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Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing globally, withMycobacterium aviumcomplex (MAC) accounting for 80% of cases andMycobacterium abscessusamong the next most prevalent pathogens. Current treatment necessitates long-term administration of poorly tolerated and modestly effective antibiotic combinations, highlighting the need for new oral agents. SPR719, the active moiety of the benzimidazole phosphate prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target with no human homolog and not exploited by current antibiotics. We demonstrated SPR719 activity against MAC (MIC90, 2 µg/mL) andM. abscessusclinical isolates (MIC90, 4 µg/mL), including those resistant to current standard-of-care (SOC) agents.In vivoefficacy of SPR720 was demonstrated againstM. aviumATCC 700898 in a chronic C3HeB/FeJ murine model of pulmonary infection, both as a monotherapy and in combination with clarithromycin, ethambutol and rifabutin. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated againstM. abscessussubspeciesabscessus1513, a virulent multidrug-resistant strain in a prolonged acute model of pulmonary infection in mice. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions when combined with SOC agents, clarithromycin and amikacin ± clofazimine. Taken together, thein vitroactivity of SPR720 against common NTM pathogens in concert with the proof-of-concept efficacy in murine infection models warrants the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.

Objectives Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis are urinary tract infection (UTI) pathogens and extended spectrum β-lactamase (ESBL)-producing pathogens exhibit co-resistance to oral fluoroquinolones (FQ) and trimethoprim-sulphamethoxazole (TMP-SMX). This study assessed the prevalence of ESBL phenotypes and co-resistance to FQ and TMP-SMX. Methods In total, 766 E. coli, 260 K. pneumoniae and 104 P. mirabilis from UTIs in 18 countries were evaluated for susceptibility in the SENTRY surveillance programme, and results interpreted using EUCAST criteria. Results E. coli, K. pneumoniae and P. mirabilis accounted for 57.1%, 11.3% and 7.8%, respectively, of the isolates. Among E. coli, resistance to levofloxacin and TMP-SMX ranged from 21.8% to 32.7% for all isolates increasing to 66.5–67.0% among those with a ESBL phenotype (17.9% of all UTI E. coli from Europe were ESBL phenotypes). In contrast, all E. coli were susceptible to meropenem. For K. pneumoniae, resistance rates for levofloxacin and TMP-SMX were 32.2–40.0% increasing to 69.1–78.6% for ESBL phenotypes. Meropenem was the most active agent, with 7.7% resistance. Among P. mirabilis resistance to levofloxacin and TMP-SMX was 26–38.5% and increased to 100% for ESBL phenotypes. No meropenem-resistant P. mirabilis were reported. Conclusions High co-resistance rates were observed for oral antibiotics among ESBL phenotypes raising concerns regarding empiric use of FQ and TMP-SMX for treating resistant UTIs outside of the hospital. In contrast, intravenous carbapenems retain activity against resistant UTI pathogens. New oral options with the spectrum of the carbapenems would address an unmet need for managing resistant UTIs.

The optimal management of achalasia in obese patients is unclear. For those who have undergone Heller myotomy and fundoplication, the long-term outcomes and their impressions following surgery are largely unknown. A retrospective review of patients who underwent laparoscopic Heller myotomy and Dor fundoplication (LHMDF) for achalasia was performed. From this cohort, Class 2 and 3 obese (BMI > 35 kg/m2) patients were identified for short- and long-term outcome analysis. Between 2003 and 2015, 252 patients underwent LHMDF for achalasia, and 17 (7%) patients had BMI > 35 kg/m2. Pre-operative Eckardt scores varied from 2 to 9, and at short-term (2–4 week) follow-up, scores were 0 or 1. Ten (58%) patients had available long-term (2–144 months) follow-up data. Eckardt scores at this time ranged from 0 to 6. Symptom recurrence was worse for patients with BMI > 40 kg/m2 compared to patients with BMI

The prospect of ever increasing antibiotic resistance eroding currently available treatment options for bacterial infections underscores the need to continue to identify new antibiotics, preferably those that act on novel targets or with novel mechanisms of action. Bacterial gyrase B subunit (GyrB), an essential component of bacterial gyrase required for successful DNA replication, represents such a target. We describe recent examples of GyrB inhibitors and point out their potential utility for treatment of mycobacterial diseases caused by Mycobacterium tuberculosis (TB) and non-tuberculous mycobacteria (NTM). Current therapeutic options for these diseases are often suboptimal due to resistance to current standard of care antibiotics. A future GyrB inhibitor-based antibiotic could offer a new and effective addition to the armamentarium for treatment of mycobacterial diseases and possibly for infections caused by other bacterial pathogens. One GyrB inhibitor, SPR720, has recently completed a first-in-human clinical trial and is in clinical development for the treatment of NTM and TB infections.

Background This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy.Methods The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission.Results Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate.Conclusion ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.Lay SummaryEnhanced recovery protocols consist of interdisciplinary interventions aimed at standardizing care and reducing the impact of surgical stress. They often include a short period of preoperative fasting during the night before surgery, early removal of lines and surgical drains, early food intake and mobilization out of bed on the day of surgery. This study gives a summary of reports assessing such care protocols in patients undergoing pancreatic head surgery, and assesses the impact of these protocols on functional recovery in an analysis of individual-patient data. The study revealed the true benefits of enhanced recovery protocols, including shorter time to food intake, earlier bowel activity, fewer complications after surgery, and a shorter hospital stay compared with conventional care.

National and international guidelines support early cholecystectomy after mild gallstone pancreatitis but a recent nationwide study suggested these recommendations are not universally followed. Our study sought to quantify the national utilization of same hospitalization cholecystectomy versus non-operative management (NOM) and its association with pancreatitis recurrence, readmissions, and costs after mild gallstone pancreatitis (GP).Adult patients admitted with mild GP were identified from the Nationwide Readmission Database 2010-2015. Primary outcomes included the rate of cholecystectomy during the index admission as well as pancreatitis recurrence and readmission at 30 and 180 days (30d, 180d) comparing NOM to same hospitalization cholecystectomy. Mortality upon readmission, total length of stay (LOS), and total costs (combined index-readmission hospital costs) were also explored. Cox proportional hazards regression and generalized linear models controlled for patient/hospital confounders.Among the 65,067 patients identified, 30% underwent cholecystectomy. The NOM cohort was older (58 vs. 50 years), had more comorbidities (Charlson index gt; 2, 23.5% vs. 11.5%), fewer female patients (56.7% vs. 67%) and less discharge-to-home (84.9% vs. 94.4%) (all p lt; 0.001). NOM was associated with increase in recurrence and unplanned readmissions at 30d [Hazard Ratio 3.53 (95% CI 2.92-4.27), 2.41 (2.11-2.74), respectively], and 180d [4.27 (3.65-4.98), 2.78 (2.54-3.04), respectively], as well as increased mortality during 180d readmission 1.88 (1.06-3.35). This approach was also associated with significant increase in LOS [predicted mean difference 2.79 days (95% CI 2.46-3.12)] and total costs [$2507.89 ($1714.4-$3301.4)].In the USA, most patients presenting with mild GP do not undergo same hospitalization cholecystectomy. This strategy results in higher recurrent pancreatitis, mortality during readmission, and an additional $4.85 M/year in hospital costs nationwide. These data support same hospitalization cholecystectomy as the gold standard for mild GP.

Surgeons often assume patients may be dissatisfied if their operations were stopped due to suspicious intraoperative findings requiring transfer of care. We sought to assess patient opinions regarding transfer of care for unexpected intraoperative findings during laparoscopic cholecystectomy with and without bile duct injury (BDI). The investigators developed two clinical scenarios comparing transfer of care for unexpected intraoperative findings during elective laparoscopic cholecystectomy: without BDI and with BDI requiring open repair. A multi-institutional structured telephone interview process was conducted with patients ≥ 18 years of age who had an outpatient, uncomplicated laparoscopic cholecystectomy within the last year. The first scenario presented a case of suspicious findings prompting the surgeon to stop and transfer for specialized care; whereas the second case was a BDI requiring transfer of care. Textual and thematic analysis as well as descriptive statistics was used for analysis, with significance set at p

Some controversy surrounds the postoperative feeding regimen utilized in patients who undergo esophagectomy. Variation in practices during the perioperative period exists including the type of nutrition started, the delivery route, and its timing. Adequate nutrition is essential for this patient population as these patients often present with weight loss and have altered eating patterns after surgery, which can affect their ability to regain or maintain weight. Methods of feeding after an esophagectomy include total parenteral nutrition, nasoduodenal/nasojejunal tube feeding, jejunostomy tube feeding, and oral feeding. Recent evidence suggests that early oral feeding is associated with shorter LOS, faster return of bowel function, and improved quality of life. Enhanced recovery pathways after surgery pathways after esophagectomy with a component of early oral feeding also seem to be safe, feasible, and cost-effective, albeit with limited data. However, data on anastomotic leaks is mixed, and some studies suggest that the incidence of leaks may be higher with early oral feeding. This risk of anastomotic leak with early feeding may be heavily modulated by surgical approach. No definitive data is currently available to definitively answer this question, and further studies should look at how these early feeding regimens vary by surgical technique. This review aims to discuss the existing literature on the optimal route and timing of feeding after esophagectomy.

Paraesophageal hernia repair (PEHR) is burdened by high recurrence rates that frequently lead to redo PEHR. Revisional surgery, because of higher complexity, higher risk of injury, and the intrinsic risk of recurrence, has increased likelihood of higher complication rates and decreased quality of life (QOL) postoperatively. We aimed to compare perioperative outcomes and QOL after revisional and primary PEHR. A retrospective review of all patients who underwent PEHR for a recurrent hernia between January 2011 and July 2016 was completed. These were matched with a contemporary cohort of patients who underwent primary PEHR by age, gender, and BMI. Perioperative measures were compared. The patients were invited to complete the Gastrointestinal Quality of Life Index (GIQLI) to assess response to surgical intervention. There were 24 patients (group 1) who underwent revisional PEHR, and they were matched to 48 patients (group 2) who had a primary hernia repair. Thirteen patients in group 1 responded to the survey (54%), whereas 21 patients’ responses were received from group 2 (44%). Conversion rates, LOS, and mean Gastrointestinal Quality of Life Index scores were significantly different between the two groups. Reoperative procedures for paraesophageal and hiatal hernias are burdened by higher conversion rates and length of stay, with similar overall complication rates. Patients who are undergoing repair of a recurrent hernia should be preoperatively counseled, and should have realistic expectations of their GI QOL after surgery.

BACKGROUND: This study was designed to determine whether a standardized recovery pathway could reduce post-pancreaticoduodenectomy hospital length of stay to 5 days without increasing complication or readmission rates. STUDY DESIGN: Pancreaticoduodenectomy patients (high-risk patients excluded) were enrolled in an IRB-approved, prospective, randomized controlled trial (NCT02517268) comparing a 5-day Whipple accelerated recovery pathway (WARP) with our traditional 7-day pathway (control). Whipple accelerated recovery pathway interventions included early discharge planning, shortened ICU stay, modified postoperative dietary and drain management algorithm, rigorous physical therapy with in-hospital gym visit, standardized rectal suppository administration, and close telehealth follow-up post discharge. The trial was powered to detect an increase in postoperative day 5 discharge from 10% to 30% (80% power, α = 0.05, 2-sided Fisher’s exact test, target accrual: 142 patients). RESULTS: Seventy-six patients (37 WARP, 39 control) were randomized from June 2015 to September 2017. A planned interim analysis was conducted at 50% trial accrual resulting in mandatory early stoppage, as the predefined efficacy end point was met. Demographic variables between groups were similar. The WARP significantly increased the number of patients discharged to home by postoperative day 5 compared with controls (75.7% vs 12.8%; p < 0.001) without increasing readmission rates (8.1% vs 10.3%; p = 1.0). Overall complication rates did not differ between groups (29.7% vs 43.6%; p = 0.24), but the WARP significantly reduced the time from operation to adjuvant therapy= initiation (51 days vs 66 days; p = 0.005) and hospital cost ($26,563 vs $31,845; p = 0.011). CONCLUSIONS: The WARP can safely reduce hospital length of stay, time to adjuvant therapy, and cost in selected pancreaticoduodenectomy patients without increasing readmission risk.

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 μg/ml for B. anthracis, ≤0.0005 - 0.03 μg/ml for Y. pestis, 0.25 - 1 μg/ml for B. mallei, and 1 - 4 μg/ml for B. pseudomallei In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p

The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

The increased incidence of anemia in patients with hiatal hernias (HH) and resolution of anemia after HH repair (HHR) have been clearly demonstrated. However, the implications of preoperative anemia on postoperative outcomes have not been well described. In this study, we aimed to identify the incidence of preoperative anemia in patients undergoing primary HHR at our institution and sought to determine whether preoperative anemia had an impact on postoperative outcomes. Using our IRB-approved institutional HH database, we retrospectively identified patients undergoing primary HHR between January 2011 and April 2017 at our institution. We identified patients with anemia, defined as serum hemoglobin levels less than 13 mg/dL in men and 12 mg/dL in women, measured within two weeks prior to surgery, and compared this group to a cohort of patients with normal preoperative hemoglobin. Perioperative outcomes analyzed included estimated blood loss (EBL), operative time, perioperative blood transfusions, failed postoperative extubation, intensive care unit (ICU) admission, postoperative complications, length of stay (LOS), and 30-day readmission. Outcomes were compared by univariable and multivariable analyses, with significance set at p

Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, have become increasingly challenging to successfully treat. The beta-lactam antibiotic subclass, the carbapenems, have proven valuable for the treatment of such Gram-negative bacterial infections due to their spectrum and β-lactamase stability properties. However, all marketed carbapenems to date are parenterally administered to adult patients. Areas covered: One carbapenem, tebipenem-pivoxil (TBPM-PI), is an oral prodrug that was approved in Japan for pediatric use only in 2009. This review summarizes preclinical and clinical data for TBPM-PI, which is now in clinical development again this time for use as the first oral carbapenem available for treatment of bacterial infections in adult patients. Expert commentary: There is an urgent unmet need with an increasing prevalence of fluoroquinolone-resistant and ESBL-producing Gram-negative pathogens in the hospital and community setting. Carbapenems have traditionally been considered the drugs of choice for infections caused by enterobacteria producing ESBL and AmpC enzymes because they are not affected by these resistance mechanisms. The carbapenem, TBPM-PI, offers an oral option, particularly as step-down therapy, for use of this class in the treatment of serious Gram-negative infections.

Postoperative pancreatic fistula (PF) remains one of the most significant complications after pancreaticoduodenectomy (PD). Recently, studies have suggested that post-PD serum hyper-amylasemia (HA) may be a risk factor. In this study, we evaluate the relationship of pancreas texture and post-operative serum amylase levels in determining PF risk. This retrospective cohort study evaluated all patients who underwent PD at Thomas Jefferson University from 2009 to 2014. The highest postoperative serum amylase level from postoperative day (POD) 0 to POD 5 was obtained. Chi-square analyses and odds ratio (OR) evaluated the relationship between pancreas texture, serum amylase level, and the development of PF. Data from 524 consecutive patients were analyzed. Serum amylase threshold value of 165 IU/L yielded greatest accuracy from the receiver operating characteristic curve analysis (Sensitivity, 0.70; specificity, 0.72). Grade B or C PF were more common among HA patients (20 vs 3%; P < 0.001). HA was associated with increased rates of PD-associated complications. On multivariable analysis, early postoperative serum HA was more predictive of PF risk (OR, 4.87; P < 0.001) than either pancreatic duct size ≤3 mm (OR, 2.97; P = 0.01) or pancreas texture (OR,1.87; P = 0.05). Conclusion: The presence of HA on POD 0 or POD 1 is more predictive than soft pancreas texture or small pancreas duct size alone.

Background Bloodstream infections (BSI) are a significant cause of morbidity and mortality. Enterobacterales (ENT) are frequently implicated in BSI with an increase in organisms producing extended-spectrum β-lactamase (ESBL). This challenges a possible transition to current oral agents due to co-resistance. Carbapenems are active against ESBL-ENT and tebipenem (TBP) is a new oral carbapenem in clinical development. The aim of the study was to assess resistance (R) among BSI isolates and activity of TBP and comparators against ENT collected in a 2019 surveillance study. Methods 2612 ENT from BSI were centrally tested by reference broth microdilution. Isolates were from medical centers in the US, Europe (EU), Latin America (LA) and Asia Pacific (AP). MIC results were interpreted according to CLSI, including ESBL assignment. CRE were sequenced to identify carbapenemase genes. Results Among the ENT, non-susceptibility (NS) rates to ceftazidime, levofloxacin were 20.4 and 27.0%, respectively, and R to trimethoprim-sulfamethoxazole was 31.1%. NS rates for ertapenem (ETP) and MER were 4.9 and 2.7%, respectively. MIC90s for TBP, ETP and MER were 0.12, 0.12 and 0.06 µg/mL, respectively. The MIC90 for TBP was 0.06 µg/mL for ENT from the US and 0.12 µg/mL for isolates from EU, LA and AP. Escherichia coli (EC) was the most prevalent (52% of ENT isolates) and the MIC90 for TBP ranged from 0.015 µg/mL for isolates in the US/EU to 0.03 µg/mL for isolates in LA/AP. ESBL-EC ranged from 15.7% in US to 34.3% in LA. TBP was active against ESBL-EC with an MIC90 of 0.03 µg/mL. Klebsiella pneumoniae (KP) accounted for 22.7% of BSI caused by ENT and TBP MIC90 ranged from 0.06 µg/mL for KP in US to >8 µg/mL in EU, LA and AP. MER-R KP ranged from 2.4% in US to 14.9% in LA. KPC-2, -3 and NDM were the most prevalent carbapenemases. TBP MIC90 values for MER-S ESBL KP in EU, LA and AP were ≤0.12 µg/mL. Conclusion TBP activity was similar to ETP and MER against ENT responsible for BSI. R to oral agents was compromised by ESBL co-resistance. TBP was among the most active agents against EC isolates and ESBL phenotypes. Among KP, TBP was more active against isolates from US where prevalence of CRE was lower than EU, LA and AP. TBP may be considered as an alternative oral option for BSI caused by non-CRE ESBL-producing ENT. Disclosures Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

Background Pulmonary infections caused by Nontuberculous Mycobacteria (NTM) are increasing in prevalence and are associated with high mortality and morbidity. Members of the Mycobacterium avium complex (MAC; primarily M. avium and M. intracellulare) and M. abscessus are most commonly associated with NTM pulmonary disease. Treatment options are limited and new agents with potent activity are needed. In this study, the activity of SPR719, a novel aminobenzimidazole, against NTM is reported. MIC range and MIC50/90 summary table Methods The susceptibility of 58 non-consecutive, non-duplicate clinical NTM isolates was determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) standard M24. Isolates included 20 rapidly-growing mycobacteria (10 M. abscessus/chelonae Group, 6 M. fortuitum Group, and 4 M. mucogenicum Group) and 38 slow-growing mycobacteria (28 MAC and 10 M. kansasii). SPR719 and comparators clarithromycin (CLA), amikacin (AMK), moxifloxacin (MXF), rifabutin (RFB), minocycline (MIN), and imipenem (IPM) were evaluated. Minimum bactericidal concentrations (MBC) for SPR719, CLA, and AMK were determined in accordance with CLSI M26. Results The activity of SPR719 and comparators by MIC range and MIC50/90 (µg/mL) is summarized in the accompanying table. SPR719 activity was not affected by resistance to CLA, AMK, or MXF. MBC:MIC ratios for SPR719 and CLA were typically >8 which indicates a bacteriostatic mode of action; AMK MBC:MIC ratios were typically ≤ 4 indicative of bactericidal activity. Conclusion SPR719 had potent activity by both MIC50/90 and MIC range across the evaluated NTM species. The SPR719 activity against clinically relevant MAC and M. abcessus/chelonae Group isolates was comparable or superior to the evaluated comparators, and SPR719 was active against isolates resistant to currently utilized agents. These results highlight the potential of SPR719 in the treatment of NTM pulmonary disease. Disclosures Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Michael Pucci, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder)

The Siewert classification system for gastroesophageal junction adenocarcinoma has provided morphological and topographical information to help guide surgical decision-making. Evidence has shown that Siewert I and III tumors are distinct entities with differing epidemiologic and histologic characteristics and distinct patterns of disease progression, requiring different treatment. Siewert II tumors share some of the characteristics of type I and III lesions, and the surgical approach is not universally agreed upon. Appropriate surgical options include transthoracic esophagogastrectomy, transhiatal esophagectomy, and transabdominal extended total gastrectomy. A review of the available evidence of the surgical management of Siewert II tumors is presented. Careful review of the data appear to support the fact that a satisfactory oncologic resection can be achieved via a transabdominal extended total gastrectomy with a slight advantage in terms of perioperative complications, and overall postoperative quality of life. Overall and disease-free survival compares favorably to the transthoracic approach. These results can be achieved with careful selection of patients balancing more than just the Siewert type in the decision-making but considering also preoperative T and N stages, histological type (diffuse type requiring longer margins that are not always achievable via gastrectomy), and the presence of Barrett’s esophagus.

The effects of neoadjuvant chemoradiation therapy on lymph node retrieval during esophagectomy for patients with esophageal cancer are unclear. The aim of this study was to quantify lymph node retrieval after R0 esophagectomy and to assess its impact on overall survival in induction therapy patients. One hundred seventy-four consecutive patients underwent esophagectomy with or without induction therapy from 2008 to 2015 for esophageal cancer. Total lymph nodes, positive lymph nodes, and lymph node ratios were compared between two groups of patients: those treated with either upfront surgery or those treated with neoadjuvant chemoradiation therapy followed by surgery. Comparisons were made using Student’s t test. Overall survival was obtained and compared using Kaplan Meier survival curves. Total lymph node counts were less in the induction therapy group (p = 0.027), while positive lymph node counts and lymph node ratios did not differ between groups (p = 0.262 and p = 0.310, respectively). In the neoadjuvant chemoradiation followed by surgery group, overall survival was significantly shorter for patients who had any positive lymph nodes in the pathologic specimen (p = 0.0065). Total lymph node counts were significantly lower in the induction therapy group, while positive lymph node counts and lymph node ratios did not differ from the upfront surgery group. Although overall survival was not different between groups, it was decreased within the induction therapy cohort among those who had any positive lymph nodes retrieved at surgery. This study confirms that unstratified gross lymph node counts do not substantially relate to prognosis in the heterogeneous population of locally advanced esophageal cancer patients who may or may not have had neoadjuvant chemoradiation.

While our institutional approach to esophageal resection for cancer has traditionally favored a minimally invasive (MI) 3-hole, McKeown esophagectomy (MIE 3-hole) during the last five years several factors has determined a shift in our practice with an increasing number of minimally invasive Ivor Lewis (MIE IL) resections being performed. We compared peri-operative outcomes of the two procedures, hypothesizing that MIE IL would be less morbid in the peri-operative setting compared to MIE 3-hole. Our institution’s IRB-approved esophageal database was queried to identify all patients who underwent totally MI esophagectomy (MIE IL vs. MIE 3-hole) from June 2011 to May 2016. Patient demographics, preoperative and peri-operative data, as well as post-operative complications were compared between the two groups. Post-operative complications were analyzed using the Clavien-Dindo classification system. There were 110 patients who underwent totally MI esophagectomy (MIE IL n = 49 [45%], MIE 3-hole n = 61 [55%]). The majority of patients were men (n = 91, 83%) with a median age of 62.5 (range 31–83). Preoperative risk stratifiers such as ECOG score, ASA, and Charlson Comorbidity Index were not significantly different between groups. Anastomotic leak rate was 2.0% in the MIE IL group compared to 6.6% in the MIE 3-hole group (p = 0.379). The rate of serious (Clavien-Dindo 3, 4, or 5) post-operative complications was significantly less in the MIE IL group (34.7 vs. 59.0%, p = 0.013). Serious pulmonary complications were not significantly different (16.3 vs. 26.2%, p = 0.251) between the two groups. In this cohort, totally MIE IL showed significantly less severe peri-operative morbidity than MIE 3-hole, but similar rates of serious pulmonary complications and anastomotic leaks. These findings confirm the safety of minimally invasive Ivor Lewis esophagectomies for esophageal cancer when oncologically and clinically appropriate. Minimally invasive McKeown esophagectomy remains a satisfactory and appropriate option when clinically indicated.

Laparoscopic cholecystectomy is a common surgical procedure, and remains the gold standard for the management of benign gallbladder and biliary disease. While this procedure can be technically straightforward, it can also represent one of the most challenging operations facing surgeons. This dichotomy of a routine operation performed so commonly that poses such a hidden risk of severe complications, such as bile duct injury, must keep surgeons steadfast in the pursuit of safety. The "difficult gallbladder" requires strict adherence to the Culture of Safety in Cholecystectomy, which promotes safety first and assists surgeons in managing or avoiding difficult operative situations. This review will discuss the management of the difficult gallbladder and propose the use of subtotal fenestrating cholecystectomy as a definitive option during this dangerous situation.

Alkyl quinolone molecules 2-heptyl-4-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) are important quorum sensing signals, which play a mediatory role in the pathogenesis of acute and chronic Pseudomonas aeruginosa infection. A targeted approach inhibiting the bacterial 'multiple virulence factor regulon' (MvfR) protein complex, offers the possibility to block the synthesis of MvfR-dependant signal molecules. Here, a high throughput bioanalytical method was developed using LC-MS/MS detection for the selective determination of HHQ and PQS in mouse tissue homogenate, over a sensitive range of 1-5000 and 10-5000pg/mL, respectively. Chromatographic peak distortion of the iron chelator PQS was overcome with the applied use of a bidentate chelator mobile phase additive 2-Picolinic acid at 0.2mM concentration, giving an improved separation and response for the analyte, whilst maintaining overall MS system robustness. Following thigh infection with P. aeruginosa strain 2-PA14 in mice, the concentration and time course of HHQ and PQS (4-hydroxy-2-alkyl-quinolone (HAQ) biomarkers) residing in the biophase were evaluated, and exhibited a low level combined with a substantial inter-individual variability. Quantifiable levels could be obtained from approximately 15h post infection, to the study termination at 21-22h. A dose dependant reduction in HAQ tissue concentrations at selected time points were obtained following MvfR inhibitor administration versus drug vehicle (p

The life and work of Dr. Lyon Henry Appleby, M.D., portrays the essence of a devoted clinician committed to scholarly excellence. Born in Deseronto, Ontario, in 1895 and passing in 1970, Dr. Appleby influenced all areas of general surgery, most notably popularizing a procedure that bears his name today. After a tour in World War I, he quickly proved himself to be a dedicated clinician with roots in academia, which translated into excellence within the Department of Surgery at St. Paul's Hospital in Vancouver, Canada. He served in various leadership roles including Chair of the Department of Surgery, President of the International College of Surgeons, and Fellow of the Royal College of Physicians and Surgeons. The Appleby procedure, or en bloc removal of the celiac axis, at the time of gastrectomy, is the technical focus of this paper, although reference is made to Appleby's extensive contributions to historical medicine.

The optimal management of achalasia in obese patients is unclear. For those who have undergone Heller myotomy and fundoplication, the long-term outcomes and their impressions following surgery are largely unknown.A retrospective review of patients who underwent laparoscopic Heller myotomy and Dor fundoplication (LHMDF) for achalasia was performed. From this cohort, Class 2 and 3 obese (BMI 35 kg/mBetween 2003 and 2015, 252 patients underwent LHMDF for achalasia, and 17 (7%) patients had BMI 35 kg/mLHMDF for achalasia in obese patients is safe and effective in the short term. At long-term follow-up, many patients had symptom recurrence and experienced minimal weight loss. Discussing weight-loss surgery at the time LHMDF may be appropriate to ensure long-term achalasia symptom relief.

Careful dissection and accurate decision-making is the key to performing a safe laparoscopic cholecystectomy. The focus of this chapter is to describe standard safety maneuvers in order to achieve the goals of this operation. Careful patient selection, appropriate timing of the operation, and adherence to safe principles, namely, achieving all three aspects of the critical view of safety (CVS) and recognizing triggers for a “safety pause,” are paramount to preventing vascular or biliary injuries.

Paraesophageal hernia repair (PEHR) is burdened by high recurrence rates that frequently lead to redo PEHR. Revisional surgery, because of higher complexity, higher risk of injury, and the intrinsic risk of recurrence, has increased likelihood of higher complication rates and decreased quality of life (QOL) postoperatively. We aimed to compare perioperative outcomes and QOL after revisional and primary PEHR. A retrospective review of all patients who underwent PEHR for a recurrent hernia between January 2011 and July 2016 was completed. These were matched with a contemporary cohort of patients who underwent primary PEHR by age, gender, and BMI. Perioperative measures were compared. The patients were invited to complete the Gastrointestinal Quality of Life Index (GIQLI) to assess response to surgical intervention. There were 24 patients (group 1) who underwent revisional PEHR, and they were matched to 48 patients (group 2) who had a primary hernia repair. Thirteen patients in group 1 responded to the survey (54%), whereas 21 patients' responses were received from group 2 (44%). Conversion rates, LOS, and mean Gastrointestinal Quality of Life Index scores were significantly different between the two groups. Reoperative procedures for paraesophageal and hiatal hernias are burdened by higher conversion rates and length of stay, with similar overall complication rates. Patients who are undergoing repair of a recurrent hernia should be preoperatively counseled, and should have realistic expectations of their GI QOL after surgery.

Urinary tract infections (UTIs) caused by Escherichia coli have been historically managed with oral antibiotics including the cephalosporins, fluoroquinolones and trimethoprim-sulfamethoxazole. The use of these agents is being compromised by the increase in extended spectrum β-lactamase (ESBL)-producing organisms, mostly caused by the emergence and clonal expansion of E. coli multilocus sequence typing (ST) 131. In addition, ESBL isolates show co-resistance to many of oral agents. Management of UTIs caused by ESBL and fluoroquinolone-resistant organisms is becoming increasingly challenging to treat outside of the hospital setting with clinicians having to resort to intravenous agents. The aim of this study was to assess the prevalence of ESBL phenotypes and genotypes among UTI isolates of E. coli collected in the US during 2017 as well as the impact of co-resistance to oral agents such as the fluoroquinolones and trimethoprim-sulfamethoxazole. The national prevalence of ESBL phenotypes of E. coli was 15.7% and was geographically distributed across all nine Census regions. Levofloxacin and trimethoprim-sulfamethoxazole-resistance rates were ≥ 24% among all isolates and this co-resistance phenotype was considerably higher among isolates showing an ESBL phenotype (≥ 59.2%) and carrying blaCTX-M-15 (≥ 69.5%). The agents with the highest potency against UTI isolates of E. coli, including ESBL isolates showing cross-resistance across oral agents, were the intravenous carbapenems. The results of this study indicate that new oral options with the spectrum and potency similar to the intravenous carbapenems would address a significant unmet need for the treatment of UTIs in an era of emergence and clonal expansion of ESBL isolates resistant to several classes of antimicrobial agents, including oral options.

Background Escherichi coli (EC) is a predominant urinary tract infection (UTI) pathogen where increasing prevalence of extended spectrum-β-lactamase (ESBL) continues to compromise the use of currently available oral antibiotics. ESBL-producing EC exhibit coresistance to the fluoroquinolones (FQs) and trimethoprim-sulfamethoxazole (TMP-SMX) making treatment of UTIs outside the hospital difficult and intravenous (IV) agents are often needed. Tebipenem (TBP) is an oral carbapenem with similar activity to IV carbapenems in clinical development for treating complicated UTIs (cUTI). This study assessed the activity of TBP against EC collected from UTIs in the US including isolates R to oral agents. Methods 1133 EC from UTIs in the 2019 STEWARD Surveillance Program were tested for susceptibility to TBP and comparators. Isolates were collected from medical centers geographically distributed across the US Census regions, centrally tested, and susceptibility (S) interpreted according to CLSI criteria. Results Overall prevalence of ESBL EC from UTI was 15.4% and R to oral cefuroxime, levofloxacin and TMP-SMX were: 15.6%, 23.9% and 33.5%, respectively. In contrast, low R was observed for the IV carbapenems. All EC were inhibited by TBP at ≤0.5 µg/mL and the MIC90 was 0.015 µg/mL compared with MIC90s of 0.03 µg/mL for meropenem (MER) and ertapenem (ETP). Using a tentative PK/PD cut off of 0.12 µg/mL 99.7% of EC were inhibited by TBP. The MIC90s for LEV and TMP-SMX were 32 and >16 µg/mL, respectively, against ESBL EC with R rates at ≥66.3%. MIC90s of 0.03, 0.03 and 0.12 µg/mL, respectively, were noted for TBP, MER (100% S) and ETP (99.6% S). TBP was active against LEV-R, TMP-SMX-R and MDR (≥3 classes) EC with MIC90s of 0.03 µg/mL. Conclusion R to oral agents remains high, raising concerns on empiric use. Carbapenems remain active against EC due to their stability to ESBLs and are not compromised by co-resistance. TBP is an oral carbapenem with similar activity to IV carbapenems based on comparison of MIC90 values. Although no breakpoints are available, ≥99.7% of EC were inhibited by TBP at ≤0.12 µg/mL highlighting potential as a new oral option for cUTIs in an era of ESBL mediated co-resistance to the FQs and TMP-SMX. Disclosures Ian A. Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Michael J. Pucci, PhD, Spero Therapeutics (Employee)Spero Therapeutics (Employee) Akash Jain, PhD, Spero Therapeutics (Employee) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)

Laparoscopic cholecystectomy (LC) is a commonly performed surgical procedure; however, it is associated with an increased rate of bile duct injury (BDI) when compared to the open approach. The critical view of safety (CVS) provides a secure method of ductal identification to help avoid BDI. CVS is not universally utilized by practicing surgeons and/or taught to surgical residents. We aimed to pilot a safe cholecystectomy curriculum to demonstrate that educational interventions could improve resident adherence to and recognition of the CVS during LC.Forty-three general surgery residents at Thomas Jefferson University Hospital were prospectively studied. Fifty-one consecutive LC cases were recorded during the pre-intervention period, while the residents were blinded to the outcome measured (CVS score). As an intervention, a comprehensive lecture on safe cholecystectomy was given to all residents. Fifty consecutive LC cases were recorded post-intervention, while the residents were empowered to "time-out" and document the CVS with a doublet photograph. Two independent surgeons scored the videos and photographs using a 6-point scale. Residents were surveyed pre- and post-intervention to determine objective knowledge and self-reported comfort using a 5-point Likert scale.In the 18-week study period, 101 consecutive LCs were adequately captured and included (51 pre-intervention, 50 post-intervention). Patient demographics and clinical data were similar. The mean CVS score improved from 2.3 to 4.3 (p 0.001). The number of videos with CVS score4 increased from 15.7 to 52 % (p 0.001). There was strong inter-observer agreement between reviewers. The pre- and post-intervention questionnaire response rates were 90.7 and 83.7 %, respectively. A greater number of residents correctly identified all criteria of the CVS post-intervention (41-93 %, p 0.001) and offered appropriate bailout techniques (77-94 %, p 0.001). Residents strongly agreed that the CVS education should be included in general surgery residency curriculum (mean Likert score = 4.71, SD = 0.54). Residents also agreed that they are more comfortable with their LC skills after the intervention (4.27, σ = 0.83).The combination of focused education along with intraoperative time-out significantly improved CVS scores and knowledge during LC in our institution.

Less than complete cholecystectomy has been advocated for difficult operative conditions for more than 100 years. These operations are called partial or subtotal cholecystectomy, but the terms are poorly defined and do not stipulate whether a remnant gallbladder is created. This article briefly reviews the history and development of the procedures and introduces new terms to clarify the field. The term partial is discarded, and subtotal cholecystectomies are divided into "fenestrating" and "reconstituting" types. Subtotal reconstituting cholecystectomy closes off the lower end of the gallbladder, reducing the incidence of postoperative fistula, but creates a remnant gallbladder, which may result in recurrence of symptomatic cholecystolithiasis. Subtotal fenestrating cholecystectomy does not occlude the gallbladder, but may suture the cystic duct internally. It has a higher incidence of postoperative biliary fistula, but does not appear to be associated with recurrent cholecystolithiasis. Laparoscopic subtotal cholecystectomy has advantages but may require advanced laparoscopic skills.

Carbapenems are potent antibacterials with broad-spectrum activity. However, poor oral absorption generally confines this important drug class to in-hospital use by intravenous (IV) administration. The continued rise in drug resistant pathogens creates a need for alternative oral therapies with broad-spectrum activity. SPR994 is a novel formulation of the orally bioavailable pivoxil prodrug of SPR859 (tebipenem) and is being developed as the first oral carbapenem for treatment of complicated urinary tract infections (cUTIs) in adults. Herein, we describe characteristics beneficial to oral administration and compare the in vitro and in vivo activity of SPR859 or SPR994 with IV carbapenems.

Postoperative pancreatic fistula (PF) remains one of the most significant complications after pancreaticoduodenectomy (PD). Recently, studies have suggested that post-PD serum hyperamylasemia (HA) may be a risk factor. In this study, we evaluate the relationship of pancreas texture and post-operative serum amylase levels in determining PF risk. This retrospective cohort study evaluated all patients who underwent PD at Thomas Jefferson University from 2009 to 2014. The highest postoperative serum amylase level from postoperative day (POD) 0 to POD 5 was obtained. Chi-square analyses and odds ratio (OR) evaluated the relationship between pancreas texture, serum amylase level, and the development of PF. Data from 524 consecutive patients were analyzed. Serum amylase threshold value of 165 IU/L yielded greatest accuracy from the receiver operating characteristic curve analysis (Sensitivity, 0.70; specificity, 0.72). Grade B or C PF were more common among HA patients (20 vs 3%; P0.001). HA was associated with increased rates of PD-associated complications. On multivariable analysis, early postoperative serum HA was more predictive of PF risk (OR, 4.87; P0.001) than either pancreatic duct size ≤3 mm (OR, 2.97; P = 0.01) or pancreas texture (OR,1.87; P = 0.05).The presence of HA on POD 0 or POD 1 is more predictive than soft pancreas texture or small pancreas duct size alone.

SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

Background Synoptic operative reports (SOR) are more accurate than dictated operative reports (DOR) in a few single institution experiences. We sought to examine the completeness of SOR for laparoscopic cholecystectomy (LC) and pancreaticoduodenectomy (PD) in a multi institutional pilot study. Methods Six institutions participated in SOR submission via a web-based survey. One institution collected DOR and case matched historical dictated operative reports (HOR) for subset analysis. A checklist evaluated completeness of all reports. A post-survey assessed participant opinions. Results 40 PD SORs were 98.5% complete and 35 LC SORs were 99.7% complete. Single institution subset analysis respective percent complete were: 11 PD SORs 99%, DORs 70% and HORs 74% and 14 LC SORs 99.7%, DORs 76%, and HORs 75%. Post-survey results yielded 10 PD and 24 LC responses. An overwhelming majority agreed that SOR were easy to use and would prefer to use SOR compared to DOR. Conclusion SOR are more complete than both study associated DOR and HOR. The majority of surgeons indicated their preference for SOR and their willingness to use them.

The increased incidence of anemia in patients with hiatal hernias (HH) and resolution of anemia after HH repair (HHR) have been clearly demonstrated. However, the implications of preoperative anemia on postoperative outcomes have not been well described. In this study, we aimed to identify the incidence of preoperative anemia in patients undergoing primary HHR at our institution and sought to determine whether preoperative anemia had an impact on postoperative outcomes.Using our IRB-approved institutional HH database, we retrospectively identified patients undergoing primary HHR between January 2011 and April 2017 at our institution. We identified patients with anemia, defined as serum hemoglobin levels less than 13 mg/dL in men and 12 mg/dL in women, measured within two weeks prior to surgery, and compared this group to a cohort of patients with normal preoperative hemoglobin. Perioperative outcomes analyzed included estimated blood loss (EBL), operative time, perioperative blood transfusions, failed postoperative extubation, intensive care unit (ICU) admission, postoperative complications, length of stay (LOS), and 30-day readmission. Outcomes were compared by univariable and multivariable analyses, with significance set at p 0.05.We identified 263 patients undergoing HHR. The median age was 66 years and most patients were female (78%, n = 206). Seventy patients (27%) were anemic. In unadjusted analyses, anemia was significantly associated with failed postoperative extubation (7 vs. 2%, p = 0.03), ICU admission (13 vs. 5%, p = 0.03), postoperative blood transfusions (9 vs. 0%, p 0.01), and postoperative complications (41 vs. 18%, p 0.01). On adjusted multivariable analysis, anemia was associated with 2.6-fold greater odds of postoperative complications (OR 2.57; 95% CI 1.36-4.86; p 0.01).In this study, anemia had a prevalence of 27% in patients undergoing primary HHR. Anemic patients had 2.6-fold greater odds of developing postoperative complications. Anemia is common in patients undergoing primary HHR and warrants consideration for treatment prior to elective repair.

New approaches to antimicrobial drug discovery are urgently needed to combat intractable infections caused by multidrug-resistant (MDR) bacteria. M ultiple v irulence f actor r egulator (MvfR or PqsR), a Pseudomonas aeruginosa quorum sensing transcription factor, regulates functions important in both acute and persistent infections. Recently identified non-ligand-based benzamine-benzimidazole (BB) inhibitors of MvfR suppress both acute and persistent P. aeruginosa infections in mice without perturbing bacterial growth. Here, we elucidate the crystal structure of the MvfR ligand binding domain (LBD) in complex with one potent BB inhibitor, M64. Structural analysis indicated that M64 binds, like native ligands, to the MvfR hydrophobic cavity. A hydrogen bond and pi interaction were found to be important for MvfR-M64 affinity. Surface plasmon resonance analysis demonstrated that M64 is a competitive inhibitor of MvfR. Moreover, a protein engineering approach revealed that Gln194 and Tyr258 are critical for the interaction between MvfR and M64. Random mutagenesis of the full-length MvfR protein identified a single-amino-acid substitution, I68F, at a DNA binding linker domain that confers M64 insensitivity. In the presence of M64, I68F but not the wild-type (WT) MvfR protein retained DNA binding ability. Our findings strongly suggest that M64 promotes conformational change at the DNA binding domain of MvfR and that the I68F mutation may compensate for this change, indicating allosteric inhibition. This work provides critical new insights into the molecular mechanism of MvfR function and inhibition that could aid in the optimization of anti-MvfR compounds and improve our understanding of MvfR regulation. IMPORTANCE Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes serious acute, persistent, and relapsing infections. New approaches to antimicrobial drug discovery are urgently needed to combat intractable infections caused by this pathogen. The Pseudomonas aeruginosa quorum sensing transcription factor MvfR regulates functions important in both acute and persistent infections. We used recently identified inhibitors of MvfR to perform structural studies and reveal important insights that would benefit the optimization of anti-MvfR compounds. Altogether, the results reported here provide critical detailed mechanistic insights into the function of MvfR domains that may benefit the optimization of the chemical, pharmacological, and safety properties of MvfR antagonist series.

Background Recommendations of the Joint Commission discourage the use of surgical skull caps in favor of bouffant or helmet headwear; however, data supporting such recommendations are limited and have been questioned in recent studies, as well as by our departmental and hospital leadership. At the end of December 2015, surgical caps were removed from our institution with the theoretic goal of decreasing surgical site infections. We aimed to assess the impact of this intervention on surgical site infection occurrence at our institution. Methods Using our institutional American College of Surgeons National Surgical Quality Improvement Program General and Vascular procedure-targeted data, we identified patients undergoing any surgical procedure classified as clean or clean-contaminated during a 12-month period before and after implementation of the surgical headwear policy. Patients without complete 30-day follow-up were excluded. Cases with active infection at the time of operation were excluded. Vascular surgery operations were excluded because of the implementation of a separate intervention to decrease surgical site infections during the study period. Patients were grouped according to timing of the operation in relation to the policy change (12 months before or after). Descriptive statistics focused on proportions and adjusted logistic regression models were used to investigate the association of alternative headwear use with any type of surgical site infection. Models were adjusted for potential confounders that included demographics and clinical characteristics (age, sex, race or ethnicity, obesity, diabetes, steroid use, smoking status, cancer, urgency of the operation, and wound classification). Results A total of 1,901 patients underwent 1,950 procedures during the study period, with 767 (40%) before and 1,183 (60%) after the headwear policy measure was adopted. The most common procedures overall were colectomy (18%), pancreatectomy (13.5%), and ventral hernia repair (8.9%). The overall rate of any surgical site infection was 5.4%, with no difference before and after policy implementation (5.3% versus 5.5%; P = .81). Multivariate analysis controlling for age, sex, race or ethnicity, obesity, diabetes, smoking status, steroid use, cancer diagnosis, and type of wound classification showed no association between implementation of this new policy and surgical site infections occurrence (odds ratio 1.12 [95% confidence interval 0.73–1.71]; P = .59). Conclusion In our institution, the strict implementation of bouffant or helmet headwear, with removal of skull caps from the operating room, was not associated with decreased surgical site infections for clean and clean-contaminated cases. Further evidence is required to assess the validity of this headwear guideline of the Joint Commission and support nationwide implementation of this policy.

Suture and needles are the most essential equipment for the surgeon. Their structure and design have evolved thoroughly in the era of modern surgery. Suture varies based on its physical properties including material, construction, absorbability, size, tensile strength, length, and color. Similarly, needles vary in their point type, curvature, strength, length, and color. An array of combinations of sutures and needles has been created with specific surgical tasks in mind. While there is no ultimate suture that will work in any circumstance, certain guiding principles allow the surgeon to choose the best option. Our aim in this chapter is to provide information on the physical properties of suture and needles so that individuals feel comfortable calling for the proper suture for any surgical task.

The creation of a gastrointestinal anastomosis is a fundamental skill essential to general surgery. This chapter will detail the history of gastrointestinal anastomoses, will provide general principles to be used when joining segments in the gastrointestinal tract, and will review key technical considerations that the general surgeon should keep in mind when constructing some of the most common intestinal anastomoses. A brief review of current controversial areas is also provided.

Acinetobacter baumanniiis responsible for 10% of all nosocomial infections and has >50% mortality rates when causing ventilator-associated pneumonia. In this proof-of-concept study, we evaluated SPR741, an antibiotic adjuvant that permeabilizes the Gram-negative membrane, in combination with rifampin against AB5075, an extensively drug-resistant (XDR)A. baumanniistrain. In standardin vitroassays and in a murine pulmonary model, we found that this drug combination can significantly reduce bacterial burden and promote animal survival despite an aggressive infection.

Background: Correct preoperative diagnosis of hepatobiliary disease can be challenging—even with current advances in radiographical imaging, laboratory testing, and endoscopic evaluation. Case presentation 1: A 65-year-old female with painless jaundice and weight loss was found to have cholelithiasis complicated by the Mirizzi syndrome. Case presentation 2: A 71-year-old female with new-onset painless jaundice and impacted stone in the gallbladder neck was found to have a cholangiocarcinoma. Case presentation 3: A 70-year-old male with progressive painless jaundice and weight loss was found to have a pancreatic adenocarcinoma. Conclusion: Proper diagnosis and management of patients with painless jaundice can be difficult in the preoperative setting and may require surgical exploration to obtain a definitive diagnosis.

Laparoscopic resection is rapidly becoming the treatment of choice for small- to medium-sized gastric gastrointestinal stromal tumors (GIST). While long-term oncologic data are available, quality of life outcomes are less known. Our IRB-approved prospectively maintained database was retrospectively queried (2003–2013) for patients who underwent laparoscopic gastric GIST resection. Demographics along with perioperative and oncologic outcomes were collected and analyzed. Patients were contacted and asked to complete a quality of life survey consisting of Likert scales scored from 1 to 5. Patients also completed the Gastrointestinal Quality of Life Index (GIQLI). A total of 69 patients were identified and 36 patients (59.0 % of eligible patients) responded to the survey. Median follow-up was 39 months. Patients most commonly reported no change in weight, appetite, early satiety, heartburn, persistent cough, dysphagia, and reflux medication dosing postoperatively. The median scores for chest pain and regurgitation were 4, falling in the “worsened” range. 8.33 % of patients reported worsened chest pain and 11.11 % of patients reported worsened regurgitation postoperatively. The GIQLI scores had a mean of 126.9 (range 77–141). While some patients reported a worsening in early satiety, most patients reported no change in symptoms postoperatively, and the GIQLI scores remained within the normal range. Laparoscopic resection of gastric GIST provides durable results with minimal effect on longer-term quality of life.