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Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs). In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin–tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram-negative bacteria as Enterobacteriaceae with extended-spectrum β-lactamase production or piperacillin–tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin–tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram-negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071. Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point-prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0·64), yielding an adjusted incidence rate ratio during mixing of 1·039 (95% CI 0·837–1·291; p=0·73). There was no difference in all-cause in-ICU mortality between intervention periods. Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. European Union Seventh Framework Programme.

PurposeUse of antibiotics can give rise to the selection of resistant bacteria. It remains unclear whether antibiotic use in primary care can influence bacterial resistance incidence in patients when hospitalised. The aim of this study is to explore the impact of prior community antibiotic usage on hospital-detected multidrug-resistant Gram-negative (MRGN) incidence rate.MethodsThis pharmacoepidemiological study was case–control in design, and was carried out in the Antrim Area Hospital (N. Ireland) in two phases. In phase 1, the controls were matched according to: age, gender, admission ward, date of admission, and age-adjusted Charlson co-morbidity index score. During the second phase, controls were selected randomly from the total population of admissions to the hospital over the 2-year study period.ResultsIn phase 1, multivariate analysis revealed that prior exposure to the second- and third-generation cephalosporins (p = 0.004) and fluoroquinolones (p = 0.023) in primary care was associated with an increased likelihood of MRGN detection in inpatients. In phase 2, an independent relationship between an increased risk of identification of MRGN, while hospitalised was associated with: prolonged hospitalisation (p < 0.001), being elderly (p < 0.001), being female (p = 0.007), and having genitourinary disease (p < 0.001).ConclusionThis study provides clear evidence which supports the need to optimise antibiotic use in primary care to help reduce MRGN incidence in hospitalised patients.

Background Intensive care units (ICU) are epicenters for the emergence of antibiotic-resistant Gram-negative bacteria (ARGNB) because of high rates of antibiotic usage, rapid patient turnover, immunological susceptibility of acutely ill patients, and frequent contact between healthcare workers and patients, facilitating cross-transmission. Antibiotic stewardship programs are considered important to reduce antibiotic resistance, but the effectiveness of strategies such as, for instance, antibiotic rotation, have not been determined rigorously. Interpretation of available studies on antibiotic rotation is hampered by heterogeneity in implemented strategies and suboptimal study designs. In this cluster-randomized, crossover trial the effects of two antibiotic rotation strategies, antibiotic mixing and cycling, on the prevalence of ARGNB in ICUs are determined. Antibiotic mixing aims to create maximum antibiotic heterogeneity, and cycling aims to create maximum antibiotic homogeneity during consecutive periods. Methods/Design This is an open cluster-randomized crossover study of mixing and cycling of antibiotics in eight ICUs in five European countries. During cycling (9 months) third- or fourth-generation cephalosporins, piperacillin-tazobactam and carbapenems will be rotated during consecutive 6-week periods as the primary empiric treatment in patients suspected of infection caused by Gram-negative bacteria. During mixing (9 months), the same antibiotics will be rotated for each consecutive antibiotic course. Both intervention periods will be preceded by a baseline period of 4 months. ICUs will be randomized to consecutively implement either the mixing and then cycling strategy, or vice versa. The primary outcome is the ICU prevalence of ARGNB, determined through monthly point-prevalence screening of oropharynx and perineum. Secondary outcomes are rates of acquisition of ARGNB, bacteremia and appropriateness of therapy, length of stay in the ICU and ICU mortality. Results will be adjusted for intracluster correlation, and patient- and ICU-level variables of case-mix and infection-prevention measures using advanced regression modeling. Discussion This trial will determine the effects of antibiotic mixing and cycling on the unit-wide prevalence of ARGNB in ICUs. Trial registration ClinicalTrials.gov NCT01293071 December 2010.

Background Ventilator-associated pneumonia (VAP) is one of the most common and severe hospital-adquired infections, and multidrugresistant gram-negative bacilli (MDR-GNB) constitute the main etiology in many countries. Inappropriate empiric antimicrobial treatment is associated with increased mortality. In this context, the empirical treatment of choice for VAP is unknown. Colistin, is now the antimicrobial with greatest in vitro activity against MDR-GNB. Methods/Design The MagicBullet clinical trial is an investigator-driven clinical study, funded by the Seventh Framework Program of the European Commission. This is designed as a phase IV, randomized, controlled, open label, non-inferiority and international trial to assess the safety and efficacy of colistin versus meropenem in late onset VAP. The study is conducted in a total of 32 centers in three European countries (Spain, Italy and Greece) with specific high incidences of infections caused by MDR-GNB. Patients older than 18 years who develop VAP with both clinical and radiological signs, and are on mechanical ventilation for more than 96 hours, or less than 96 hours but with previous antibiotic treatment plus one week of hospitalization, are candidates for inclusion in the study. A total sample size of 496 patients will be randomized according to a severity clinical score (at the time of VAP diagnosis in a 1:1 ratio to receive either colistin 4.5 MU as a loading dose, followed by 3 MU every eight hours (experimental arm), or meropenem 2 g every eight hours (control arm), both combined with levofloxacin. Mortality from any cause at 28 days will be considered as the main outcome. Clinical and microbiological cure will be evaluated at 72 hours, eight days, the finalization of antibiotic treatment, and 28 days of follow-up. The efficacy evaluation will be performed in every patient who receives at least one study treatment drug, and with etiologic diagnosis of VAP, intention-to-treat population and per protocol analysis will be performed. Discussion Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance. Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance. Trial registration This trial is registered with ClinicalTrials.gov (identifier: NCT01292031 ; registered on 29 June 2012) and EudraCT (identifier: 2010-023310-31; registered on 7 February 2011).

Introduction.Nephrotoxicity has been a concern with new dosing regimens of colistin. This study was designed to compare nephrotoxicity of high dose and conventional dose of colistin and the ability of detecting it using neutrophil gelatinase-associated lipocalin (NGAL).Materials and Methods.A randomized clinical trial was carried out on 40 patients with multidrug-resistant gram-negative infections assigned into 2 groups to receive high and conventional doses of colistin. Blood samples were taken 4 times for measuring serum NGAL. The incidence of acute kidney injury was also evaluated based on the risk, injury, failure, loss, end-stage renal disease (RIFLE) criteria.Results.Baseline levels of NGAL were not significantly different between the patients on the high dose and conventional dose of colistin. The mean NGAL levels on day 10 were 762.14 ± 415.44 pg/mL and 623.67 ± 272.61 pg/mL, respectively. However, between-group analysis did not show a significant difference in the NGAL levels. The prevalence of acute kidney injury was 60% and 15% based on the RIFLE criteria, in the high-dose and conventional-dose groups, respectively (P = .003).Conclusions.Although colistin-induced nephrotoxicity was not confirmed with NGAL levels, our findings, however, showed a higher incidence of acute kidney injury associated with high-dose colistin, defined by the RIFLE criteria. Higher levels of NGAL in the acute kidney injury patients were associated with high-dose regimen of colistin.

This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance. Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. NCT02257931.

Abstract Multilocus sequence typing reveals that many bacterial species have a clonal structure and that some clones are widespread. This underlying phylogeny was not revealed by pulsed-field gel electrophoresis, a method better suited to short-term outbreak investigation. Some global clones are multiresistant and it is easy to assume that these have disseminated from single foci. Such conclusions need caution, however, unless there is a clear epidemiological trail, as with KPC carbapenemase-positive Klebsiella pneumoniae ST258 from Greece to northwest Europe. Elsewhere, established clones may have repeatedly and independently acquired resistance. Thus, the global ST131 Escherichia coli clone most often has CTX-M-15 extended-spectrum β-lactamase (ESBL), but also occurs without ESBLs and as a host of many other ESBL types. We explore this interaction of clone and resistance for E. coli, K. pneumoniae, Acinetobacter baumannii– a species where three global lineages dominate – and Pseudomonas aeruginosa, which shows clonal diversity, but includes the relatively ‘tight’ serotype O12/Burst Group 4 cluster that has proved adept at acquiring resistances – from PSE-1 to VIM-1 β-lactamases – for over 20 years. In summary, ‘high-risk clones’ play a major role in the spread of resistance, with the risk lying in their tenacity – deriving from poorly understood survival traits – and a flexible ability to accumulate and switch resistance, rather than to constant resistance batteries. We explore the spread of resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, and the importance of tenacious ‘high risk clones’ with flexible abilities to accumulate and switch resistance mechanisms.

Infections caused by extended-spectrum beta-lactamases (ESBL) producing Gram-negative bacteria has emerge as a global threat in clinical practices. The treat is more serious in developing countries due to inappropriate use, poor adherence, use of counterfeit, sub-standard antibiotics and poor infection control practices. Data on ESBL producing Gram-negative bacteria are limited in developing countries including Ethiopia. The aim of this study was therefore, to describe the burden of ESBL producing Gram negative pathogens isolated from patients attending at Felege Hiwot Comprehensive Specialized Hospital, Bahir Dar, Amhara region. A total of 532 clinical samples of blood, urine, stool, wound, abscess, ear discharge, nasal discharge, cervical discharge and body fluid specimens were aseptically collected and bacteriologically processed. Identification of the bacterial species was performed using an automated system (Vitek-2 Compact 27530, USA) and antibiotic susceptibility test was determined by disk diffusion method and selection of antibiotics were in accordance with CLSI guidelines. The MDR pattern of the Gram-negative pathogens was assessed using phenotypic methods of ESBL and carbapenemase production following standard procedure. A total of 532 samples were processed and 263 pathogens were isolated. Of these, 185 (70.3%) were Gram-negative and 78 (29.7%) Gram-positive. Of the Gram-negative bacteria the high proportion of the isolates were identified from blood 146/185 (78.9%) and 29/185 (15.7%) were from urine cultures. The most common isolate in all clinical samples was Klebsiella pneumoniae 97/185 (52.4%) followed by Escherichia coli 23/185 (12.4%), Acinetobacter baumannii 15/185 (17.6%) and Enterobacter aerogenes 12/185(6.5%). Of the total Gram negatives, the prevalence of MDR was 148/185 (80.0%). Of the MDR isolates the prevalence of ESBL producers were, 127/148 (85.8%) and 24/148 (16.2%) were carbapenemase producers. Prevalence of MDR and ESBL producing Gram-negative pathogens in this hospital is alarmingly high. Therefore, continuous monitoring of the problem with effective infection prevention and careful selection of empirical therapy are warranted in the study area.

Skin and soft-tissue infections (SSTIs) are an important cause of morbidity and mortality among hospitalized patients and a major therapeutic challenge for clinicians. Although uncomplicated SSTIs are managed successfully on an outpatient basis, more serious infections extending to the subcutaneous tissue, fascia, or muscle require complex management. Early diagnosis, selection of appropriate antimicrobials, and timely surgical intervention are key to successful treatment. Surgical-site infections, an important category of SSTI, occur in approximately half a million patients in North America annually. SSTIs are also a potential source for life-threatening bacteremia and metastatic abscesses. Gram-positive organisms, such as Staphylococcus aureus and Streptococcus pyogenes, are the dominant organisms isolated early in the infectious process, whereas gram-negative organisms are found in chronic wounds. Methicillin-resistant S. aureus (MRSA) is a potential bloodstream invader that requires aggressive antimicrobial treatment and surgery. Recent concerns regarding vancomycin activity include heteroresistance in MRSA and increase in the minimum inhibitory concentrations (>1 or 2 μg/mL); however, alternative agents, such as telavancin, daptomycin, linezolid, ceftaroline, dalbavancin, oritavancin, and tedizolid, are now available for the treatment of severe MRSA infections. Here, we present a review of the epidemiology, etiology, and available treatment options for the management of SSTIs.

The emergence of multidrug-resistance (MDR), production of extended-spectrum β-lactamases, and carbapenemase in members of fermentative gram-negative bacilli are a serious threat to public health. The aim of this study was to determine the burden of multi-drug resistance, the production of extended-spectrum β-lactamases (ESBLs), and carbapenemase in fermentative Gram-negative bacilli in Ethiopian Public Health Institute. A cross-sectional study was carried out from December 2017 to June 2018. Different clinical samples were collected, inoculated, and incubated according to standard protocols related to each sample. Bacterial identification was performed by using the VITEKR 2 compact system using the GNR card. Antimicrobial susceptibility testing was carried out by the Kirby-Bauer disc diffusion method. Production of ESBL and carbapenemase were confirmed by combination disc and modified Hodge Test method respectively. A total of 238 fermentative Gram-negative bacilli were recovered during the study period, among which E.coli were the predominant isolates followed by K. pneumoniae. The highest percentage of antibiotic resistance was noted against ampicillin (100%) followed by trimethoprim/sulfamethoxazole (81.9%). The isolates showed better sensitivity towards carbapenem drugs. Out of 238 isolates, 94.5% were MDR and of which 8.8% and 0.8% were extensively and pan drug resistant, respectively. Nearly 67% and 2% of isolates were producers of ESBL and carbapenemase, respectively. The isolation rates of MDR, ESBL, and carbapenemase producing stains of the isolates were ≥70% in intensive care unit while the isolation rates in other wards were ≤25%. The findings of this study revealed that the burden of MDR and ESBL was high and carbapenemase producing isolates were also identified which is concerning. This situation warrants a consistent surveillance of antimicrobial resistance of fermentative Gram-negative bacilli and implementation of an efficient infection control program.