Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria

Background

The alarming increase in drug resistance and decreased production of new antibiotics necessitate the evaluation of combinations of existing antibiotics. Fosfomycin shows no cross-resistance to other antibiotic classes. Thus, its combination with other antibiotics may potentially show synergy against resistant bacteria.

Objective

To evaluate the available published evidence regarding the in vitro synergistic activity of fosfomycin with other antibiotic agents against Gram-positive and Gram-negative bacteria.

Methods

PubMed and the Cochrane Library were searched.

Results

Forty-one studies, including 34 (82.9%) conducted/published before 2000, were eligible for inclusion. The relatively limited number of isolates examined and the considerable heterogeneity of the retrieved studies regarding the definitions of synergy and the methodologies used hamper conclusive remarks for specific combinations of fosfomycin with other antibiotics. Yet, in the 27 studies providing data for Gram-positive strains (16 for Staphylococcus aureus, 3 for coagulase-negative staphylococci, 5 for Streptococcus pneumoniae, and 3 for Enterococcus spp.), fosfomycin showed synergy against methicillin-resistant Staphylococcus aureus when combined with cefamandole, cephazolin, ceftriaxone, ciprofloxacin, imipenem, and rifampicin. Data regarding Gram-negative strains reported from 15 studies (12 exclusively for P. aeruginosa, 2 exclusively for Enterobacteriaceae, 1 for both, and 1 for Acinetobacter baumannii) suggested that fosfomycin showed an estimable synergistic effect with gentamicin, amikacin, ceftazidime, cefepime, ciprofloxacin, levofloxacin, and aztreonam against P. aeruginosa.

Conclusions

The synergistic combination of fosfomycin with other antibiotics may be a useful alternative treatment option for Gram-negative and Gram-positive infections. Additional studies using more stringent definitions of synergy, and studies reporting on the clinical efficacy of fosfomycin combinations in the current era of high antimicrobial resistance are needed.     

A randomized trial comparing intensified CNOP vs. CHOP in patients with aggressive non-Hodgkin's lymphoma

The standard CHOP regimen may cure 30-40% of patients with advanced aggressive non-Hodgkin's lymphoma (ANHL). Mitoxantrone is an anthracenedione, which is active in NHL and its toxicity profile may be more favorable than doxorubicin with respect to alopecia, mucositis and cardiotoxicity. This study was designed to compare the effectiveness of an escalated dose of mitoxantrone with that of standard doxorubicin, used in the CHOP regimen in patients with ANHL. One hundred and forty three eligible patients with ANHL were randomized to receive 6 cycles of either CHOP (n = 71) or intensified CNOP (iCNOP) (n = 72), with mitoxantrone 20 mg/m2, i.v., d.1 instead of doxorubicin. Complete responders (CR) were again randomized either to receive interferon-alpha (IFN-alpha) maintenance (3 MU t.i.w., s.c.) or not. The CR rate was 70 vs. 76% for iCNOP and CHOP (p = 0.45), and the overall response rate was 81 vs. 83%, respectively (p = 0.71). The 5-year failure free survival (FFS) was 48 and 50% in the iCNOP and CHOP arm, respectively (p = 0.45), and the 5-year overall survival (OS) was 61 vs. 64% (p = 0.56). IFN-alpha did not prolong relapse free survival (p = 0.91). iCNOP produced less alopecia (p = 0.001) but more febrile episodes (p = 0.04) than CHOP, while requiring more frequent G-CSF support (p = 0.01). Two cases of acute myelogenous leukemia (AML) were recorded, both in the iCNOP arm (p = 0.14). In conclusion, iCNOP was equally effective to CHOP in patients with ANHL, producing more leukopenia and febrile episodes, but less alopecia. The development of two cases of secondary AML in th e iCNOP arm is of concern.     

Baccalaureate nursing students' perceptions of learning and supervision in the clinical environment

This study is an exploration of nursing students' experiences within the clinical learning environment (CLE) and supervision provided in hospital settings. A total of 357 second‐year nurse students from all universities in Cyprus participated in the study. Data were collected using the Clinical Learning Environment, Supervision and Nurse Teacher instrument. The dimension “supervisory relationship (mentor)”, as well as the frequency of individualized supervision meetings, were found to be important variables in the students' clinical learning. However, no statistically‐significant connection was established between successful mentor relationship and team supervision. The majority of students valued their mentor's supervision more highly than a nurse teacher's supervision toward the fulfillment of learning outcomes. The dimensions “premises of nursing care” and “premises of learning” were highly correlated, indicating that a key component of a quality clinical learning environment is the quality of care delivered. The results suggest the need to modify educational strategies that foster desirable learning for students in response to workplace demands.     

Validation of the Greek maternal adjustment and maternal attitudes scale for assessing early postpartum adjustment

The Maternal Adjustment and Maternal Attitudes Scale is a self- administered scale, designed for use in primary care settings to identify postpartum maternal adjustment problems regarding body image, sex, somatic symptoms, and marital relationships. Women were recruited within four weeks of giving birth. Responses to the Maternal Adjustment and Maternal Attitudes Scale were compared for agreement with responses to the Edinburgh Postnatal Depression Scale as a gold standard. Psychometric measurements included: reliability coefficients, explanatory factor analysis, and confirmatory analysis by linear structural relations. A receiver operating characteristic analysis was carried out to evaluate the global functioning of the scale. Of 300 mothers screened, 121 (40.7%) were experiencing difficulties in maternal adjustment and maternal attitudes. Scores on the Maternal Adjustment and Maternal Attitudes Scale correlated well with those on the Edinburgh Postnatal Depression Scale. The internal consistency of the Maternal Adjustment and Maternal Attitudes Scale, Greek version-tested using Cronbach's alpha coefficient-was 0.859, and that of Guttman split-half coefficient was 0.820. Findings confirmed the multidimensionality of the Maternal Adjustment and Maternal Attitudes Scale, demonstrating a six-factor structure. The area under the receiver operating characteristic curve was 0.610, and the logistic estimate for the threshold score of 57/58 fitted the model sensitivity at 68% and model specificity at 64.6%. Data confirmed that the Greek version of the Maternal Adjustment and Maternal Attitudes Scale is a reliable and valid screening tool for both clinical practice and research purposes to detect postpartum adjustment difficulties.     

Birth weight and prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): a meta-analysis within 12 European Birth Cohorts

Objectives: Exposure to high concentrations of persistent organochlorines may cause fetal toxicity, but the evidence at low exposure levels is limited. Large studies with substantial exposure contrasts and appropriate exposure assessment are warranted. Within the framework of the EU (European Union) ENRIECO (ENvironmental Health RIsks in European Birth Cohorts) and EU OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life) projects, we examined the hypothesis that the combination of polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) adversely affects birth weight.Methods: We used maternal and cord blood and breast milk samples of 7,990 women enrolled in 15 study populations from 12 European birth cohorts from 1990 through 2008. Using identical variable definitions, we performed for each cohort linear regression of birth weight on estimates of cord serum concentration of PCB-153 and p,p´-DDE adjusted for gestational age and a priori selected covariates. We obtained summary estimates by meta-analysis and performed analyses of interactions.Results: The median concentration of cord serum PCB-153 was 140 ng/L (range of cohort medians 20–484 ng/L) and that of p,p´-DDE was 528 ng/L (range of cohort medians 50–1,208 ng/L). Birth weight decreased with increasing cord serum concentration of PCB-153 after adjustment for potential confounders in 12 of 15 study populations. The meta-analysis including all cohorts indicated a birth weight decline of 150 g [95% confidence interval (CI): –250, –50 g] per 1-µg/L increase in PCB-153, an exposure contrast that is close to the range of exposures across the cohorts. A 1-µg/L increase in p,p´-DDE was associated with a 7-g decrease in birth weight (95% CI: –18, 4 g).Conclusions: The findings suggest that low-level exposure to PCB (or correlated exposures) impairs fetal growth, but that exposure to p,p´-DDE does not. The study adds to mounting evidence that low-level exposure to PCBs is inversely associated with fetal growth.     

Current evidence on the associations of breastfeeding, infant formula, and cow's milk introduction with type 1 diabetes mellitus: a systematic review

Current evidence provides contradictory results in regards to the associations of breastfeeding or early introduction of cow's milk and formula with the development of type 1 diabetes (T1D). The aim of this systematic review was to evaluate the type of feeding, duration of breastfeeding, time of introduction of formula or cow's milk, and the potential impact on developing T1D. The literature search was conducted based on the standards outlined in the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies and yielded a total of 161 studies, 28 of which were included in this review. Twenty seven of the included studies were case-control and one was a prospective cohort study. Eight of the studies indicated breastfeeding has a protective role against the development of T1D. Seven additional studies emphasized that a short period or absence of breastfeeding could be a risk factor for T1D development. The results of this systematic review indicate a short duration and/or a lack of breastfeeding may constitute a risk factor for the development of T1D later in life.     

Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction

The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.