Ceftazidime/avibactam in the era of carbapenemase-producing Klebsiella pneumoniae: experience from a national registry study.

BACKGROUND: Infections caused by KPC-producing Klebsiella pneumoniae (Kp) are associated with high mortality. Therefore, new treatment options are urgently required. OBJECTIVES: To assess the outcomes and predictors of mortality in patients with KPC- or OXA-48-Kp infections treated with ceftazidime/avibactam with an emphasis on KPC-Kp bloodstream infections (BSIs). METHODS: A multicentre prospective observational study was conducted between January 2018 and March 2019. Patients with KPC- or OXA-48-Kp infections treated with ceftazidime/avibactam were included in the analysis. The subgroup of patients with KPC-Kp BSIs treated with ceftazidime/avibactam was matched by propensity score with a cohort of patients whose KPC-Kp BSIs had been treated with agents other than ceftazidime/avibactam with in vitro activity. RESULTS: One hundred and forty-seven patients were identified; 140 were infected with KPC producers and 7 with OXA-48 producers. For targeted therapy, 68 (46.3%) patients received monotherapy with ceftazidime/avibactam and 79 (53.7%) patients received ceftazidime/avibactam in combination with at least another active agent. The 14 and 28 day mortality rates were 9% and 20%, respectively. The 28 day mortality among the 71 patients with KPC-Kp BSIs treated with ceftazidime/avibactam was significantly lower than that observed in the 71 matched patients, whose KPC-Kp BSIs had been treated with agents other than ceftazidime/avibactam (18.3% versus 40.8%; P = 0.005). In the Cox proportional hazards model, ultimately fatal disease, rapidly fatal disease and Charlson comorbidity index ≥2 were independent predictors of death, whereas treatment with ceftazidime/avibactam-containing regimens was the only independent predictor of survival. CONCLUSIONS: Ceftazidime/avibactam appears to be an effective treatment against serious infections caused by KPC-Kp.

Bloodstream infections in ICU with increased resistance: epidemiology and outcomes.

BACKGROUND: Aim of this study was to evaluate the epidemiology and outcomes of hospital-acquired bloodstream infections (HA-BSI) in Greek intensive care units (ICU). METHODS: Secondary analysis of data from 29 ICU collected during the EUROBACT study, a large prospective, observational, multination survey of HA-BSI. First episodes of HA-BSI acquired in the ICU or within 48 hours prior to admission were recorded. RESULTS: Gram-negative bacteria predominated namely Acinetobacter sp, Klebsiella sp, Pseudomonas sp (73.3% of monomicrobial infections) followed by Gram-positive cocci (18.3%); fungi (7.6%) and anaerobes (0.8%). Overall 73.3% of isolates were multidrug resistant (MDR), 47.1% extensively resistant (XDR) and 1.2% pan-drug resistant (PDR). Carbapenems were the most frequent empirically prescribed antibiotics, while colistin was the most frequently adequate; for both, calculated mean total daily doses were suboptimal. Overall 28-day all-cause mortality was 33.3%. In the multivariate analysis, factors adversely affecting outcome were higher SOFA score at HA-BSI onset (OR 1.19; 95% CI 1.08-1.31, P=0.0006), need for renal supportive therapy (OR 2.75; 95% CI 1.35-5.59, P=0.0053), and for vasopressors/inotropes (OR 2.68; CI 1.18-6.12, P=0.02); adequate empirical treatment had a protective effect (OR 0.48; CI 0.24-0.95, P=0.03). CONCLUSION: TIMELY administration of adequately dosed treatment regimens and early ICU admission of critically ill patients could help in improving outcomes.

Epidemiology of Pseudomonas aeruginosa and risk factors for carriage acquisition in an intensive care unit.

Because of a high prevalence of Pseudomonas aeruginosa infections, we conducted an epidemiological study to assess the need for systematic surveillance, as well as the value of applying barrier precautions toP. aeruginosa carriers. From July 1997 to February 1998, we conducted a prospective cohort study in an 18-bed medical intensive care unit (ICU), which is part of the infectious diseases department in a 1200-bed tertiary-care teaching hospital. Rectal and oropharyngeal swabs were obtained on admission and twice weekly. Acquired strains were genotypically characterized by pulsed-field gel electrophoresis (PFGE). A risk factor analysis for carriage, colonization and infection was performed. Among 269 eligible patients, 116 (43%) were P. aeruginosa carriers, with 46 (17%) detected on admission and 70 (26%) who acquired carriage during their stay in ICU. Among these 70 patients, 29 became colonized (N=13) or developed infection (N=16). Conversely, in the 121 patients who remained free of carriage, no colonization or infection were detected. Genotyping analysis using PFGE was performed for 81/85 (95%) acquired strains in 67 patients. The same genotype I was observed for 58/81 (70%) of these strains issued from 47 patients, and a distinct genotype II affected two other patients (three strains). The last 20 strains were not genetically related. In a multivariate model, mechanical ventilation was associated with the acquisition of P. aeruginosa carriage. Antibiotics ineffective against P. aeruginosa significantly increased the risk of colonization or infection in ICU. Although several recent studies concluded that endogenous sources account for the majority of P. aeruginosa colonizations or infections, we conclude that epidemiology may vary according to the ICU, and that cross-colonization (i.e., exogenous source) may occur and warrant reinforced barrier precautions.

Lipid deposition in rats centrally infused with leptin in the presence or absence of corticosterone.

The aim of the present study was to assess whether the glucocorticoid corticosterone (Cort) modulates the effects of leptin on food intake and lipid deposition. Rats were subjected to a 6-day intracerebroventricular infusion of leptin and were either sham-adrenalectomized (Sham-ADX) or ADX and supplemented with 0 (C0), 40 (C40), or 80 mg (C80) of Cort. Investigation of potential peripheral sites of interaction of leptin and Cort included liver and plasma triglyceride (TG) content and lipoprotein lipase (LPL) activity in adipose and muscle tissues. The study confirmed the respective anorectic and orexigenic effects of leptin and Cort and revealed that the leptin-induced reduction in food intake was dampened by the high dose of Cort replacement. Such an interaction did not, however, extend to body and adipose tissue weights, which were lowered by leptin infusion independently of the Cort status. Leptin and ADX significantly reduced liver TG content and triglyceridemia, whereas Cort replacement significantly increased these variables. Central infusion of leptin also lowered plasma insulin levels, accompanied by a reduction in LPL activity of storage tissues (inguinal and epididymal white adipose tissue, 2- and 3-fold, respectively). In contrast, leptin infusion increased LPL activity in oxidative tissues (soleus and vastus lateralis muscles, 3- and 4-fold, respectively). Cort replacement prevented the ADX-induced fall in epididymal LPL activity but failed to do so in leptin-infused rats. The study demonstrates that, whereas the anorectic effect of leptin is dampened by high but physiological plasma levels of corticosterone, leptin can produce its effects on body weight, lipid transport and accumulation, and adipose and muscle LPL activity in the absence or presence of an intact hypothalamic-pituitary-adrenal axis.

Effects of leptin and corticosterone on the expression of corticotropin-releasing hormone, agouti-related protein, and proopiomelanocortin in the brain of ob/ob mouse.

The present study was conducted to assess the effect of leptin and corticosterone on the expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC) and agouti-related protein (AGRP) in the mouse brain. To this end, a 3 x 3 factorial experiment was designed in which adrenalectomized (ADX) ob/ob mice were treated with leptin and corticosterone. Leptin and corticosterone downregulated CRH expression in the paraventricular hypothalamic nucleus (PVH). Leptin prevented the stimulating effects of ADX on the expression of CRH and the combination of small doses of leptin and corticosterone was as potent as the high dose of corticosterone in suppressing CRH mRNA expression in the PVH. Leptin and corticosterone enhanced the expression of CRH in the central nucleus of amygdala and in the bed nucleus of the stria terminalis. In addition, the present results confirmed the downregulating effects of leptin on the expression of AGRP mRNA in the hypothalamic arcuate nucleus (ARC), and demonstrated that this effect was more apparent in ADX mice treated with corticosterone than in ADX mice not supplemented with corticosterone. Also, leptin and corticosterone had opposite effects on the expression of POMC in the ARC. The opposite effect of leptin and corticosterone on the expression of POMC and AGRP seems consistent with the reported effects that these hormones and peptides have on food intake and thermogenesis, suggesting that the modulation of POMC and AGRP expression can be a mechanism whereby leptin and corticosterone exert their effects in the regulation of energy balance. In contrast, the similarity in the action of leptin and corticosterone is not a priori consistent with a role of CRH in the effects of these hormones in the regulation of energy balance. The downregulating effect of leptin on the expression of CRH in the PVH strongly suggests that leptin can be a potent regulator of hypothalamic-pituitary-adrenal axis activity. Finally, the present results suggest that the effects of leptin on the expression of CRH, POMC and AGRP are not curbed by glucocorticoids.

[Septic shock with liver abscess in an immunocompetence patient. Presentation of an unusual Fusobacterium nucleatum infection]. / Choc septique avec abcès hépatiques chez une patiente immunocompétente. Présentation inhabituelle d'infection à Fusobacterium nucleatum.

BACKGROUND: Fusobacterium septicemia with septic metastasis is a very rare and potentially serous condition when complicated by septic shock. Most cases have been described in patients with humoral immunity disorders and/or severe underlying chronic disease. CASE REPORT: A 24-year-old immunocompetent woman with a tonsil infection developed F. nucleatum septic shock with liver abscess formation. Outcome was rapidly favorable with antibiotic treatment and adapted intensive care, probably favored by the absence of an associated immune deficit. DISCUSSION: Despite its low incidence, F. nucleatum should be entertained as a possible cause of septicemia originating from a pelviperitoneal, pulmonary with abscess formation, or upper airway infection. Proper diagnosis is essential due to the risk of poor prognosis. Fusobacterium nucleatum is a commensal strictly anaerobic bacteria of the buccal cavity. It can cause dental and upper airway infections. Septicemia with secondary localization of F. nucleatum is very rare and the severity depends on the presence of associate septic shock. The immunopathological implications of these infections remain to be elucidated.

Reproducibility of energy and macronutrient intake and related substrate oxidation rates in a buffet-type meal.

The aim of this present study was to determine the reliability of a buffet-type meal as a measure of spontaneous energy and macronutrient intake. In addition, we evaluated the short-term effects of diet on the composition of the substrate mix oxidized postprandially. Fourteen male subjects had ad libitum access to a variety of foods from a buffet-type meal offered in the laboratory during two identical sessions. The foods comprising the test meal had varying amounts of protein, lipid and carbohydrate. The results showed that there were significant intraclass correlations (ri) for energy (ri 0.97, P = 0.0001), lipid (ri 0.97, P = 0.0001), carbohydrate (ri 0.92, P = 0.0003) and protein (ri 0.82, P = 0.0072) intake between the two meal sessions. Hunger and fullness levels measured immediately before and during 4 h after the meal were identical under the two conditions. In addition, there was no significant difference between the two sessions for RQ and resting energy expenditure, which showed significant reproducibility for measurements obtained immediately before, immediately after, as well as 30 min after, the buffet. This present study demonstrates the high reproducibility of energy and macronutrient intake and oxidation rate values obtained with a buffet-type meal in healthy male subjects and suggests that the use of this test is a reliable method for assessment of macronutrient preferences in the laboratory.

Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lep(ob)/lep(ob) mice.

The present study was conducted to assess the interaction effect of leptin and corticosterone on food intake and the expression of uncoupling protein 1 (UCP1) mRNA in interscapular brown adipose tissue (IBAT). To this end, a 3 x 3 factorial experiment was designed in which adrenalectomized (ADX) lep(ob)/lep(ob) mice were subjected to three doses of corticosterone and three doses of leptin. The results confirm the anorectic and orexigenic effects of leptin and corticosterone, respectively. The results also emphasize the abilities of leptin and corticosterone to respectively increase and reduce the expression of UCP1 mRNA in IBAT. The effects of leptin and corticosterone on food intake and the expression of UCP1 mRNA translated into effects on body weight and body composition; leptin reduced body weight and corticosterone increased the weight of IBAT. The present results do not provide evidence for leptin-corticosterone interactions in the control of food intake and thermogenesis. Corticosterone increased food intake and reduced the expression of IBAT UCP1 regardless of the leptin status, and leptin reduced food intake and induced the expression of IBAT UCP1 independently of the corticosterone levels.

Effect of leptin on energy balance does not require the presence of intact adrenals.

The present study was conducted to assess the effects of leptin on food intake and energy balance in the presence or absence of corticosterone. Three cohorts of C57BL/6 mice differing in their corticosterone status [nonadrenalectomized (intact), adrenalectomized (ADX), and ADX with corticosterone replacement] were infused with either saline or leptin at a dose of 150 microg . kg-1 . day-1. Throughout the study, mice had free access to both a high-starch and a high-fat diet. At the end of the experimental period, mice were decapitated and their carcasses were processed for the determination of energy, protein, and lipid contents. Leptin significantly reduced body gains in weight, fat, and energy, whereas corticosterone therapy significantly promoted all of these gains. Leptin and ADX significantly reduced food intake and gross energetic efficiency, whereas corticosterone therapy significantly increased these variables. The effects of leptin, ADX, and corticosterone on food intake were accounted for by changes in the intake of the high-fat diet. Leptin also attenuated the preference for fat that developed quickly in mice simultaneously exposed to the high-starch and high-fat regimen. Altogether, the results of this study 1) emphasize the abilities of leptin and corticosterone to, respectively, decrease and increase energy deposition and ingestion of fat, 2) do not substantiate any leptin-corticosterone interaction in the regulation of energy balance, and 3) demonstrate that leptin can produce its effect on energy and fat gains in the absence of an intact hypothalamic-pituitary-adrenal axis.

Effect of dehydroepiandrosterone on brown adipose tissue and energy balance in mice.

In order to investigate the reported antiobesity action of dehydroepiandrosterone (DHEA), a complete energy balance was made on four groups of mice. Group A was fed the standard Purina diet, group B the same diet to which DHEA was added (0.3%), group C the Purina diet supplemented with palatable high fat food (meat spread), and group D the same diet as group C, to which DHEA was added. Food intake which was larger in groups C and D, was not altered by DHEA treatment. Body weight gain which was comparable for groups A and C, was significantly reduced in the two groups receiving DHEA. The resulting reduced food efficiency caused by DHEA was completely explained by body fat utilization. It was also found that the weight and the protein content of the interscapular brown adipose tissue (BAT) were increased by DHEA treatment suggesting, because of the great thermogenic capacity of this tissue in mice, that it may have been involved in causing the observed reduction in food efficiency. It is also proposed that the action of DHEA may be related to the activation of other tissues such as the liver and muscles. Further investigations are needed to verify this possibility.

Serum markers of immune activation in women undergoing in-vitro fertilization and embryo transfer.

We evaluated serum concentrations of two early and sensitive markers of immune activation, interleukin-2 receptor (sIL-2R) and intercellular adhesion molecule-1 (ICAM-1) in two age-matched groups of in-vitro fertilization (IVF)-embryo transfer women, group I (n = 26) without and group II (n = 40) with methylprednisolone (MPD) supplementation of the luteal phase, on the days of oocyte retrieval (sample A) and embryo transfer (B), and second (C) and 13th (D) days post-transfer and in 20 normally cycling women (controls) on the day of luteinizing hormone (LH) peak. No difference in the outcome of the IVF-embryo transfer was observed between groups I and II. In sample A, both immunomarker concentrations showed no significant difference between the two groups of IVF women, while they were significantly higher (P < 0.01) than values in controls. In cycles in which conception occurred, significantly higher immunomarker concentrations were observed in sample A of both groups I and II compared with those in unsuccessful cycles of the same group. A significant decrease of both sIL-2R and ICAM-1 was noticed in sample B only in group II (P < 0.0001 and P < 0.001 respectively; paired t-test) that continued further in the late luteal phase only in the case of conception, independently of MPD supplementation. These data suggest that (i) due to multiple ovulations, IVF-embryo transfer women show elevated concentrations of sIL-2R and ICAM-1 at oocyte retrieval; (ii) since, even at oocyte retrieval stage, high concentrations of immunomarkers are associated with IVF-embryo transfer success, sIL-2R and ICAM-1 could be used as early indicators for conception cycles; (iii) transient suppression of T cell activity by MPD supplementation following IVF-embryo transfer does not improve pregnancy rate.

Pregnancy results after ovum donation following one to seven embryo transfers.

OBJECTIVE: To determine whether failure to achieve pregnancy after repeated ET after ovum donation was due to an endometrial defect or to the embryo quality. DESIGN: Retrospective data analysis. SETTING: A private infertility center. PATIENT(S): Four hundred sixty-seven donors (513 cycles) undergoing IVF donating oocytes to 266 recipients (423 cycles). INTERVENTION(S): Hormonal endometrial preparation with increasing dosages of valerate E2 (2,4, and 6 mg) and 100 mg of P. MAIN OUTCOME MEASURE(S): Pregnancy rates (PRs) and abortion rates in patients undergoing one to seven ETs after ovum donation. RESULT(S): Pregnancy rates in recipients that had one or two ETs were significantly higher (34.8%) compared with those of recipients having three or more ETs (15.1%). Abortion rates were significantly higher (54.5%) in recipients repeating more than three ETs than in the recipients having one or two ETs (29.1%). CONCLUSION(S): Recipients that had failed to establish a pregnancy after two ETs had a lower PR in successive attempts, possibly because of a defect of their endometrial lining.

Triplet pregnancy and fetal reduction counselling.

The aim of this study was to compare the fetal loss between triplet pregnancies that underwent fetal reduction to twins and triplets which continued in spite of reduction being suggested to all of them. During a five year period a total of 3,518 cycles underwent ovarian stimulation with GnRH analogues, HMG, pure-FSH and HCG for the purpose of IVF; 2,918 women underwent ovarian aspiration leading to 2,380 embryotransfers. A total of 560 clinical pregnancies were detected with 24 clinical triplet pregnancies. Fourteen women continued their triplet pregnancy while 10 women underwent fetal reduction to twins. From 42 fetuses (14 triplets) starting the third trimester only 29 survived (total fetal loss 30.9%). From 14 fetuses (7 twins) starting the third trimester all survived. Three twins were lost during the second trimester due to cervix incompetence. Fetal reduction to twins must be proposed to each multifetal pregnancy, considering the very serious high mortality rate.

The effect of pentoxifylline on sperm motility, oocyte fertilization, embryo quality, and pregnancy outcome in an in vitro fertilization program.

OBJECTIVE: To study the effect of pentoxifylline on sperm motility, oocyte fertilization, embryo cleavage, and quality as well as pregnancy outcome on asthenospermic patients participating in an IVF program. DESIGN: Prospective randomized study. SETTING: Private IVF unit. PATIENTS: Ninety-seven couples, 24 of whom were repeating IVF. Two semen specimens were obtained from each patient and each specimen was divided equally into two parts, nontreated (control semen) and pentoxifylline-treated (treated semen). MAIN OUTCOME MEASURE: Sperm progressive motility, oocyte fertilization. RESULTS: Overall and progressive motility did not differ significantly between the two semen specimens. There was a significant increase in the progressive motality of the pentoxifylline-treated semen compared with control semen. No significant difference was noticed between control and treated semen in fertilization rate, cleavage rate, embryo quality, and pregnancy rate. The percentage of patients who fertilized only with control semen (9.3%) was not significantly different from that of patients who fertilized only with treated semen (10.3%). Couples who were repeating IVF did not show significant difference in fertilization between the present study and previous attempts. CONCLUSION: Our results showed that although the sperm progressive motility is improved after pentoxifylline treatment, it is doubtful whether this effect is of any clinical significance.

Hormone levels of follicular fluids with and without oocytes in patients who received gonadotropin-releasing hormone analogues and gonadotropins in an in vitro fertilization program.

BACKGROUND: Are follicles where no oocytes are retrieved "empty follicles"? METHODS: The levels of estradiol (E2), progesterone (P), testosterone (T), cortisol (F), and prolactin (PRL) of follicular fluids (FF) aspirated individually from 34 randomly selected IVF patients in whom no oocytes were recovered were compared with the respective hormone levels of FF obtained from the same patients when oocytes were retrieved. Two FF without oocytes of a 35th patient in whom no oocytes were retrieved were analyzed. RESULTS: Hormones did not differ significantly in the paired samples, while in the two FF of the 35th woman they were in agreement with cystic follicles. CONCLUSIONS: It is necessary to differentiate aspirated follicles where no oocytes are retrieved from the "empty follicle syndrome," which was not observed in the IVF series studied and should be rare in IVF patients.