the addition of meropenem restored the in vivo efficacy., Conclusions: As monotherapy, cefiderocol was active in vivo against all tested isolates. The activities of meropenem or ceftazidime/avibactam alone were variable; however, a combination of both was active against all isolates. Cefiderocol and ceftazidime/avibactam/meropenem could be valuable therapeutic options for GES-producing P. aeruginosa infections. Clinical confirmatory data are warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Purpose: The oncologic outcomes for atypical meningiomas can be poor. Generally, patients that have had a prior recurrence have a substantially elevated risk of a future recurrence. Additionally, certain tumor genomic profiles have been shown as markers of poor prognosis. We sought to characterize the genomic differences between primary and recurrent tumors as well as assess if those differences had implications on recurrence., Methods: We identified primary and recurrent gross totally resected WHO grade II meningiomas with > 30 days of post-surgical follow-up at our institution. For genes with a prevalence of > 5% in the cohort, we compared the mutational prevalence in primary and recurrent tumors. For a gene of interest, we assessed the time to radiographic recurrence using adjusted cox-regression., Results: We identified 88 meningiomas (77 primary, 16 recurrent) with a median follow-up of 5.33 years. Mutations in ARID1A found in association with recurrent tumors (7/16 recurrent tumors vs 5/72 primary tumors, p < 0.001). In the whole cohort, mutations in ARID1A were not associated with alterations in time to recurrence after adjusting for recurrence status (p = 0.713). When restricted to primary tumors, ARID1A is associated with a 625% increase in the hazard of recurrence (HR = 7.26 [1.42-37.0]; p = 0.017)., Conclusion: We demonstrate mutations in ARID1A, a chromatin remodeling gene, in a higher prevalence in recurrent tumors. We further demonstrate that when mutations in ARID1A are present in primary atypical meningiomas, these tumors tend to have worse prognosis. Further prospective study may validate ARID1A as a prognostic marker., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...

The objective was to determine the magnitude of the EVER206 free-plasma area under the concentration time curve ( f AUC)/MIC target associated with bacteriostasis and 1-log 10 kill against clinically relevant Gram-negative bacteria in the murine thigh model. Twenty-seven clinical isolates (Pseudomonas aeruginosa, n  = 10; Escherichia coli , n  = 9; Klebsiella pneumoniae, n  = 5; Enterobacter cloacae, n  = 2; and Klebsiella aerogenes, n  = 1) were tested. Mice were pretreated with cyclophosphamide (induce neutropenia) and uranyl nitrate (increase the exposure of test compound through predictable renal dysfunction). Two hours postinoculation, five doses of EVER206 were administered subcutaneously. EVER206 pharmacokinetics were determined in infected mice. Data were fit using maximum effect ( E max ) models to elucidate the f AUC/MIC targets for stasis and 1-log 10 bacterial kill (reported as mean [range] by species). EVER206 MICs (mg/L) ranged from 0.25 to 2 mg/L (P. aeruginosa), 0.06 to 2 mg/L (E. coli), 0.06 to 0.125 mg/L (E. cloacae), 0.06 mg/L (K. aerogenes), and 0.06 to 2 mg/L (K. pneumoniae). In vivo , the mean 0-h baseline bacterial burden was 5.57 ± 0.39 log 10 CFU/thigh. Stasis was achieved in 9/10 P. aeruginosa ( f AUC/MIC, 88.13 [50.33 to 129.74]), 9/9 E. coli ( f AUC/MIC, 112.84 [19.19 to 279.38]), 2/2 E. cloacae ( f AUC/MIC, 259.28 [124.08 to 394.47]), 0/1 K. aerogenes, and 4/5 K. pneumoniae ( f AUC/MIC, 99.26 [62.3 to 144.43]) isolates tested. 1-log 10 kill was achieved in 9/10 for P. aeruginosa ( f AUC/MIC, 106.43 [55.22 to 152.08]), 3/9 for E. coli ( f AUC/MIC, 258.96 [74.08 to 559.4]), and 1/2 for E. cloacae ( f AUC/MIC, 255.33). Using the murine thigh model, the f AUC/MIC targets of EVER206 were assessed across a broad MIC distribution. Integrating these data with microbiologic and clinical exposure data will aid in determining the clinical dose of EVER206., Competing Interests: The authors declare a conflict of interest. C.M.G. has received research grants from Cepheid, Everest Medicines, Shionogi, and Entasis. D.P.N. is a consultant, speaker bureau member and has received other research grants from Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, and Tetraphase. more...

Purpose: Meningiomas occur more frequently in older adults, with the incidence rates increasing from 5.8/100,000 for adults 35-44 years old to 55.2/100,000 for those 85+. Due to the increased risk of surgical management in older adults, there is a need to characterize the risk factors for aggressive disease course to inform management decisions in this population. We therefore sought to determine age-stratified relationships between tumour genomics and recurrence after resection of atypical meningiomas., Methods: We identified 137 primary and recurrent Grade 2 meningiomas from our existing meningioma genomic sequencing database. We examined the differential distribution of genomic alterations in those older than 65 compared to younger. We then performed an age stratified survival analysis to model recurrence for a mutation identified as differentially present., Results: In our cohort of 137 patients with grade 2 meningiomas, alterations in NF2 were present at a higher rate in older adults compared to younger (37.8% in < 65 vs. 55.3% in > 65; recurrence adjusted p-value =0.04). There was no association between the presence of NF2 and recurrence in the whole cohort. In the age-stratified model for those less than 65 years old, there was again no relationship. For patients in the older age stratum, there is a relationship between NF2 and worsened recurrence outcomes (HR = 3.64 (1.125 - 11.811); p  = 0.031)., Conclusions: We found that mutations in NF2 were more common in older adults. Further, the presence of mutant NF2 was associated with an increased risk of recurrence in older adults. more...

Objective: Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model., Methods: In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking., Results: Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA -3.75 ± 0.37 reduction in log10 cfu/thigh, C-SAM produced -3.55 ± 0.50 and C-MEM produced -2.18 ± 1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy., Conclusions: Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

With increasing use of rituximab and other B-cell depleting monoclonal antibodies for multiple indications, infectious complications are being recognized. We summarize clinical findings of patients on rituximab with arboviral diseases identified through literature review or consultation with the Centers for Disease Control and Prevention. We identified 21 patients on recent rituximab therapy who were diagnosed with an arboviral disease caused by West Nile, tick-borne encephalitis, eastern equine encephalitis, Cache Valley, Jamestown Canyon, and Powassan viruses. All reported patients had neuroinvasive disease. The diagnosis of arboviral infection required molecular testing in 20 (95%) patients. Median illness duration was 36 days (range, 12 days to 1 year), and 15/19 (79%) patients died from their illness. Patients on rituximab with arboviral disease can have a severe or prolonged course with an absence of serologic response. Patients should be counseled about mosquito and tick bite prevention when receiving rituximab and other B-cell depleting therapies., Competing Interests: Potential conflicts of interest. D. P. reports lecture honorarium from American Academy of Neurology. 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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.) more...

Background: Two of the three recently approved β-lactam agent (BL)/β-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity., Methods: OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae wild-type, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls., Results: On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold., Conclusions: Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Purpose: This study evaluates the in vitro potency of piperacillin/tazobactam among a global collection of carbapenem-resistant Pseudomonas aeruginosa (CR-PA) and assesses the adequacy of the Clinical and Laboratory Standards Institute (CLSI) P aeruginosa breakpoint dose in the setting of CR-PA using Monte Carlo simulation., Methods: Isolates were collected during the Enhancing Rational Antimicrobials Against Carbapenem-Resistant P aeruginosa (ERACE-PA) Global Surveillance Program. Piperacillin/tazobactam MICs were determined using broth microdilution per CLSI standards. A 5000-patient Monte Carlo simulation was performed using various piperacillin/tazobactam dosing regimens to determine the probability of target attainment (PTA) for 50% free time above the MIC. The MIC distribution of piperacillin/tazobactam-susceptible CR-PA was used to calculate cumulative fraction of response (CFR). Optimal PTA and CFR were defined as 90% target achievement., Findings: A total of 28% of tested CR-PA were piperacillin/tazobactam susceptible. Of these, 71% had MICs of 8 to 16/4 mg/L. Doses of 3.375 g q6h as 0.5-hour infusion (current breakpoint dose) had adequate PTA at MIC of 8/4 mg/L (CFR, 81%); however, extended infusion of 3 or 4 hours improved PTA at 16/4 mg/L (CFR, >90%). Doses of 4.5 g q8h as a 4-hour infusion and 4.5 g q6h as a 3-hour infusion both provide >90% PTA at an MIC of 16 mg/L (CFRs, 97 and 100%, respectively), favoring susceptible dose dependent interpretive criteria with these regimens., Implications: Although susceptible, piperacillin/ tazobactam has reduced potency in CR-PA. If piperacillin/tazobactam is used for susceptible CR-PA, high-doses (4.5 g q6h) and extended infusion (3 hours or continuous infusion) are needed to optimize exposure., Competing Interests: Declaration of Interest Dr Gill has received research grants from Cepheid, Everest Medicines, and Shionogi. Dr Nicolau is a consultant and speaker bureau member and has received other research grants from Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, and Tetraphase. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Purpose: High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT)., Methods: From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status., Results: Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068-0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88-6.73, p = 0.087)., Conclusion: This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Objectives: To evaluate the genotypic and ceftazidime/avibactam-susceptibility profiles amongst ceftolozane/tazobactam-non-susceptible (NS), MBL-negative Pseudomonas aeruginosa in a global surveillance programme., Methods: Isolates were collected as part of the ERACE-PA Global Surveillance programme. Carbapenem-resistant P. aeruginosa deemed clinically relevant by the submitting laboratories were included. Broth microdilution MICs were conducted per CLSI standards to ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime and cefepime. Genotypic carbapenemases were detected using CarbaR and CarbaR NxG (research use only). Isolates negative for carbapenemases by PCR were assessed via WGS. Isolates were included in the analysis if they were ceftolozane/tazobactam-NS and lacked detection of known MBLs., Results: Of the 807 isolates collected in the ERACE-PA programme, 126 (16%) were ceftolozane/tazobactam-NS and lacked MBLs. Cross-resistance to ceftazidime and cefepime was common, with only 5% and 16% testing susceptible, respectively. Ceftazidime/avibactam retained in vitro activity, with 65% of isolates testing susceptible. GES was the most common enzymology, detected in 57 (45%) isolates, and 89% remained susceptible to ceftazidime/avibactam. Seven isolates harboured KPC and all tested susceptible to ceftazidime/avibactam. In the remaining 62 isolates, WGS revealed various ESBLs or OXA β-lactamases. While 39% remained susceptible to ceftazidime/avibactam, marked variability was observed among the diverse resistance mechanisms., Conclusions: Ceftazidime/avibactam remained active in vitro against the majority of ceftolozane/tazobactam-NS, MBL-negative P. aeruginosa. Ceftazidime/avibactam was highly active against isolates harbouring GES and KPC β-lactamases. These data highlight the potential clinical utility of genotypic profiling as well as the need to test multiple novel agents when carbapenem-resistant P. aeruginosa are encountered., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Background: Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel., Materials and Methods: We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a p -value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors., Results: ATM (HR = 4.448; 95% CI: 1.517-13.046), CREBBP (HR = 2.727; 95% CI = 1.163-6.396), and POLE (HR = 0.544; HR = 0.311-0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in ATM (HR = 7.333; 95% CI = 2.318-23.195) and POLE (HR = 0.413; 95% CI = 0.229-0.743) as predictive of recurrence., Conclusions: Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare. more...

Carbapenem-resistant Pseudomonas aeruginosa (CR-PA) is a major healthcare-associated pathogen worldwide. In the United States, 10-30% of P. aeruginosa isolates are carbapenem-resistant, while globally the percentage varies considerably. A subset of carbapenem-resistant P. aeruginosa isolates harbour carbapenemases, although due in part to limited screening for these enzymes in clinical laboratories, the actual percentage is unknown. Carbapenemase-mediated carbapenem resistance in P. aeruginosa is a significant concern as it greatly limits the choice of anti-infective strategies, although detecting carbapenemase-producing P. aeruginosa in the clinical laboratory can be challenging. Such organisms also have been associated with nosocomial spread requiring infection prevention interventions. The carbapenemases present in P. aeruginosa vary widely by region but include the Class A beta-lactamases, KPC and GES; metallo-beta-lactamases IMP, NDM, SPM, and VIM; and the Class D, OXA-48 enzymes. Rapid confirmation and differentiation among the various classes of carbapenemases is key to the initiation of early effective therapy. This may be accomplished using either molecular genotypic methods or phenotypic methods, although both have their limitations. Prompt evidence that rules out carbapenemases guides clinicians to more optimal therapeutic selections based on local phenotypic profiling of non-carbapenemase-producing, carbapenem-resistant P. aeruginosa . This article will review the testing strategies available for optimizing therapy of P. aeruginosa infections. more...

Background: Historically, multi-drug resistant organisms have been associated with the ICU setting. The present study sought to define the frequency of isolation from ICU versus non-ICU, phenotypic and genotypic profiles of carbapenem-resistant Pseudomonas aeruginosa (CR-PA) from a global cohort., Methods: Multicenter surveillance study (17 centers from 12 countries) including 672 CR-PA isolates from 2019 to 2021. Phenotypic carbapenemase testing was assessed. Genotypic carbapenemase testing was conducted (CarbaR and CarbaR NxG) to detect β-lactamases. Broth microdilution MICs were established for ceftazidime, cefepime, ceftolozane/tazobactam, and ceftazidime/avibactam., Results: 59% of CR-PA were isolated from patients outside the ICU. The most common source in ICU and non-ICU patients was respiratory (55% and 30%, respectively). In the ICU, 35% of isolates were phenotypically carbapenemase-positive versus 29% for non-ICU. VIM was the most common carbapenemase (54% and 44%, respectively) followed by GES (27% and 28%, respectively). Susceptibility to ceftazidime or cefepime were relatively low in ICU (39% and 41% of isolates, respectively) and non-ICU (47% and 52% of isolates, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam were more active with 56% and 66% of isolates susceptible in the ICU while 65% and 76% in non-ICU, respectively. When carbapenemase-negative, 86% and 88% of ICU isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam. Similarly, in the carbapenemase-negative, non-ICU isolates 88% and 92% of isolates were susceptible, respectively., Conclusion: Although multidrug resistant pathogens are often regarded as a challenge in the ICU population, the majority of CR-PA were isolated from non-ICU patients. Implementing phenotypic/genotypic testing will assist in guiding treatment. Carbapenem-resistance in P. aeruginosa should be regarded as a surrogate for MDR and this phenotype is increasingly prevalent outside the ICU., (© 2022. The Author(s).) more...

Background: Late development of forefoot ulcers is a common finding after transmetatarsal amputation (TMA). The primary aim of this study was to examine whether concomitant prophylactic Achilles tendon lengthening (ATL) was associated with a reduction in the incidence of forefoot ulcers postoperatively., Methods: A retrospective chart review was performed by 2 authors to identify patients who underwent TMA over a period of 5.5 years from January 1, 2015, through July 31, 2020. They identified 110 feet in 107 patients; the 83 patients (85 feet) who had ≥120 days of follow-up were used for the study. Follow-up was performed with telephone calls (80 patients) or during the last office visit (3 patients). Those who were contacted by telephone were asked if they developed an ulcer after healing from the original surgery. Mean follow-up time was 672 ± 258 days for the 30 feet with concomitant Achilles lengthening and 663 ± 434 days for the 55 feet without Achilles lengthening. Demographic data were analyzed for association with late development of forefoot ulceration., Results: Eighty-five feet were included in the analysis. Late forefoot ulcers developed in 35% of feet that had a TMA alone (n = 55) compared with 3% of feet who received a concomitant ATL (n = 30; p < 0.001); the 2 groups had similar mean follow-up times. Mean time to ulcer development was 587 ± 420 days in the 19 patients without Achilles lengthening. Of the patients who developed late forefoot ulcers, 47% also developed osteomyelitis, and 16% went on to proximal amputation. Patients who developed forefoot ulcers were younger (55 ± 12 versus 63 ± 11 years of age; p = 0.006) than those who did not., Conclusions: ATL at the time of TMA is associated with a reduction in the risk of later development of forefoot ulcers, especially in younger patients., Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H194 )., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.) more...

Background: Two out of the three recently approved β-lactam (BL)/β-lactamase inhibitors (BLIs) have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity., Methods: OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae WT, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls., Results: On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1 log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs and 73% (37/51) of isolates exceeded the ≥1 log bacterial reduction threshold., Conclusions: Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Objectives: To evaluate the in vivo killing profile of human-simulated exposures of ceftazidime, ceftazidime/avibactam and meropenem against GES-harbouring Pseudomonas aeruginosa in the murine thigh infection model., Methods: Five P. aeruginosa isolates [three isogenic (GES-1, GES-5 and GES-15) and two clinical (GES-5 and GES-15)] were evaluated. MICs were determined using broth microdilution. Human-simulated regimens (HSRs) of ceftazidime 2 g IV q8h as a 2 h infusion, ceftazidime/avibactam 2.5 g IV q8h as a 2 h infusion and meropenem 2 g IV q8h as a 3 h infusion were administered. Change in bacterial burden relative to baseline was assessed., Results: Modal MICs ranged from 8 to &gt;64 mg/L for ceftazidime, from 1 to 16 mg/L for ceftazidime/avibactam and from 1 to &gt;64 mg/L for meropenem. In vivo, for the isogenic strains, avibactam augmented ceftazidime activity against the GES-1- and GES-15-harbouring isolates. Both ceftazidime and ceftazidime/avibactam resulted in significant kill against the GES-5 isogenic isolate. The meropenem HSR produced &gt;1 log10 kill against each isogenic isolate (MICs of 1-4 mg/L). Against the GES-5 clinical isolate, ceftazidime and ceftazidime/avibactam resulted in &gt;1 log10 kill compared with bacterial growth with the meropenem HSR. In the clinical isolate harbouring GES-15, the elevated MICs of ceftazidime and ceftazidime/avibactam reduced the effectiveness of both compounds, while the observed reduction in meropenem MIC translated into in vivo efficacy of the HSR regimen, predictive of clinical efficacy., Conclusions: In GES-harbouring P. aeruginosa, quantitative reductions in bacterial density observed with the translational murine model suggest that the phenotypic profile of ceftazidime, ceftazidime/avibactam and meropenem is predictive of clinical efficacy when using the evaluated dosing regimens., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM., (©2022 American Association for Cancer Research.) more...

Objectives: This study evaluated the sustained kill and potential for resistance development of Acinetobacter baumannii exposed to human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models., Methods: Seven A. baumannii isolates with cefiderocol MICs of 0.12-2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an in vitro chemostat and an in vivo murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion)., Results: In the in vitro model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates in vivo . The mechanism of one resistant isolate that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified., Conclusions: The discrepancy in the sustained efficacy and resistance emergence between in vitro and in vivo models was observed for A. baumannii . Although the resistance mechanisms in vitro have not been fully identified, sustained efficacy without resistance emergence was observed in vivo for six of seven isolates. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among A. baumannii evaluated under human-simulated exposures., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Up to 4-fold differences in zinc concentrations have been observed in commercial broth routinely utilized for susceptibility testing via manual broth microdilution. Herein, we report the concentration of zinc in the broth of common automated susceptibility testing (AST) platforms (Vitek, MicroScan, BD Phoenix, and Sensititre). For AST platforms with lyophilized broth contents (Vitek and MicroScan), wells were rehydrated with appropriate diluent, and contents were aliquoted out for zinc assay. Aliquots from the manufacturer-specific broth (premade cation-adjusted Mueller-Hinton broth [caMHB]) for BD Phoenix and Sensititre were also assayed by inductively coupled plasma mass spectrometry. Up to a 10-fold difference in zinc concentrations was observed across the 4 platforms (MicroScan: 0.46 mg/L; BD Phoenix: 1.16 mg/L; Vitek: 1.22 mg/L; Sensititre: 4.49 mg/L). Attention should be given to the supraphysiologic and variable zinc concentrations observed in broth used in automated platforms and the subsequent implications for susceptibility testing of metallo-β-lactamase (MBL)-harboring isolates. This variability also hampers efforts to develop a standardized method to uniformly reduce zinc concentrations in broth and mimic physiologic zinc conditions. IMPORTANCE Growing data on the impact of extracellular zinc concentration on metallo-β-lactamase-mediated resistance has shed light on the importance of susceptibility testing media. However, there are no studies documenting the amount of zinc in commonly utilized automated susceptibility testing (AST) platforms. This study reveals supraphysiologic zinc concentrations as well as large zinc variability among AST platforms and highlights the challenges this raises in the development of zinc-limited media. more...

Objectives: We assessed the plasma and soft-tissue pharmacokinetic exposure of omadacycline in infected patients with diabetic foot infection (DFI) and healthy volunteers using in vivo microdialysis., Methods: Eight patients and six healthy volunteers were enrolled and received an omadacycline IV loading dose (200 mg) followed by two oral doses (300 mg) every 24 h. Microdialysis catheters were placed in the soft tissue near the infected diabetic foot wound (patients) or thigh (healthy volunteers). Plasma and dialysate fluid samples were collected, starting immediately prior to the third dose and continued for 24 h post-dose. Protein binding was determined by ultracentrifugation., Results: The mean ± SD omadacycline pharmacokinetic parameters in plasma for infected patients and healthy volunteers were: Cmax, 0.57 ± 0.15 and 1.14 ± 0.26 mg/L; t½, 16.19 ± 5.06 and 25.34 ± 12.92 h; and total omadacycline AUC0-24, 6.27 ± 1.38 and 14.06 ± 3.40 mg·h/L, respectively. The omadacycline mean plasma free fraction was 0.21 and 0.20 for patients and healthy volunteers, corresponding to free plasma AUC0-24 of 1.13 ± 0.37 and 2.78 ± 0.55 mg·h/L, respectively. Omadacycline tissue AUC0-24 was 0.82 ± 0.38 and 1.37 ± 0.48 mg·h/L for patients and volunteers, respectively., Conclusions: The present study describes the plasma and soft-tissue exposure of omadacycline in patients with DFI and healthy volunteers. Integrating these data with the microbiological, pharmacokinetic/pharmacodynamic and clinical efficacy data is foundational to support clinical assessments of omadacycline efficacy specifically for DFI. This, coupled with the once-daily oral administration, suggests omadacycline could be an advantageous translational therapy for the hospital and outpatient setting., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) more...

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. It is estimated that 25% of the world's population are infected with Mycobacterium tuberculosis , with a 5-10% lifetime risk of progression into TB disease. Early recognition of TB disease and prompt detection of drug resistance are essential to halting its global burden. Culture, direct microscopy, biomolecular tests and whole genome sequencing are approved methods of diagnosis; however, their widespread use is often curtailed owing to costs, local resources, time constraints and operator efficiency. Methods of optimising these diagnostics, in addition to developing novel techniques, are under review. The selection of an appropriate drug regimen is dependent on the susceptibility pattern of the isolate detected. At present, there are 16 new drugs under evaluation for TB treatment in phase I or II clinical trials, with an additional 22 drugs in preclinical stages. Alongside the development of these new drugs, most of which are oral medications, new shorter regimes are under evaluation. The aim of these shorter regimens is to encourage patient adherence, and prevent relapse or the evolution of further drug resistance. Screening for TB infection, especially in vulnerable populations, provides an opportunity for intervention prior to progression towards infectious TB disease. New regimens are currently under evaluation to assess the efficacy of shorter durations of treatment in this population. In addition, there is extensive research into the use of post-exposure vaccinations in this cohort. Worldwide collaboration and sharing of expertise are essential to our ultimate aim of global eradication of TB disease., Educational Aims: Differentiate between TB infection and TB disease.Understand the different methods of diagnosing TB disease and resistance.Recognise the different drugs and regimens currently in use for TB disease.Be able to discuss risk of TB disease in TB infection, and assist patients in making an informed decision on treatment for TB infection., Competing Interests: Conflict of interest: C.M. Gill has nothing to disclose. Conflict of interest: L. Dolan has nothing to disclose. Conflict of interest: L.M. Piggott has nothing to disclose. Conflict of interest: A.M. McLaughlin has nothing to disclose., (Copyright ©ERS 2022.) more...

Objective: Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication., Methods: Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression., Results: In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation., Conclusions: A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas. more...

Object: The authors performed an extensive comparison between patients treated with open versus an endoscopic approach for skull base malignancy with emphasis on surgical outcomes., Methods: A single-institution retrospective review of 60 patients who underwent surgery for skull base malignancy between 2009 and 2018 was performed. Disease features, surgical resection, post-operative morbidities, adjuvant treatment, recurrence, and survival rates were compared between 30 patients who received purely open surgery and 30 patients who underwent purely endoscopic resection for a skull base malignancy., Results: Of the 60 patients with skull base malignancy, 30 underwent open resection and 30 underwent endoscopic resection. The most common hisotype for endoscopic resection was squamous cell carcinoma (26.7%), olfactory neuroblastoma (16.7%), and sarcoma (10.0%), and 43.3%, 13.3%, and 10.0% for the open resection cohort, respectively. There were no statistical differences in gross total resection, surgical-associated cranial neuropathy, or ability to achieve negative margins between the groups ( p  > 0.1, all comparisons). Patients who underwent endoscopic resection had shorter surgeries (320.3 ± 158.5 minutes vs. 495.3 ± 187.6 minutes ( p  = 0.0003), less intraoperative blood loss (282.2 ± 333.6 ml vs. 696.7 ± 500.2 ml ( p  < 0.0001), and shorter length of stay (3.5 ± 3.7 days vs. 8.8 ± 6.0 days ( p  < 0.0001). Additionally, patients treated endoscopically initiated adjuvant radiation treatment more quickly (48.0 ± 20.3 days vs. 72.0 ± 20.5 days ( p  = 0.01)., Conclusions: An endoscopic endonasal approach facilitates a clinically meaningful improvement in surgical outcomes for skull base malignancies. more...

Background: Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) is a global challenge. However, detection efforts can be laborious because numerous mechanisms produce carbapenem resistance. A minimum inhibitory concentration-based algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) was proposed to identify the isolates most likely to harbor a carbapenemase; however, prospective validation in geographies displaying genotypic diversity and varied carbapenemase prevalence is warranted., Methods: CRPA isolates were collected during the Enhancing Rational Antimicrobials for P. aeruginosa (ERACE-PA) global surveillance program from 17 sites in 12 countries. Isolates underwent susceptibility testing following local standards to ceftazidime, cefepime, and ceftolozane/tazobactam. Isolates underwent initial phenotypic carbapenemase screening followed by molecular testing if positive. The primary algorithm criteria were applied, and results were compared with phenotypic carbapenemase results to assess the performance of the algorithm. A secondary criterion, the algorithm criterion or imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible, was assessed., Results: A total of 807 CRPA were assessed, and 464 isolates met the algorithm criteria described above. Overall, testing was reduced by 43% compared with testing all CRPA. Carbapenemase-positive isolates missed by the algorithm were largely driven by Guiana extended spectrum (GES). Addition of the criterion of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible decreased the number of CP-CRPA missed by the algorithm (21 vs 40 isolates, respectively), reducing number of isolates tested by 39%., Conclusions: Application of the initial algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) performed well in a global cohort, with 33% phenotypically carbapenemase-positive isolates. The addition of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible reduced the number of phenotypically carbapenemase-positive isolates missed and may be useful in areas with a prominence of GES., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.) more...

The cephalosporin-β-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019-2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC 50/90 was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC 50/90 values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies., (© 2021. The Author(s).) more...

Purpose: While SWI/SNF chromatin remodeling complex alterations occur in approximately 20% of cancer, the frequency and potential impact on clinical outcomes in meningiomas remains to be comprehensively elucidated., Methods: A large series of 255 meningiomas from a single institution that was enriched for high grade and recurrent lesions was identified. We performed next-generation targeted sequencing of known meningioma driver genes, including NF2, AKT1, PIK3CA, PIK3R1, and SMO and SWI/SNF chromatin remodeling complex genes, including ARID1A, SMARCA4, and SMARCB1 in all samples. Clinical correlates focused on clinical presentation and patient outcomes are presented., Results: The series included 63 grade I meningiomas and 192 high-grade meningiomas, including 173 WHO grade II and 19 WHO grade III. Samples from recurrent surgeries comprised 37.3% of the series. A total of 41.6% meningiomas were from the skull base. NF2, AKT1, PIK3CA, PIK3R1, and SMO were mutated in 40.8, 7.1, 3.5, 3.9, and 2.4% of samples, respectively. ARID1A, SMARCA4, and SMARCB1 mutations were observed in 17.3, 3.5, and 5.1% of samples, respectively. A total of 68.2% of ARID1A-mutant meningiomas harbored a p.Gln1327del in-frame deletion. ARID1A mutations were seen in 19.1% of Grade I, 16.8% of Grade II, and 15.8% of Grade III meningiomas (P = 0.9, Fisher's exact). Median overall survival was 16.3 years (95% CI 10.9, 16.8). With multivariable analysis, the presence of an ARID1A mutation was significantly associated with a 7.421-fold increased hazard of death (P = 0.04)., Conclusion: ARID1A mutations occur with similar frequency between low and high-grade meningiomas, but ARID1A mutations are independently prognostic of worse prognosis beyond clinical and histopathologic features., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...

Purpose of Review: To evaluate the impact of the COVID-19 pandemic on the care of people with sleep disorders, to explore relationships between OSA and COVID-19, and to describe current knowledge of the effect of the pandemic on sleep globally., Recent Findings: COVID-19 has led to significant changes in the practice of sleep medicine, including the care of patients with OSA. An OSA diagnosis may portend a worse prognosis with COVID-19, whilst prior COVID-19 may have an impact on sleep breathing., Summary: The pandemic has caused marked difficulties with access to diagnostic sleep studies and reduced capacity for CPAP initiation. Conversely, adherence to CPAP therapy may have improved, and use of remote consultations and telemonitoring has increased. An OSA diagnosis may be associated with increased risk of severe COVID-19, although any apparent relationship may be attributable to confounding factors, such as obesity and metabolic disease. Small studies have reported some increase in CPAP requirements in OSA patients following COVID-19 infection. More generally, the pandemic has been associated with a deterioration in subjective sleep quality across the population; much of this appears because of increased anxiety and stress. Finally, studies assessing putative links between COVID-19 and REM sleep issues are ongoing., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.) more...

The present study evaluated the in vitro potency of ceftazidime and cefepime among carbapenem-resistant Pseudomonas aeruginosa isolates collected as part of a global surveillance program and assessed the pharmacodynamic implications using previously published population pharmacokinetics. When susceptible, MICs resulted at the high end of distribution for both ceftazidime and cefepime, thus 6 g/day was required to achieve optimal pharmacodynamic profiles. These findings should be considered in the clinic and for the application of CLSI susceptibility breakpoints. more...

Introduction: The density and distribution of the tumor immune microenvironment associated with brain metastases (BM) from gynecologic malignancies are unknown and have not been previously reported. We sought to describe the clinical features of a cohort of patients with BM from gynecologic malignancies and to characterize the tumor immune microenvironment from available archival surgical specimens., Methods: We performed a retrospective review of electronic medical records from 2002 to 2018 for patients with BM from gynecologic malignancies. Data on patient characteristics, treatment regimens, and clinical outcomes were procured. CD4, CD8, CD45RO, CD68, CD163, and FOXP3 immunohistochemistry were evaluated from available archival surgical specimens from primary disease site and neurosurgical resection., Results: A cohort of 44 patients with BM from gynecologic malignancies was identified, 21 (47.7%) endometrial primaries and 23 (52.3%) ovarian primaries. Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) were evaluated in 13 primary cases and 15 BM cases. For the 13 primary cases, CD4 + TILs were evident in 76.9% of cases, CD8 + in 92.3%, CD45RO + in 92.3%, and FOXP3 + in 46.2%, as well as CD68 + TAMs in 100% and CD163 + in 100%. For the 15 BM cases, CD4 + TILs were evident in 60.0% of cases, CD8 + in 93.3%, CD45RO + in 73.3%, and FOXP3 + in 35.7%, as well as CD68 + TAMs in 86.7% and CD163 + in 100%., Conclusion: An active tumor immune microenvironment is present with similar distribution in the primary disease site and BM from patients with gynecologic malignancies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...