Cefiderocol for Carbapenem-Resistant Bacteria: Handle with Care! A Review of the Real-World Evidence.

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile.

Mechanisms of Action of Carbapenem Resistance.

Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of ß-lactams that include the penicillins, cephalosporins, monobactams and carbapenems. This class of antimicrobials has a broader spectrum of activity than most other beta-lactams antibiotics and are the most effective against Gram-positive and Gram-negative bacteria. All ß-lactams antibiotics have a similar molecular structure: the carbapenems together with the ß-lactams. This combination gives an extraordinary stability to the molecule against the enzymes inactivating the ß-lactams. They are safe to use and therefore widespread use in many countries has given rise to carbapenem resistance which is a major global public health problem. The carbapenem resistance in some species is intrinsic and consists of the capacity to resist the action of antibiotics with several mechanisms: for the absence of a specific target, or an intrinsic difference in the composition of cytoplasmatic membrane or the inability to cross the outer membrane. In addition to intrinsic resistance, bacteria can develop resistance to antibiotics with several mechanisms that can be gathered in three main groups. The first group includes antibiotics with poor penetration into the outer membrane of bacterium or antibiotic efflux. The second includes bacteria that modify the target of the antibiotics through genetic mutations or post-translational modification of the target. The third includes bacteria that act with enzyme-catalyzed modification and this is due to the production of beta-lactamases, that are able to inactivate carbapenems and so called carbapenemases. In this review, we focus on the mode of action of carbapenem and the mechanisms of carbapenem resistance.

Pain in Intensive Care: A Narrative Review.

All critically ill adult patients in intensive care units (ICU) typically experience pain. Critically ill adults suffer pain of different intensities. It depends on individual characteristics, specific procedural interventions, and underlying diseases. Inadequate management of acute pain is a risk factor for the emergence of chronic pain, where the incidence is up to 33% into the ICU survivor population. For the management of pain, agitation, and delirium, several coexisting clinical practice guidelines have been published. The first problem is that the patient recovered in intensive care unit should not be able to communicate its pain state. Opioids are the analgesic drugs of choice in critically ill patients with non-neuropathic pain. All intravenous opioids have the same effects, respecting the equianalgesic table. Observational research has shown that opioids are the main analgesic treatment in over 80% of mechanically ventilated patients. It is interesting that opioid consumption in an ICU and the memory of painful experience are linked to the development of post-traumatic stress disorder after ICU discharge. In order to reduce the side effects and maintain analgesia, it is useful to associate adjuvant medications with opioids. An opportunity to improve patients' experience in an ICU is to manage pain through multimodal approaches.

Double-responsive hyaluronic acid-based prodrugs for efficient tumour targeting.

Hyaluronic acid (HA)-based prodrugs bearing double-responsive (acid pH or oxidation) boronates of catechol-containing drugs were used to treat xenografted human prostate tumours (LNCaP) in SCID mice. The HA prodrugs accumulated significantly only in tumours (impressively, up to 40% of the injected dose after 24 h) and in liver, with negligible - actually anti-inflammatory - consequences in the latter. A quercetin-HA prodrug significantly slowed down tumour growth, in a dose-dependent fashion and with a much higher efficacy (up to 4 times) than equivalent doses of free quercetin. In short, boronated HA appears to be a very promising platform for targeted chemotherapy.

Chitosan-coated liposomes loaded with butyric acid demonstrate anticancer and anti-inflammatory activity in human hepatoma HepG2 cells.

Butyric acid (BA) has been reported to induce anticancer effects on hepatocellular carcinoma (HCC) cells both in vitro and in vivo. However, its delivery and release in cancer tissues must be optimized. On the basis of these requirements, we prepared liposomes coated with chitosan and uncoated liposomes and both types were loaded with BA through a thin-film hydration method. The liposomes coated or uncoated with chitosan had a mean hydrodynamic size of 83.5 and 110.3 nm, respectively, with a homogeneous size distribution of the particles. For evaluation of the biological effects of the nanoformulations, the hepatoblastoma (HB) HepG2 cell line was utilized. BA-loaded liposomes coated with chitosan showed a considerable higher cytotoxicity than both uncoated liposomes and free BA, with IC50 values, after 72 h of incubation, of 7.5, 2.5 and 1.6 mM, respectively. Treatment of HepG2 cells for 5 h with the BA-loaded liposomes coated with chitosan at 5 mM lowered the extent of the increase in IL-8, IL-6, TNF-α and TGF-ß expression of approximately 64, 58, 85 and 73.8%, respectively, when compared to the untreated cells. The BA-loaded liposomes coated with chitosan had marked capacity to be internalized in human HB cells showing an increased cytotoxic activity when compared with free BA and important anti-inflammatory effects by inhibiting production of cytokines with a central role in liver cell survival.

Late Shoulder-Arm Morbidity Using Ultrasound Scalpel in Axillary Dissection for Breast Cancer: A Retrospective Analysis.

BACKGROUND: We aimed to assess whether the use of the harmonic scalpel (HS) in axillary dissection would reduce long-term shoulder-arm morbidity compared to traditional instruments (TIs). MATERIALS AND METHODS: A retrospective analysis on 180 patients who underwent standard axillary dissection for breast cancer between 2007 and 2015 was carried out. All patients were evaluated for postoperative pain, impairment of shoulder-arm mobility, seroma formation in axilla, frozen shoulder, and lymphedema. RESULTS: HS procedure on average was 50% shorter compared to the TI technique. HS reduced by 4.5 times the risk of axillary seroma. TIs were associated with 4 times higher risk of developing a painful frozen shoulder. CONCLUSIONS: Use of the HS was associated with reduced costs and a positive long-term effect on shoulder-arm morbidity. Axillary seromas are not the only reason of later postoperative shoulder-arm morbidity: other mechanisms are hypothesized in the onset of this very disabling disorder.

A 4-Week Preoperative Ketogenic Micronutrient-Enriched Diet Is Effective in Reducing Body Weight, Left Hepatic Lobe Volume, and Micronutrient Deficiencies in Patients Undergoing Bariatric Surgery: a Prospective Pilot Study.

BACKGROUND: Before bariatric surgery (BS), moderate weight loss, left hepatic lobe volume reduction, and micronutrient deficiency (MD) identification and correction are desirable. OBJECTIVES: The objective of this study was to assess the safety and the effectiveness of a 4-week preoperative ketogenic micronutrient-enriched diet (KMED) in reducing body weight (BW), left hepatic lobe volume, and correcting MD in patients scheduled for BS. MATERIALS AND METHODS: In this prospective pilot study, a cohort of morbidly obese patients (n = 27, 17 females, 10 males) with a mean body mass index (BMI) of 45.2 kg/m2 scheduled for BS underwent a 4-week preoperative KMED. Their BW, BMI, fat mass (FM), fat-free mass (FFM), resting metabolic rate (RMR), left hepatic lobe volume, micronutrient status, and biochemical and metabolic patterns were measured before and after the 4-week KMED. Patient compliance was assessed by validated questionnaires (3-day estimated food records and 72-h recall). Qualitative methods (5-point Likert questionnaire) were used to measure diet acceptability and side effects. RESULTS: All patients completed the study. We observed highly significant decreases in BW (- 10.3%, p < 0.001, in males; - 8.2%, p < 0.001, in females), left hepatic lobe volume (- 19.8%, p < 0.001), and an amelioration of patient micronutrient status. All patients showed a high frequency of acceptability and compliance in following the diet. No adverse side effect was reported. CONCLUSION: This study demonstrates that a 4-week preoperative KMED is safe and effective in reducing BW, left hepatic lobe volume, and correcting MD in obese patients scheduled for BS.

Low-Purine Diet Is More Effective Than Normal-Purine Diet in Reducing the Risk of Gouty Attacks After Sleeve Gastrectomy in Patients Suffering of Gout Before Surgery: a Retrospective Study.

BACKGROUND: Obese patients with preoperative gout often suffer of gouty attacks after bariatric surgery (BS), probably due to the lack of an adequate postoperative diet. OBJECTIVES: The objectives of the study are to assess whether sleeve gastrectomy (SG) is effective in reducing the frequency of gouty attacks and also whether a postoperative low-purine diet (LPD) may further reduce these attacks as compared to a normal-purine diet (NPD) in a series of patients suffering of gout before SG. METHODS: In this retrospective study, we measured and compared total body weight (TBW), body mass index (BMI), uric acid levels (UAL), anti-gout medication (allopurinol) requirements, and frequency in gouty attacks in 40 patients that underwent SG and who received either a LPD (n = 24) or NPD (n = 16). Compliance in following the prescribed diet was assessed in both groups study. RESULTS: Before surgery, LPD and NPD patients had hyperuricemia and were receiving allopurinol. One year after SG, LPD and NPD groups showed a significant decrease in serum UAL (p < 0.001 and p = 0.00175, respectively). However, serum UAL decreased more significantly with the LPD compared to the NPD (p < 0.001). Furthermore, while NPD group showed a significant decrease in allopurinol requirements (p = 0.00130) and on the frequency in gouty attacks (p < 0.001), LPD group were off allopurinol therapy and had no gouty attacks 12 months after SG. Both groups showed high compliance in following the prescribed diets. CONCLUSION: LPD is more effective in reducing the frequency of gouty attacks after SG compared with NPD in patients suffering of gout before surgery.

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme.

Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.

Suture thread check test for detection of surgical site contamination: a prospective study.

BACKGROUND: Surgical site infection (SSI) is a common complication of surgical procedures. AIM: Our study aimed at investigating a new method based on assessment of suture thread colonization to identify patients developing an SSI. MATERIALS AND METHODS: We prospectively enrolled 119 patients undergoing elective surgery. For each patient, a synthetic absorbable thread in Lactomer 9-1 (Polisorb Gauge 2) inserted in the surgical site at the end of surgery was sent to the microbiology laboratory after 48 h to assess colonization of its inner tract. RESULTS: Forty (33.6% of cases) patients had a colonized thread. Antibiotic prophylaxis was administered to 66 of 79 patients who did not display a colonized thread and to 20 of the 40 patients with a colonized thread (83.5% versus 50%, respectively, P = 0.0002). An SSI was observed only in patients with a colonized thread (10% versus 0, P = 0.02). The microorganisms identified in colonized threads were the same identified in SSIs. CONCLUSIONS: Since an SSI was found only in patients with colonized threads, the method described here may be valuable for identifying patients developing an SSI. Moreover, the method can also be useful for targeting efficient antibiotic therapy to the culprit microorganisms.

Fat mass, fat-free mass, and resting metabolic rate in weight-stable sleeve gastrectomy patients compared with weight-stable nonoperated patients.

BACKGROUND: There is evidence that body composition and resting metabolic rate (RMR) in weight-stable patients after Roux-en-Y gastric bypass and duodenal switch is similar to that of nonoperated individuals within the same body mass index (BMI) interval. Currently, data concerning fat mass (FM), fat-free mass (FFM), and RMR on weight-stable patients after sleeve gastrectomy (SG) are lacking. OBJECTIVES: To assess FM, FFM, and RMR, in a selected and homogenous population of weight-stable SG patients (WSSG) and compare them with those obtained from healthy normal weight-stable nonoperated (WSNO) volunteers controls of similar sex, age, and BMI. SETTING: University hospital, Italy. METHODS: We assessed total weight, FM, and FFM by bioelectrical impedance assay, and RMR by indirect calorimetry, in 70 WSSG patients (47 females, 23 males) at a mean follow-up of 3.2 ± 2.1 years after SG and compared them with 70 healthy WSNO volunteers, as controls (47 females, 23 males). RESULTS: There was no significant difference between WSSG and WSNO groups concerning total weight (males, 72 ± 2.66 versus 72.8 ± 1.99 kg, P = .0254; females 65.1 ± 2.53 versus 63.7 ± 2.87 kg, P = .0139), FM (males, 17.7 ± 1.53 versus 16.7 ± 1.57 kg, P = .0341; females 19.6 ± 0.50 versus 18.5 ± 2.85 kg, P = .0104), FFM (males, 54.3 ± 3.07 versus 56.1 ± 3.30 kg; P = .049; females 45.5 ± 2.29 versus 45.1 ± 1.13 kg, P = .287), and RMR (males, 1541 ± 121.3 versus 1463 ± 74.4 kcal/d; P = .0118; females 1214 ± 54.9 versus 1250 ± 90.1 kcal/d, P = .0215). CONCLUSION: At a mean follow-up of 3.2 ± 2.1 years after SG, WSSG patients of both sexes have a FM, FFM, and RMR comparable to that of healthy WSNO individuals within the same age and BMI interval. These findings further support bariatric surgery-induced weight loss as a physiologic process and indicate that young patients, in the setting of an adequate preoperative and postoperative specific diet and moderate physical activity, do not suffer from excessive FFM depletion after SG in the mid-term.

A Comparative Study Examining the Impact of a Protein-Enriched Vs Normal Protein Postoperative Diet on Body Composition and Resting Metabolic Rate in Obese Patients after Sleeve Gastrectomy.

BACKGROUND: We recently showed that an 8-week preoperative protein-enriched diet (PED) is associated with significant reductions in body weight and fat mass (FM) without significant loss of fat-free mass (FFM) in morbidly obese patients scheduled for laparoscopic sleeve gastrectomy (LSG). OBJECTIVES: The objective of this study is to evaluate the impact of PED vs a normal protein diet (NPD) on total weight loss (TWL), FM, FFM, and resting metabolic rate (RMR) in patients after LSG. METHODS: Before LSG and at 3, 6, and 12 months after, we prospectively measured and compared total body weight (TBW), FM, FFM, and RMR in 60 male patients who received either a NPD (n = 30) with protein intake 1.0 g/kg of ideal body weight, or a PED (n = 30) with protein intake 2.0 g/kg of ideal body weight. Compliance in following the prescribed diet was determined with food frequency questionnaires in all patients. The impact of NPD and PED on renal function was also evaluated. RESULTS: Despite non-significant variation in total body weight (TBW), FM decreased more significantly (p < 0.01) with the PED compared to the NPD. In addition, the PED group showed a significantly (p < 0.01) lower decrease in FFM and RMR when compared with the NPD group. Both groups showed high compliance in following the prescribed diets, without negative impact on renal function. CONCLUSION: PED is more effective than NPD in determining FM loss and is associated with a lower decrease in FFM and RMR, without interfering with renal function in male patients after LSG.

Hyaluronic Acid Nanohydrogel Loaded With Quercetin Alone or in Combination to a Macrolide Derivative of Rapamycin RAD001 (Everolimus) as a New Treatment for Hormone-Responsive Human Breast Cancer.

The aim of this study is based on the evaluation of anticancer, anti-inflammatory activities, and cellular uptake of hyaluronic acid nanohydrogel of quercetin tested alone and in combination to a macrolide derivative of rapamycin RAD001 (everolimus) on hormone-responsive breast cancer cell line MCF-7. Biological investigations were focused on the receptor mediated cellular internalization of the nanohydrogel and its abilities to reduce secretion of several cytokines (IL-8, IL-6, IL-19), VEGF, and metalloproteases (MMP-2, MMP-9) under pro-inflammatory conditions. Nanohydrogel show a CD44 dependent endocytosis with evident time dependent cytoplasmatic accumulation with abilities to reduce secretion of all cytokines of ∼60% compared to untreated cells. Combination of formulated quercetin and everolimus leads to a synergistic cytotoxic effects with a Combination Index of 0.38. These results highlights the importance of synergistic effect of the hyaluronic acid nanohydrogel of quercetin with everolimus in the regulation of human breast cancer cell proliferation and emphasize the antitumor and anti-inflammatory properties of the nanocarrier. J. Cell. Physiol. 232: 2063-2074, 2017. © 2016 Wiley Periodicals, Inc.

A giant inguinoscrotal hernia associated with other abdominal wall defects A case report.

INTRODUCTION: Giant inguinoscrotal hernias are unusual in developed countries and rarely associated with other wall hernias, such as controlateral inguinal hernia, umbilical hernia. The presence of more parietal defects can facilitate reinstatement of giant hernia content without respiratory and circulatory compromise, but the risk of occlusion and bowel strangulation results increased. CASE REPORT: Here, we report an unusual case of an asymptomatic giant inguinal hernia associated with controlateral inguinal and umbilical hernia in a 60 years old Caucasian male treated with sequential surgical approach. In particular, the Lichtenstein's technique under spinal anesthesia was performed and it could be considered the gold standard for this disease. CONCLUSION: Giant inguinal hernia and abdomen wall defects should not be repaired at the same time. It is more useful to be less aggressive, monitoring the progressive and natural adaptation of the viscera into the abdomen. Anyway, thereby literature results very poor and additional reports are required. KEY WORDS: Giant inguinoscrotal hernia, Hernia, Hernia treatment, Wall defects.

New Treatment of Medullary and Papillary Human Thyroid Cancer: Biological Effects of Hyaluronic Acid Hydrogel Loaded With Quercetin Alone or in Combination to an Inhibitor of Aurora Kinase.

The aim of this paper is based on the use of a hyaluronic acid hydrogel of Quercetin tested alone and in combination to an inhibitor of Aurora Kinase type A and B (SNS-314) on human medullary and papillary thyroid cancer cells. Biological investigations were focused on the cellular uptake of the hydrogel, cell viability, antioxidant, and cytokines secretion studies. Quercetin delivered from hydrogel show a time and CD44 dependent interaction with both cell lines with significant anti-inflammatory effects. Combination of Quercetin and SNS-314 leads to a synergistic cytotoxic effect on medullary TT and papillary BCPAP cell lines with a significant reduction of the IC50 value. These results, highlights the importance of synergistic effect of the hyaluronic acid hydrogel of Quercetin with SNS-314 in the regulation of human thyroid cancer cell proliferation and emphasize the anti-tumor activity of these molecules. J. Cell. Physiol. 231: 1784-1795, 2016. © 2015 Wiley Periodicals, Inc.

Sleeve gastrectomy to treat concomitant polycystyc ovary syndrome, insulin and leptin resistance in a 27-years morbidly obese woman unresponsive to insulin-sensitizing drugs: A 3-year follow-up.

INTRODUCTION: Insulin resistance (IR), leptin resistance (LR), and polycystic ovary syndrome (PCOS) commonly coexists with obesity. IR and PCOS are often successfully treated with the use of insulin-sensitizing drugs (ISDs). However, some women are poorly responsive or intolerant to them. If we additionally consider that currently no medical treatment for LR exists, it is crucial for the physician to find different therapeutic ways to treat patients with such multifactorial endocrinopathy. PRESENTATION OF CASE: We present a case where sleeve gastrectomy (SG) was applied to a 27-year-old obese woman affected by concomitant IR, LR and PCOS, and unresponsive to ISDs. At three years from surgery the patient is now 71.6kg. More importantly, her levels of insulin and leptin started to improve at postoperative month 6 and became normal at postoperative month 24. Patient's ovaries that at baseline had characteristic aspects related to PCOS, at postoperative month 36 were normal. DISCUSSION: SG is one of the most commonly performed bariatric procedures. The literature has moved away from labeling SG as a purely restrictive procedure, as its interactions with several hormones (ghrelin, leptin, insulin, etc.) are now recognized. CONCLUSION: In the present report, SG was applied to resolve an intricate endocrinological framework confirming its therapeutic value not only in determining weight loss but also as endocrine/metabolic surgery able to treat multifactorial endocrinopathy. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention, mostly in those patients unresponsive to classical pharmacotherapy.