Styliani Karanika

Fecal Colonization With Extended-spectrum Beta-lactamase–Producing Enterobacteriaceae and Risk Factors Among Healthy Individuals: A Systematic Review and Metaanalysis

BACKGROUND Gut colonization is a risk factor for infections with extended-spectrum beta-lactamase (ESBL)-producing organisms. We aimed to determine the ESBL class A reservoir among healthy individuals. METHODS We searched PubMed and EMBASE (through 10 July 2015) looking for studies that contained data for fecal colonization with ESBL class A bacteria among healthy individuals for each World Health Organization-defined region. Distribution of isolates among cefotaximase (CTX-M), sulfhydryl variable, and temoneira enzymes and data on previous antibiotic use, international travel, previous hospitalization, and animal contacts were extracted. RESULTS Sixty-six of 17 479 studies on 28 909 healthy individuals were included. The pooled prevalence of ESBL class A colonization was 14% (95% confidence interval [CI], 9, 20), with an increasing trend of 5.38% annually (P = .003). The pooled prevalence was higher in Asia and Africa (ranging from 46%, 95% CI, 29, 63 to 15%, 95% CI, 4, 31) and lower but still significant in central (3%, 95% CI, 1, 5), northern (4%, 95% CI, 2, 6), and southern Europe (6%, 95% CI, 1, 12) and the Americas (2%, 95% CI, 0, 5). CTX-Ms were the prevalent ESBL enzyme (69%). Antibiotic use for the prior 4 or 12 months was associated with a high colonization risk (risk ratio [RR] = 1.63; 95% CI, 1.19, 2.24 and RR = 1.58; 95% CI, 1.16, 2.16, respectively). International travel was also correlated with ESBL colonization [(RR = 4.06, (95% CI, 1.33, 12.41)]. CONCLUSIONS The ESBL colonization rate among healthy individuals is significant worldwide. This should be taken into consideration in infection control and antibiotic management decisions.

Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs

ABSTRACT The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was −19.1% (95% confidence interval [CI] = −30.1 to −7.5), and the use of restricted antimicrobial agents decreased by −26.6% (95% CI = −52.3 to −0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was −39.5% (95% CI = −72.5 to −6.4). The use of broad-spectrum antibiotics (−18.5% [95% CI = −32 to −5.0] for carbapenems and −14.7% [95% CI = −27.7 to −1.7] for glycopeptides), the overall antimicrobial cost (−33.9% [95% CI = −42.0 to −25.9]), and the hospital length of stay (−8.9% [95% CI = −12.8 to −5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] = −0.017 [95% CI = −0.029 to −0.005]), imipenem-resistant Pseudomonas aeruginosa (RD = −0.079 [95% CI = −0.114 to −0.040]), and extended-spectrum beta-lactamase Klebsiella spp. (RD = −0.104 [95% CI = −0.153 to −0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = −0.001 [95% CI = −0.009 to 0.006], RD = −0.005 [95% CI = −0.016 to 0.007], and RD = −0.045% [95% CI = −0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates.

DNA damage response and prostate cancer: defects, regulation and therapeutic implications

DNA damage response (DDR) includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Specific genes involved in the DDR such as BRCA1/2 and P53 are mutated during prostate cancer progression, while various oncogenic signaling such as Akt and c-Myc are activated, enhancing the replication stress and increasing the genomic instability of cancer cells. These events may render prostate cancer cells particularly sensitive to inhibition of specific DDR pathways, such as PARP in homologous recombination DNA repair and Chk1 in cell cycle checkpoint and DNA repair, creating opportunities for synthetic lethality or synergistic cytotoxicity. Recent reports highlight the critical role of androgen receptor (AR) as a regulator of DDR genes, providing a rationale for combining DNA-damaging agents or targeted DDR inhibitors with hormonal manipulation or AR inhibition as treatment for aggressive disease. The aims of this review are to discuss specific DDR defects in prostate cancer that occur during disease progression, to summarize recent advances in understanding the regulation of DDR in prostate cancer, and to present potential therapeutic opportunities through combinational targeting of the intact components of DDR signaling pathways.

Targeting Poly(ADP-Ribose) Polymerase and the c-Myb–Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

The DNA damage response is an appealing target for androgen inhibitor–resistant prostate cancer. Improving Therapy in Prostate Cancer Blocking androgen receptor (AR) signaling is standard therapy for prostate cancer, but tumor growth often recurs. Li et al. examined the gene expression profile in patient samples of primary and metastatic prostate cancer from patients in which AR signaling was blocked. Metastatic disease, which is associated with androgen inhibitor–resistant relapse, correlated with increased expression of genes encoding proteins in the DNA damage response (DDR) and MYB expression. AR and c-Myb shared a subset of target genes that encode DDR proteins; thus, c-Myb may functionally substitute for AR in the regulation of their common DDR targets. Targeting proteins within the Myb-regulated network in combination with a poly[adenosine 5′-diphosphate (ADP)–ribose] polymerase (PARP) inhibitor, which compromises the DDR, generated synergistic lethality in prostate cancer cells in culture and in mouse xenografts, suggesting potential new options for prostate cancer patients. Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition–resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5′-diphosphate (ADP)–ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated– and Rad3-related (ATR), and Chk1.

Do anastomotic leaks impair postoperative health-related quality of life after rectal cancer surgery? A case-matched study.

BACKGROUND: Anastomotic leaks after colorectal resections for cancer are a leading cause of postoperative morbidity, mortality, and long hospital stay. Few data exist on the potentially deleterious effect of the anastomotic leaks after proctectomy for cancer on patient health-related quality of life. OBJECTIVE: The aim of this study was to explore the effect of clinically evident anastomotic leaks on health-related quality of life after rectal cancer excision. DESIGN: This is a case-matched study. SETTINGS: This study was conducted in a Greek academic surgical department. PATIENTS: Included were 25 patients undergoing low anterior resection complicated by an anastomotic leak (Clavien classification II, n = 14, and III, n = 11) and 50 patients undergoing low anterior resection with an uncomplicated course. MAIN OUTCOME MEASURES: Health-related quality-of-life data were prospectively collected at fixed assessment time points (baseline, 3, 6, and 12 months postoperatively) by the use of validated questionnaires (Medical Outcomes Study Short Form 36, Gastrointestinal Quality of Life Index, European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-C30, and European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-CR29). RESULTS: “Leak” patients required a longer hospitalization. Although the numbers of initially constructed defunctioning loop ileostomies were not significantly different between cases and controls, “leak” patients were required to remain with a stoma significantly more often at all postoperative assessment time points. No differences were observed in the baseline scores between the 2 groups. Physical function of “leak” patients was significantly worse at all postoperative assessment time points. At 6 and 12 months, their emotional and social function and overall quality-of-life scores were significantly decreased in comparison with the patients with an uncomplicated course. “Leak” patients experienced significantly more “stoma-related problems” and “sore skin” around the stoma site. LIMITATIONS: Limited number of patients, restriction of follow-up to the end of the first year, and heterogeneity in terms of the presentation, severity, and management of anastomotic leaks were the limitations of this study. CONCLUSIONS: Anastomotic leaks have an adverse effect on postoperative health-related quality of life.

Androgen receptor inhibitor???induced ???BRCAness??? and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

Androgen receptor inhibition induces a “BRCAness” state that may be exploited with PARP inhibitors in patients with advanced prostate cancer. Engineering BRCAness and chemotherapeutic sensitivity BRCA mutations impair a double-strand break DNA repair pathway that forces cells to use a PARP-dependent repair pathway. PARP inhibitors are selectively toxic to breast cancers with BRCA mutations, spurring the search for other tumors or ways in which to apply such exquisitely tumor-targeted therapy. Few other tumors have BRCA mutations as commonly as do breast tumors. However, Li et al. found that a common therapy for prostate cancer patients created a BRCA-deficient state that sensitized tumor cells to PARP inhibitors and leveraged this finding into a potential treatment strategy. Noting that the androgen receptor inhibitor enzalutamide decreased the expression of BRCA1 in prostate cancer cells, the authors treated a mouse model of prostate cancer first with enzalutamide and then with the PARP inhibitor olaparib. Sequential treatment of enzalutamide and olaparib suppressed tumor growth in these mice better than either drug by itself or when both drugs were administered at the same time. The results suggest that “BRCAness” could be therapeutically induced to provide more treatment options not only for prostate cancer patients but also for patients with other types of cancers lacking BRCA mutations. Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as “BRCAness” and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1, RAD54L, and RMI2. Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A “lead-in” treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage–induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.

Prevalence and Clinical Outcomes of Clostridium difficile Infection in the Intensive Care Unit: A Systematic Review and Meta-Analysis.

We found that ICU setting is associated with higher Clostridium difficile infection (CDI) prevalence than general hospital population and 25% among CDI cases in ICU develop pseudomembranous colitis. CDI also affects adversely overall hospital mortality, ICU and overall hospital stay.

Immune response after laparoscopic colectomy for cancer: a review

Background and aim: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and laparoscopic colectomy has been established as equivalent to the open approach in terms of oncological results and patients’ safety. Survival benefits have been reported in favor of laparoscopic colectomy (LC) in stage III CRC patients. Different immune responses after surgery, in terms of innate and cellular immunity, may potentially explain some of the reported differences. This review summarizes the literature on differences in immune response after the laparoscopic and the open approach for CRC. Materials and Methods: A literature search of electronic databases was conducted and all studies published on ‘colorectal cancer’, ‘laparoscopic and open colectomy’ ‘immune response’ and ‘surgical stress laparoscopy versus open’ were collected. Among these, the ones referring to CRC and those that had any clinical relevance offering information on perioperative parameters were used. Results: Despite the heterogeneity of studies, they support the view that innate immune response is activated to a greater degree in open colectomy (OC), which may be related to the more extensive trauma and surgical stress. On the other hand, cellular immunity is better preserved after LC. These differences are more pronounced in the immediate postoperative period. Conclusions: LC has been related to decreased up-regulation of innate immunity and better-preserved cellular immunity. The latter may be related to better anti-tumor activity and may be beneficial in terms of oncological survival in a subgroup of LC patients.

Icu Acquisition Rate, Risk Factors, and Clinical Significance of Digestive Tract Colonization With Extended-spectrum Beta-lactamase–producing Enterobacteriaceae: A Systematic Review and Meta-analysis*

Objective: To evaluate the acquisition rate, identify risk factors, and estimate the risk for subsequent infection, associated with the colonization of the digestive tract with extended-spectrum beta-lactamase–producing Enterobacteriaceae during ICU-hospitalization. Data Sources: PubMed, EMBASE, and reference lists of all eligible articles. Study Selection: Included studies provided data on ICU-acquired colonization with extended-spectrum beta-lactamase–producing Enterobacteriaceae in previously noncolonized and noninfected patients and used the double disk synergy test for extended-spectrum beta-lactamase–producing Enterobacteriaceae phenotypic confirmation. Studies reporting extended-spectrum beta-lactamase–producing Enterobacteriaceae outbreaks or data on pediatric population were excluded. Data Extraction: Two authors independently assessed study eligibility and performed data extraction. Data Synthesis: Thirteen studies (with 15,045 ICUs-patients) were evaluated using a random-effect model and a meta-regression analysis. The acquisition rate of digestive tract colonization during ICU stay was 7% (95% CI, 5–10) and it varies from 3% (95% CI, 2–4) and 4% (95% CI, 2–6) in the Americas and Europe to 21% (95% CI, 9–35) in the Western Pacific region. Previous hospitalization (risk ratio, 1.57 [95% CI, 1.07–2.31]) or antibiotic use (risk ratio, 1.65 [95% CI, 1.15–2.37]) and exposure to beta-lactams/beta-lactamase inhibitors (risk ratio, 1.78 [95% CI, 1.24–2.56]) and carbapenems (risk ratio, 2.13 [95% CI, 1.49–3.06]) during the ICU stay were independent risk factors for ICU-acquired colonization. Importantly, colonized patients were more likely to develop an extended-spectrum beta-lactamase–producing Enterobacteriaceae infection (risk ratio, 49.62 [95% CI, 20.42–120.58]). The sensitivity and specificity of prior colonization to predict subsequent extended-spectrum beta-lactamase–producing Enterobacteriaceae infection were 95.1% (95% CI, 54.7–99.7) and 89.2% (95% CI, 77.2–95.3), respectively. Conclusions: The ICU acquisition rate of extended-spectrum beta-lactamase–producing Enterobacteriaceae ranged from 5% to 10%. Previous use of beta-lactam/beta-lactamase or carbapenems and recent hospitalization were independent risk factors for extended-spectrum beta-lactamase–producing Enterobacteriaceae colonization, and colonization was associated with significantly higher frequency of extended-spectrum beta-lactamase–producing Enterobacteriaceae subsequent infection and increased mortality.

Colonisation with extended-spectrum β-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis

Cancer patients are vulnerable to infections, including those with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), and most of these infections are associated with colonisation of the gastrointestinal tract. The aim of this study was to estimate the prevalence of gastrointestinal colonisation with ESBL-PE cancer populations and to determine the risk for subsequent bloodstream infection (BSI) with these pathogens. PubMed and EMBASE databases were searched from 1 January 1991 to 1 March 2016 to identify studies regarding ESBL-PE colonisation among patients with malignancies. Ten studies (out of 561 non-duplicate articles) were included, providing data on 2211 patients. The pooled prevalence of ESBL-PE colonisation was 19% [95% confidence interval (CI) 8-32%]. Stratifying per region, the pooled prevalence in Europe was 15% (95% CI 10-21%), whereas in Asia the pooled prevalence was 31% (95% CI 4-69%). In addition, the pooled prevalence was 15% (95% CI 7-24%) among patients with haematological malignancy, whereas no studies were identified that included solely patients with solid tumours. Notably, cancer patients with ESBL-PE colonisation were 12.98 times (95% CI 3.91-43.06) more likely to develop a BSI with ESBL-PE during their hospitalisation compared with non-colonised patients. We found that, overall, one in five patients with cancer is colonised with ESBL-PE and the incidence can be as high as one in three in Asia. This is important because colonisation was associated with an almost 13 times higher risk for developing BSI with ESBL-PE. Screening measures should be evaluated to identify their clinical benefit in patients with malignancy.