Topical antibiotics for preventing surgical site infection in wounds healing by primary intention

BACKGROUND: Surgical site infections (SSI) can delay wound healing, impair cosmetic outcome and increase healthcare costs. Topical antibiotics are sometimes used to reduce microbial contaminant exposure following surgical procedures, with the aim of reducing SSIs.OBJECTIVES: The primary objective of this review was to determine whether the application of topical antibiotics to surgical wounds that are healing by primary intention reduces the incidence of SSI and whether it increases the incidence of adverse outcomes (allergic contact dermatitis, infections with patterns of antibiotic resistance and anaphylaxis).SEARCH METHODS: In May 2015 we searched: the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process &amp; Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL. We also searched clinical trial registries for ongoing studies, and bibliographies of relevant publications to identify further eligible trials. There was no restriction of language, date of study or setting. The search was repeated in May 2016 to ensure currency of included studies.SELECTION CRITERIA: All randomized controlled trials (RCTs) and quasi-randomised trials that assessed the effects of topical antibiotics (any formulation, including impregnated dressings) in people with surgical wounds healing by primary intention were eligible for inclusion.DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and independently extracted data. Two authors then assessed the studies for risk of bias. Risk ratios were calculated for dichotomous variables, and when a sufficient number of comparable trials were available, trials were pooled in a meta-analysis.MAIN RESULTS: A total of 10 RCTs and four quasi-randomised trials with 6466 participants met the inclusion criteria. Six studies involved minor procedures conducted in an outpatient or emergency department setting; eight studies involved major surgery conducted in theatre. Nine different topical antibiotics were included. We included two three-arm trials, two four-arm trials and 10 two-arm trials. The control groups comprised; an alternative topical antibiotic (two studies), topical antiseptic (six studies) and no topical antibiotic (10 studies), which comprised inert ointment (five studies) no treatment (four studies) and one study with one arm of each.The risk of bias of the 14 studies varied. Seven studies were at high risk of bias, five at unclear risk of bias and two at low risk of bias. Most risk of bias concerned risk of selection bias.Twelve of the studies (6259 participants) reported infection rates, although we could not extract the data for this outcome from one study. Four studies (3334 participants) measured allergic contact dermatitis as an outcome. Four studies measured positive wound swabs for patterns of antimicrobial resistance, for which there were no outcomes reported. No episodes of anaphylaxis were reported. Topical antibiotic versus no topical antibioticWe pooled the results of eight trials (5427 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with no topical antibiotic (RR 0.61, 95% CI 0.42 to 0.87; moderate-quality evidence downgraded once for risk of bias). This equates to 20 fewer SSIs per 1000 patients treated with topical antibiotics (95% CI 7 to 29) and a number needed to treat for one additional beneficial outcome (NNTB) (i.e. prevention of one SSI) of 50.We pooled the results of three trials (3012 participants) for the outcome of allergic contact dermatitis, however this comparison was underpowered, and it is unclear whether topical antibiotics affect the risk of allergic contact dermatitis (RR 3.94, 95% CI 0.46 to 34.00; very low-quality evidence, downgraded twice for risk of bias, once for imprecision). Topical antibiotic versus antiseptic We pooled the results of five trials (1299 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with using topical antiseptics (RR 0.49, 95% CI 0.30 to 0.80; moderate-quality evidence downgraded once for risk of bias). This equates to 43 fewer SSIs per 1000 patients treated with topical antibiotics instead of antiseptics (95% CI 17 to 59) and an NNTB of 24.We pooled the results of two trials (541 participants) for the outcome of allergic contact dermatitis; there was no clear difference in the risk of dermatitis between topical antibiotics and antiseptics, however this comparison was underpowered and a difference cannot be ruled out (RR 0.97, 95% CI 0.52 to 1.82; very low-quality evidence, downgraded twice for risk of bias and once for imprecision). Topical antibiotic versus topical antibioticOne study (99 participants) compared mupirocin ointment with a combination ointment of neomycin/polymyxin B/bacitracin zinc for the outcome of SSI. There was no clear difference in the risk of SSI, however this comparison was underpowered (very low-quality evidence downgraded twice for risk of bias, once for imprecision).A four-arm trial involved two antibiotic arms (neomycin sulfate/bacitracin zinc/polymyxin B sulphate combination ointment versus bacitracin zinc, 219 participants). There was no clear difference in risk of SSI between the combination ointment and the bacitracin zinc ointment. The quality of evidence for this outcome was low, downgraded once for risk of bias, and once for imprecision.AUTHORS' CONCLUSIONS: Topical antibiotics applied to surgical wounds healing by primary intention probably reduce the risk of SSI relative to no antibiotic, and relative to topical antiseptics (moderate quality evidence). We are unable to draw conclusions regarding the effects of topical antibiotics on adverse outcomes such as allergic contact dermatitis due to lack of statistical power (small sample sizes). We are also unable to draw conclusions regarding the impact of increasing topical antibiotic use on antibiotic resistance. The relative effects of different topical antibiotics are unclear.</p

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development

Tracking genomic cancer evolution for precision medicine: The Lung TRACERx Study

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance

Behavioural and Physiological Responses of Gammarus pulex Exposed to Cadmium and Arsenate at Three Temperatures: Individual and Combined Effects

This study aimed at investigating both the individual and combined effects of cadmium (Cd) and arsenate (AsV) on the physiology and behaviour of the Crustacean Gammarus pulex at three temperatures (5, 10 and15°C). G. pulex was exposed during 96 h to (i) two [Cd] alone, (ii) two [AsV] alone, and (iii) four combinations of [Cd] and [AsV] to obtain a complete factorial plane. After exposure, survival, [AsV] or [Cd] in body tissues, behavioural (ventilatory and locomotor activities) and physiological responses (iono-regulation of [Na+] and [Cl−] in haemolymph) were examined. The interactive effects (antagonistic, additive or synergistic) of binary mixtures were evaluated for each tested temperature using a predictive model for the theoretically expected interactive effect of chemicals. In single metal exposure, both the internal metal concentration in body tissues and the mortality rate increased along metallic gradient concentration. Cd alone significantly impaired both [Na+] and [Cl−] while AsV alone had a weak impact only on [Cl−]. The behavioural responses of G. pulex declined with increasing metal concentration suggesting a reallocation of energy from behavioural responses to maintenance functions. The interaction between AsV and Cd was considered as ‘additive’ for all the tested binary mixtures and temperatures (except for the lowest combination at 10°C considered as “antagonistic”). In binary mixtures, the decrease in both ventilatory and locomotor activities and the decline in haemolymphatic [Cl−] were amplified when respectively compared to those observed with the same concentrations of AsV or Cd alone. However, the presence of AsV decreased the haemolymphatic [Na+] loss when G. pulex was exposed to the lowest Cd concentration. Finally, the observed physiological and behavioural effects (except ventilation) in G. pulex exposed to AsV and/or Cd were exacerbated under the highest temperature. The discussion encompasses both the toxicity mechanisms of these metals and their interaction with rising temperature

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049