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Linezolid is an oxazolidinone, a new class of antibacterial with a unique mechanism of action, namely inhibition of the formation of a functional 70S initiation complex in the 50S bacterial ribosomal subunit. Linezolid is highly active against multidrug-resistant Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus, and vancomycin-resistant enterococci; its spectrum of activity also includes some anaerobic bacteria. Linezolid has been studied in several randomized controlled trials for the treatment of patients with community-acquired and nosocomial pneumonia, skin and soft tissue infections (SSTIs), urinary tract infections and bacteraemia. The available evidence suggests that linezolid is at least as effective as vancomycin for patients with nosocomial pneumonia, and there are some retrospective analyses supporting its superiority in comparison with vancomycin for MRSA nosocomial pneumonia, including ventilator-associated pneumonia. Linezolid is more effective than glycopeptides, macrolides and beta-lactams for SSTIs. The limited available data for the treatment of patients with bacteraemia suggest that it may be a better treatment option than vancomycin and beta-lactams for these patients, but questions have arisen regarding patients with catheter-related bacteraemias. Compared with other antibacterials, linezolid is associated with a greater frequency of adverse events, mainly nausea, vomiting, diarrhoea and headaches. Thrombocytopenia also occurs more frequently in patients taking linezolid but there is no increased frequency of anaemia. Other adverse events potentially related to linezolid therapy include fungal infections (moniliasis), hypertension and serotonin-like syndrome, tongue discolouration and taste alterations, dizziness, insomnia, rash and Clostridium difficile-related diarrhoea. The majority of adverse events develop after prolonged administration (i.e. >2 weeks) and subside shortly after discontinuation of linezolid. Peripheral or optic neuropathy, another possible adverse effect, is associated with an even longer duration of treatment (3-6 months). In conclusion, linezolid is an important treatment option for the treatment of patients with multidrug-resistant, Gram-positive bacterial infections. However, in order to reduce the possibility of development of resistance and preserve its activity, the use of linezolid should be restricted to treatment of patients with infections associated with high morbidity and mortality, particularly those caused by multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]

Background: [corrected] Neutropenia is a common complication of intensive chemotherapy in patients with solid organ or hematologic malignancies that is associated with a high risk for life-threatening infections. Many interventions have been employed in order to limit the incidence of these infections or to treat them when the prophylactic measures fail.Scope: The commonest characteristic of the randomized controlled trials (RCTs) conducted on this issue was the small sample size. In addition, if RCTs studying the prophylactic interventions were excluded, the aim of most of the rest of relevant RCTs was to prove the equal effectiveness of the tested interventions in terms of treatment success. We searched PubMed and Cochrane database to identify meta-analyses of RCTs in the field of febrile neutropenia.Results: The most prominent findings of these meta-analyses were the promising effect, although based on open label RCTs, of antimicrobial prophylaxis with fluoroquinolones on the mortality of all neutropenic patients and the beneficial effect of antifungal prophylaxis on mortality of neutropenic patients with allogeneic hematopoetic stem cell transplantation. Another noteworthy finding was the higher mortality associated with empiric cefepime treatment when compared with other beta-lactams. In other cases, the findings of the published meta-analyses either confirmed or consolidated the results of individual RCTs.Conclusion: Meta-analyses are very useful for obtaining a better overview and to provide some general qualitative and quantitative conclusions, but are not always a substitute for appropriately powered, well-designed RCTs. In addition, the reported findings should be interpreted with caution taking into account the limitations of various methodological aspects of meta-analysis in general, as well as the limitations of the individual meta-analyses in this field. [ABSTRACT FROM AUTHOR]

Objective: Previous meta-analyses reported advantages of passive (i.e., heat and moisture exchangers, or HMEs) compared with active (i.e., heated humidifiers, or HHs) humidifiers in reducing the incidence of ventilator-associated pneumonia, but they did not examine the effect of these devices on mortality, length of intensive care unit stay, and duration of mechanical ventilation. In addition, relevant data were recently published.Design: Meta-analysis of randomized controlled trials comparing HMEs with HHs for the management of mechanically ventilated patients to determine the impact of these devices on clinical outcomes of such patients.Methods: We searched PubMed and the Cochrane Central Register of Controlled Trials as well as reference lists from publications, with no language restrictions. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs), using a random effects model.Results: Thirteen randomized controlled trials, studying 2,580 patients, were included. There was no difference in incidence of ventilator-associated pneumonia among patients managed with HMEs and HHs (OR 0.85, 95% CI 0.62-1.16). There was no difference between the compared groups regarding mortality (OR 0.98, 95% CI 0.80-1.20), length of intensive care unit stay (weighted mean differences, -0.68 days, 95% CI -3.65 to 2.30), duration of mechanical ventilation (weighted mean differences, 0.11 days, 95% CI -0.90 to 1.12), or episodes of airway occlusion (OR 2.26, 95% CI 0.55-9.28). HMEs were cheaper than HHs in each of the randomized controlled trials.Conclusion: The available evidence does not support the preferential performance of either passive or active humidifiers in mechanical ventilation patients in terms of ventilator-associated pneumonia incidence, mortality, or morbidity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The use of antifungal prophylaxis remains controversial in most populations including surgical intensive care unit patients. A meta-analysis of randomized controlled trials was performed to evaluate the safety and effectiveness of azoles as antifungal prophylaxis in high-risk patients receiving treatment in the surgical intensive care unit. DATA SOURCE: Data were obtained from PubMed, Current Contents, Cochrane central register of controlled trials, and references from relevant articles. STUDY SELECTION: Randomized controlled trials using azoles as antifungal prophylaxis vs. placebo were included in the study. DATA EXTRACTION: Two independent reviewers extracted data concerning the development of fungal infections (superficial or invasive), adverse effects, and mortality. SYNTHESIS: Six randomized controlled trials were included in the main analysis. Publication bias and statistically significant heterogeneity were not observed among the analyzed studies. Patients receiving antifungal prophylaxis developed fewer episodes of candidemia (odds ratio [OR] = 0.28, 95% confidence interval [CI] 0.09-0.86), nonbloodstream invasive fungal infections (OR = 0.26, 95% CI 0.12-0.53), and noninvasive (superficial) fungal infections (OR = 0.22, 95% CI 0.11-0.43), respectively. No reduction in mortality was observed among patients who received azole prophylaxis (OR = 0.74, 95% CI 0.52-1.05). There was no significant difference in reported adverse effects (OR = 1.28, 95% CI 0.82-1.98). CONCLUSIONS: Despite its limitations, our meta-analysis suggests that the prophylactic use of azoles in high-risk surgical intensive care unit patients is associated with a reduction of fungal infections but not in all-cause mortality. However, although not noted in the analyzed randomized controlled trials, there is concern about the use of azoles due to possible shift toward non-albicans species and development of resistance to azoles. [ABSTRACT FROM AUTHOR]

Summary: Linezolid has been approved for the treatment of patients with infections caused by Gram-positive cocci that are resistant to traditionally used antibiotics, including glycopeptides. This oxazolidinone antibiotic has been reported to have excellent pharmacokinetics and effectiveness. We did a meta-analysis of randomised controlled trials (RCTs) to clarify whether linezolid is superior to glycopeptides or β-lactams for the treatment of Gram-positive infections. 12 RCTs, involving 6093 patients, were included. Overall, with respect to treatment success, linezolid was more effective than glycopeptides or β-lactams (odds ratio [OR] 1·41 [95% CI 1·11–1·81]). Mortality was similar between the groups (OR 0·97 [0·79–1·19]). Linezolid was more effective than comparators in patients with skin and soft-tissue infections (OR 1·67 [1·31–2·12]) and bacteraemia (OR 2·07 [1·13–3·78]). However, there was no difference in treatment success for patients with pneumonia (OR 1·03 [0·75–1·42]). Treatment with linezolid was not associated with more adverse effects in general (OR 1·40 [0·95–2·06]); however, thrombocytopenia was recorded more commonly in patients receiving linezolid (OR 11·72 [3·66–37·57]). Although linezolid is more effective than its comparators for the empirical treatment of selected patients, several points, such as the use of less potent antistaphylococcal β-lactams, the same all-cause mortality, and the higher probability of thrombocytopenia, should be taken into account and may limit the use of linezolid to specific patient populations or infections that are difficult to treat with other antibiotics. [Copyright &y& Elsevier]

Introduction: Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined., Methods: We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256)., Results: IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56-3.04; I 2  = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24-2.47; I 2  = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70-4.16; I 2  = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36-3.59; I 2  = 58%)., Conclusion: Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.

Objectives: To study mortality changes in Greece prior to and during the financial crisis., Study Design: Analysis of data by the Hellenic Statistical Authority (1955-2015)., Results: During the crisis, mortality increased from 9.76/1000 in 2009 to 10.52/1000 in 2012 and to 11.16/1000 in 2015, driven by an increase in the number of deaths and a decrease in the estimated population. The annual increase of the expected mortality accelerated during the crisis; in contrast, age-adjusted mortality continued to decrease up to 2014 and increased in 2015. The subpopulations that seemed to be affected more during the crisis were the elderly (especially those over 70 years), women, and citizens in southern Greece. The common denominator of all these subgroups was older age. Mortality due to heart diseases continued to decline at an accelerated pace; due to neoplasia continued to increase at an accelerated pace; and stroke mortality reversed (from decline to increment)., Conclusions: The increment of crude mortality during the financial crisis in Greece should be attributed to the increase in deaths, only in part due to the aging population, the reduction in births, and the increase in emigration that contracted the population.

Objectives: The aim of this review was to investigate the outcomes of patients infected with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria following synergy-guided antibiotic combination therapy (SGACT)., Methods: A systematic review of PubMed and Scopus databases was performed. Published studies of any design reporting outcomes of patients with MDR Gram-negative bacteria treated with SGACT were included. Two reviewers independently assessed the relevancy and quality of the retrieved articles and extracted the available data., Results: Nineteen reports (530 patients) were included. Eleven case reports/series described 26 cases of systemic infection due to MDR Gram-negative bacteria treated with SGACT. Five deaths were reported, two of which were attributed to the infection. Six studies (including one randomised controlled trial) provided comparative data for patients treated with SGACT and those treated with unguided combination therapy (UCT) or active monotherapy. In the pooled analysis of unadjusted data from these studies (504 patients), there was no difference between SGACT and UCT or monotherapy (OR=0.47, 95% CI 0.21-1.04; I 2 =52%). Analysis of adjusted data showed that SGACT was significantly associated with survival (OR=0.44, 95% CI 0.20-0.98; I 2 =54%)., Conclusion: These limited but promising findings warrant further investigation of SGACT in the outcome of patients with MDR Gram-negative infections in well-designed trials., (Copyright © 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Fosfomycin has been used for the treatment of infections due to susceptible and multidrug-resistant (MDR) bacteria. It inhibits bacterial cell wall synthesis through a unique mechanism of action at a step prior to that inhibited by β-lactams. Fosfomycin enters the bacterium through membrane channels/transporters and inhibits MurA, which initiates peptidoglycan (PG) biosynthesis of the bacterial cell wall. Several bacteria display inherent resistance to fosfomycin mainly through MurA mutations. Acquired resistance involves, in order of decreasing frequency, modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell, acquisition of plasmid-encoded genes that inactivate fosfomycin, and MurA mutations. Fosfomycin resistance develops readily in vitro but less so in vivo. Mutation frequency is higher among Pseudomonas aeruginosa and Klebsiella spp. compared with Escherichia coli and is associated with fosfomycin concentration. Mutations in cAMP regulators, fosfomycin transporters and MurA seem to be associated with higher biological cost in Enterobacteriaceae but not in Pseudomonas spp. The contribution of fosfomycin inactivating enzymes in emergence and spread of fosfomycin resistance currently seems low-to-moderate, but their presence in transferable plasmids may potentially provide the best means for the spread of fosfomycin resistance in the future. Their co-existence with genes conferring resistance to other antibiotic classes may increase the emergence of MDR strains. Although susceptibility rates vary, rates seem to increase in settings with higher fosfomycin use and among multidrug-resistant pathogens., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC 50 and MIC 90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC 90 , 2 mg/L), followed by minocycline (MIC 90 , 8 mg/L). TP-6076 exhibited MIC 90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC 90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: β-lactams have been consistently associated with the majority of drug-related adverse events. Generally, these are mild under proper dosing and judicious selection., Areas Covered: Immediate hypersensitivity reactions are the most feared adverse events encountered after β-lactam administration. Emerging evidence shows that immediate reactions are not as common as previously thought. Specialist consultation and testing seems prudent before a patient is officially declared allergic to β-lactams. The risk of cross-reactions between not only members of the β-lactam super-family but also between specific classes is also lower than previously thought. Newer studies have shown that cross-reactions are not universal and pertain to specific agents with similar side chains or metabolites of the β-lactam core. The frequency of severe kidney or liver toxicity, neurotoxicity, cytopenias and Clostiridium difficile infection following β-lactam administration seem to be agent-specific., Expert Opinion: The currently available data denote that in addition to age, gender, co-morbidity, renal or liver function, and co-administered agents, the antibiotic levels rather than the dose itself seem to be associated with the emergence of adverse events. Most of them subside with time after withdrawal of the offending agent, but the number of cases resulting in chronic disabilities or even deaths in not negligible.

Objective: The impact factor has emerged as the most popular index of scientific journals' resonance. In this study we aimed to examine the impact factor trends of journals published by scientific bodies in the United States of America (USA) and Europe (EU)., Methods: We randomly chose 11 categories of Journal of Citation Reports and created three research classes: clinical medicine, laboratory medicine, and basic science. The impact factor values for the years 1999-2015 were abstracted, and the impact factor of US and EU journals was studied through the years., Results: A total of 265 journals were included in the final analysis. The impact factor of US journals was higher than that of EU journals throughout the study period. In addition, for both US and EU journals the median impact factor increased throughout the study period. The rate of annual change in the impact factor throughout the study period was lower for US than EU journals (1.85% versus 3.55%, P=0.019). A higher median annual increase was seen in the impact factor during the period 1999-2008 compared to the period 2009-2015 for both US (P<0.001) and EU (P=0.001) journals. In fact, during the second period the US median impact factor value did not show significant changes (P=0.31), while the EU median impact factor continued to increase (P<0.001)., Conclusion: The impact factor of EU journals increased at a significantly higher rate than and approached that of the US journals during the last 16 years.

Objective: To evaluate whether intravenous plus inhaled combination (IV/INHCC) compared to intravenous monotherapy (IVCM) was associated with patient outcomes and identify factors influencing study outcomes., Methods: PubMed and Scopus were searched till November 2016. Studies were included if they evaluated adult patients with lower respiratory tract infections due to MDR/XDR Gram-negative bacteria and reported comparative mortality data (adjusted and unadjusted) for patients receiving IV/INHCC versus IVCM. Random effects meta-analyses were performed., Results: Thirteen studies (11 retrospective, 2 prospective) were included. The overall quality of data was low to very low and characterized by the lack of adjusted data. The majority of the studies were designed to evaluate the outcome of the meta-analysis. Both IV and inhaled colistin were administered at variable doses. There was no difference in mortality between IV/INHCC and IVCM when all studies were combined (13 studies, 1115 patients, risk ratio 0.94, 95% confidence interval 0.81-1.08). Only the analysis that included studies with low-dose IV colistin showed significant difference in favor of IV/INHCC versus IVCM (0.65, 0.45-0.94)., Conclusions: Overall, low quality data suggest that IV/INHCC did not lower mortality in patients with MDR Gram negative infections unless low IV colistin dose was administered., (Copyright © 2018 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: To evaluate whether intravenous colistin in combination with other antibiotics (IVCC) is associated with lower mortality compared with intravenous colistin monotherapy (IVCM), and to identify factors influencing study outcomes., Methods: PubMed and Scopus were searched up to November 2016. Studies were included if they evaluated adult patients with multi-drug-resistant (MDR) or extensively-drug-resistant Gram-negative infections, and reported comparative mortality data (adjusted and unadjusted) for patients receiving IVCC vs. IVCM. Random effects meta-analyses were performed., Findings: Thirty-two studies (29 observational, three randomized) were included. The overall quality of data was low to very low, and studies were characterized by the lack of adjusted data. The majority of studies were not designed to evaluate the outcome of the meta-analysis, and focused mainly on infections due to Acinetobacter baumannii and Klebsiella pneumoniae. Colistin was administered at variable doses, with or without a loading dose, and in combination with several antibiotics. Overall, IVCC was not associated with lower mortality than IVCM [32 studies, 2328 patients, risk ratio (RR) 0.91, 95% confidence interval (CI) 0.81-1.02, I 2 8%]. A significant difference was observed in favour of IVCC when high-dose (>6 million international units) colistin was used (RR 0.80, 95% CI 0.69-0.93), in studies conducted in Asia (RR 0.82, 95% CI 0.71-0.95), in patients with bacteraemia (RR 0.75, 95% CI 0.57-0.98) and in patients with acinetobacter infections (RR 0.88, 95% CI 0.78-1.00)., Interpretation: Overall, low-quality data suggest that IVCC did not lower mortality in patients with MDR Gram-negative infections. However, there is some evidence for a benefit observed with high intravenous doses of colistin., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: The findings of randomised controlled trials (RCT), observational studies, and meta-analyses vary regarding the effectiveness of prolonged β-lactam infusion. We aimed to identify the effectiveness of prolonged versus short-term infusion of antipseudomonal β-lactams in patients with sepsis., Methods: We did a systematic review and meta-analysis to compare prolonged versus short-term intravenous infusion of antipseudomonal β-lactams in patients with sepsis. Two authors independently searched PubMed, Scopus, and the Cochrane Library of clinical trials until November, 2016, without date or language restrictions. Any RCT comparing mortality or clinical efficacy of prolonged (continuous or ≥3 h) versus short-term (≤60 min) infusion of antipseudomonal β-lactams for the treatment of patients with sepsis was eligible. Studies were excluded if they were not RCTs, the antibiotics in the two arms were not the same, neither mortality nor clinical efficacy was reported, only pharmacokinetic or pharmacodynamic outcomes were reported, or if ten or fewer patients were enrolled or randomised. Data were extracted in prespecified forms and we then did a meta-analysis using a Mantel-Haenszel random-effects model. The primary outcome was all-cause mortality at any timepoint. This meta-analysis is registered with the PROSPERO database, number CRD42016051678, and is reported according to PRISMA guidelines., Findings: 2196 articles were identified and screened, and 22 studies (1876 patients) were included in the meta-analysis. According to the Grading of Recommendations Assessment, Development, and Evaluation tool, the quality of evidence for mortality was high. Carbapenems, penicillins, and cephalosporins were studied. Patients with variable age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis and renal function were enrolled. Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR] 0·70, 95% CI 0·56-0·87). Heterogeneity was not observed (p=0·93, I 2 =0%). The funnel plot and the Egger's test (p=0·44) showed no evidence of publication bias., Interpretation: Prolonged infusion of antipseudomonal β-lactams for the treatment of patients with sepsis was associated with significantly lower mortality than short-term infusion. Further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction, and immunocompetence are warranted., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Inhaled colistin is becoming increasingly popular against respiratory tract infections caused by multidrug resistant (MDR) Gram-negative bacteria because it may overcome the problems associated with intravenous (IV) administration., Objective: To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant IV administration of colistin) in the treatment of respiratory tract infections caused by MDR or colistin-only susceptible Gram-negative bacteria., Methods: PubMed and Scopus databases were searched. A systematic review and meta-analysis were conducted., Results: Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 studies with ventilator-associated pneumonia) and 2 studies evaluated patients with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% - 43.6%), clinical success was 70.4% (58.5% - 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% - 83.2%) of cases., Conclusions: Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections caused by MDR A. baumannii and P. aeruginosa., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Scope: To study the factors associated with mortality in hospitalized patients with community-acquired pneumonia treated with monotherapy or combination therapy., Methods: PubMed and Scopus were searched. Patients receiving macrolides, β-lactams and fluoroquinolones, as monotherapy or in combination, were included. Meta-analyses and meta-regressions were performed., Results: Fifty studies were included. Overall, monotherapy was not associated with higher mortality than combination (RR 1.14, 95% CI 0.99-1.32, I 2 84%). Monotherapy was associated with higher mortality than combination in North American and retrospective studies. β-lactam monotherapy was associated with higher mortality than β-lactam/macrolide combination in the primary (1.32, 1.12-1.56, I 2 85%) and most sensitivity analyses. There was no difference in mortality between fluoroquinolone monotherapy and β-lactam/macrolide combination (0.98, 0.78-1.23, I 2 73%). In meta-regressions, the moderators that could partially explain the observed statistical heterogeneity were the frequency of cancer patients (P = .03) and Pneumonia Severity Index score IV (P = .008)., Conclusion: Due to the considerable heterogeneity and inclusion of unadjusted data, it is difficult to recommend a specific antibiotic regimen over another. Specific antibiotic regimens, study design and the characteristics of the population under study seem to influence the reported outcomes., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: To study changes in the susceptibility of Serratia spp. in Crete, Greece (2010-2015)., Methods: Non-duplicate isolates were examined using automated systems. Phenotypic confirmatory tests were applied., Results: Three hundred and seventy-eight Serratia spp. were analyzed. Serratia marcescens (88.3%) was the predominant species. Fluoroquinolones (97.9%), carbapenems (97.4%) and fosfomycin (97.4%) were the most active followed by amikacin (95.5%), piperacillin/tazobactam (94.7%), and trimethoprim/sulfamethoxazole (94.4%). The activity of 3rd and 4th generation cephalosporins was 87-88.6%. The distribution of multi-drug resistant (MDR) strains varied, with a trend towards increasing frequency. ESBL (7.9%), carbapenemase (2.9%), AmpC (2.1%) and aminoglycoside modifying enzyme (10.6%) production were the commonest resistant phenotypes., Conclusion: The susceptibility of Serratia spp. varied during the study period a trend towards decreasing susceptibility, especially for non-carbapenem β-lactams and aminoglycosides.

Background: Data on Citrobacter spp. susceptibility are scarce. We sought to study the evolution in the susceptibility of 385 Citrobacter spp. at the University Hospital of Heraklion, Crete, Greece during a six-year period (2010-2015)., Methods: Non-duplicate strains isolated from inpatients (intensive care unit, oncology, surgery, internal medicine, paediatrics) and outpatients were studied using Vitek 2. Phenotypic confirmatory tests were applied for detection of β-lactamases and aminoglycoside modifying enzymes., Results: C. freundii (172, 44.7%) and C. koseri (166, 43.1%) were the most commonly isolated species. C. braakii (34), C. amalonaticus (6), C. youngae (6) and C. sedlakii (1) were the remaining isolates. Colistin and fosfomycin were the most active antibiotics (both 99.2%) followed by carbapenems (99%) aminoglycosides (96.6-98.4%), tigecycline (96.1%), cefepime (94.8%), ciprofloxacin (94.3%), tetracycline (92.7%), trimethoprim/sulphamethoxazole (91.4%), chloramphenicol (88.1%), piperacillin/tazobactam (86.5%) and 3rd generation cephalosporins (85.7%). C. freundii were more resistant than C. koseri. Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility to all antibiotics was observed among multi-drug resistant (MDR) strains. AmpC was the most common resistant mechanism (10.9%); carbapenemases (1.3%) and aminoglycoside modifying enzymes (2.9%) were also detected. All AmpC producers were resistant to cephalosporins but not to carbapenems. In all but one isolates aminoglycoside resistance was accompanied by acquired β-lactamases., Conclusions: Although Citrobacter species in general were susceptible, antibiotic susceptibility testing is required for the detection of resistant isolates.

Aim: To study the evolution in the susceptibility of Enterobacter spp. in Crete, Greece from 2010 to 2015., Methods: Non-duplicate isolates were studied using automated systems. Phenotypic confirmatory tests were applied., Results: A total of 939 Enterobacter isolates were included. Colistin was the most active antibiotic (97.9%) followed by imipenem (96.1%), gentamicin (95.7%), tigecycline (91.8%), cefepime (89.4%), chloramphenicol (85.8%), fosfomycin (85.5%), trimethoprim/sulfamethoxazole (83.3%) and piperacillin/tazobactam (73.3%). Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility was observed among multidrug-resistant strains and carbapenem-nonsusceptible isolates. AmpC was the most common resistant mechanism (21%); carbapenemases (3.7%) and aminoglycoside-modifying enzymes (6.5%) were also detected., Conclusion: A significant proportion of Enterobacter spp. was resistant to several antibiotics, most notably β-lactams.

Background: Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases., Methods: A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs., Results: In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa ) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae , 14 Enterobacter cloacae and 11 Providencia stuartii ) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/L. For K. pneumoniae , E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/L, respectively. Tigecycline was the second most active antibiotic, followed by colistin., Conclusions: Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The best treatment option for hospitalized patients with community-acquired pneumonia (CAP) has not been defined. The effectiveness of β-lactam/fluoroquinolone (BLFQ) versus β-lactam/macrolide (BLM) combinations for the treatment of patients with CAP was evaluated., Methods: PubMed, Scopus and the Cochrane Library were searched for observational cohort studies, non-randomized and randomized controlled trials providing data for patients with CAP receiving BLM or BLFQ. Mortality was the primary outcome. A meta-analysis was performed. MINORS and GRADE were used for data quality assessment., Results: Seventeen studies (16 684 patients) were included. Randomized trials were not identified. A variety of β-lactams, fluoroquinolones and macrolides were used within and between the studies. Mortality was reported at different time points. The available body of evidence had very low quality. In the analysis of unadjusted data, mortality with BLFQ was higher than with BLM (risk ratio 1.33, 95% CI 1.15-1.54, I 2 28%). BLFQ was associated with higher mortality regardless of the study design, mortality recording time, study period and study BLM group mortality. BLFQ was associated with higher mortality in American but not European studies. No difference was observed in patients with bacteraemia and septic shock. In the meta-analysis of adjusted mortality data, a non-significant difference between the two regimens was observed (eight studies, adjusted risk ratio 1.26, 95% CI 0.95-1.67, I 2 43%)., Conclusion: In the absence of data from randomized controlled trials recommendations cannot be made for or against either of the studied regimens in this group of hospitalized patients with CAP. Well designed randomized controlled trials comparing the two regimens are warranted., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Colistin and polymyxin B (PMB) have different pharmacokinetic profiles and minor differences in antimicrobial activities that may result in discrepancies in mortality and nephrotoxicity. A systematic review and meta-analysis was conducted. PubMed, Scopus and Cochrane Library databases were searched. There was no significant difference in unadjusted mortality between patients treated with colistin and PMB [risk ratio (RR) = 0.71, 95% confidence interval (CI) 0.45-1.13]. Adjusted data were not available. Unadjusted nephrotoxicity was more common in patients treated with colistin than PMB (RR = 1.55, 95% CI 1.36-1.78). According to the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, there was no difference regarding risk, injury or failure between colistin and PMB. Although episodes of loss of renal function were few in general, they developed primarily in colistin-treated patients (RR = 8.55, 95% CI 1.48-49.49). Colistin was associated with more episodes of nephrotoxicity that also occurred sooner in the analysis of adjusted data (hazard ratio = 2.16, 95% CI 1.43-3.27). Colistin administration was an independent risk factor for nephrotoxicity in two studies. Future studies should evaluate in depth the factors associated with mortality and nephrotoxicity in patients treated with polymyxins and the impact of polymyxin-associated nephrotoxicity on mortality., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Colistin (polymyxin E) has been widely used since the beginning of the century as a last-option antibiotic for the treatment of patients with multidrug-resistant and extensively-drug resistant bacterial infections. However, colistin dosing is troublesome because each batch of the drug contains a mixture of components and because it is administered as the inactive pro-drug colistimethate sodium (CMS), which has different pharmacokinetic (PK) properties from the active drug. Significant inter-individual and intra-individual variability in colistin plasma concentrations have been observed in all available studies. Low plasma concentrations of the drug during the first hours from initiation of administration suggested that a loading dose would be appropriate. However, other PK studies challenge this approach. Clinical data from randomised controlled trials are not available, whilst data from observational studies do not support higher effectiveness of a loading dose. In this review, we summarise the available data regarding the administration of a loading dose and discuss the issues surrounding the potential advantages and disadvantages as well as the context within which such an approach could be beneficial to patients., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

To evaluate the factors associated with oseltamivir prescription and to study the effectiveness of oseltamivir in reducing influenza-related complications. A prospective cohort study using the SOS Doctors (a network of physicians who perform house-call visits in Attica, Greece). Patients with confirmed or clinically suspected influenza were followed up to 14 days during the 2011-2012 influenza period. 410 patients with confirmed or suspected influenza were included. Healthy adults were mainly enrolled, with a median age of 44 years. Influenza diagnosis was mainly based on clinical criteria (65.8 % of patients). Oseltamivir was prescribed for 45.4 % of them. In a multivariate analysis, prescription of oseltamivir was associated with the attending physician (p < 0.001), positive influenza test (p < 0.001) and diabetes (p = 0.027). Data on complications were available for 351 patients, and 50 (15.8 %) of them reported at least one. Seven patients required hospitalization. Types of complications (pneumonia, bronchitis, etc.) were not significantly different between patients receiving and those not receiving oseltamivir. In the multivariate analysis, higher oseltamivir prescription rate was associated with fewer complications (p < 0.001). Bearing in mind the limitations of a non-randomized study, in a real-life setting, oseltamivir prescription and the rate of complications in patients with influenza were associated with the attending physician, underlying diseases and diagnostic tests. Overall, when the frequency of oseltamivir prescription increased, the influenza-related complications decreased.

Introduction: A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians., Areas Covered: We searched PUBMED and GOOGLE databases. Combinations of already approved β-lactams or monobactams with new β-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new β-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review. Expert commentary: For the majority of the upcoming antibiotics the currently available data is limited to their microbiology and pharmacokinetics. Their effectiveness and safety against infections due to MDR bacteria remain to be proved. Significant issues are also the impact of these antibiotics on the human intestinal microbiota and their possible co-administration with already-known antimicrobial agents in difficult-to-treat-infections; further studies should be conducted for these objectives.

Antibiotics have been the most important risk factor for Clostridium difficile infection (CDI). However, only data from non-randomised studies have been reviewed. We sought to evaluate the risk for development of CDI associated with the major antibiotic classes by analysing data from randomised controlled trials (RCTs). The PubMed, Cochrane and Scopus databases were searched and the references of selected RCTs were also hand-searched. Eligible studies should have compared only one antibiotic versus another administered systemically. Inclusion of studies comparing combinations of antibiotics was allowed only if the second antibiotic was the same or from the same class or if it was administered in a subset of the enrolled patients who were equally distributed in the two arms. Only a minority of the selected RCTs (79/1332; 5.9%) reported CDI episodes. Carbapenems were associated with more CDI episodes than fluoroquinolones [risk ratio (RR) = 2.44, 95% confidence interval (CI) 1.32-4.49] and cephalosporins (RR = 2.24, 95% CI 1.46-3.42), but not penicillins (RR = 2.53, 95% CI 0.87-7.41). Cephalosporins were associated with more CDIs than penicillins (RR = 2.36, 95% CI 1.32-4.23) and fluoroquinolones (RR = 2.84, 95% CI 1.60-5.06). There was no difference in CDI frequency between fluoroquinolones and penicillins (RR = 1.34, 95% CI 0.55-3.25). Finally, clindamycin was associated with more CDI episodes than cephalosporins and penicillins (RR = 3.92, 95% CI 1.15-13.43). In conclusion, data from RCTs showed that clindamycin and carbapenems were associated with more CDIs than other antibiotics., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The aim of this review was to evaluate the susceptibility of contemporary Gram-positive and Gram-negative bacteria to fosfomycin. PubMed and Scopus databases were systematically searched to identify studies published in print or electronically from January 2010 until June 2015. In total, 84 studies were selected. Susceptibility to fosfomycin of Staphylococcus aureus ranged between 33.2% and 100% (frequency=91.7%, 95% confidence interval 88.7-94.9%), of Enterococcus spp. from 30% to 100% (Enterococcus faecium 92.6%, 85.2-100%; Enterococcus faecalis 96.8%, 92.5-100%), of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli from 81% to 100% (95.1%, 94.3-95.9%), of ESBL-producing Klebsiella pneumoniae from 15% to 100% (83.8%, 78.7-89.4%) and of carbapenem-resistant (CR) K. pneumoniae from 39.2% to 100% (73.5%, 66.4-81.4%). Staphylococcus aureus (including meticillin-resistant strains) and E. coli (including ESBL-producing strains) were the most likely to be susceptible with low minimum inhibitory concentrations (MICs). Enterococci (particularly vancomycin-resistant E. faecium) and K. pneumoniae (especially CR strains) were less susceptible with higher MIC50 and MIC90 values. Two studies reported decreasing susceptibility of ESBL-producing E. coli to fosfomycin. In conclusion, guided by local susceptibility data, fosfomycin could be considered for the treatment of patients with infections due to problematic multidrug-resistant bacteria., (Copyright © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

We studied the epidemiology and microbiology of Clostridium difficile and the characteristics of patients with C. difficile infection (CDI) in Crete in three groups of hospitalized patients with diarrhoea: group 1 [positive culture and positive toxin by enzyme immunoassay (EIA)]; group 2 (positive culture, negative toxin); group 3 (negative culture, negative toxin). Patients in group 1 were designated as those with definitive CDI (20 patients for whom data was available) and matched with cases in group 2 (40 patients) and group 3 (40 patients). C. difficile grew from 6% (263/4379) of stool specimens; 14·4% of these had positive EIA, of which 3% were resistant to metronidazole. Three isolates had decreased vancomycin susceptibility. Patients in groups 1 and 2 received more antibiotics (P = 0·03) and had more infectious episodes (P = 0·03) than patients in group 3 prior to diarrhoea. Antibiotic administration for C. difficile did not differ between groups 1 and 2. Mortality was similar in all three groups (10%, 12·5% and 5%, P = 0·49). CDI frequency was low in the University Hospital of Crete and isolates were susceptible to metronidazole and vancomycin.

We performed a systematic review of the data regarding rapid diagnostic tests and their advantages or limitations on patients' clinical outcomes. The PubMed and Scopus databases were searched independently by two reviewers. Mortality was the primary outcome. Most studies compared rapid tests with blood cultures. Although not observed in all studies, only studies comparing rapid tests in conjunction with antimicrobial stewardship programs (ASPs) showed a mortality benefit. A reduction in hospital or intensive care unit (ICU) length of stay was also observed in almost all studies when the rapid tests, with or without ASPs, were used. Finally, treatment decisions were taken earlier in the rapid test groups. Despite a faster treatment decision, a clear mortality benefit was not seen when rapid tests were used. It is crucial to differentiate the influence of rapid tests from that of ASPs and clarify the actual effect of each factor separately.

Clinicians nowadays are confronted with an epidemic of multidrug-resistant (MDR) Acinetobacter infections and are forced to consider every treatment alternative, including older antibiotic agents, not conventionally used. This review aimed to evaluate the published evidence on the antimicrobial activity and clinical effectiveness of trimethoprim/sulfamethoxazole (TMP-SMX) against Acinetobacter spp. Selected in vitro studies included antimicrobial surveillance reports, microbiological studies regarding the activity of TMP-SMX against MDR Acinetobacter isolates, and clinical studies published after the year 2000. Non-susceptibility rates for Acinetobacter spp. in surveillance studies ranged from 4% to 98.2%; in 23 of 28 studies, non-susceptibility to TMP-SMX was >50% and in a subset of 15 studies non-susceptibility was >70%. In studies regarding MDR Acinetobacter spp., non-susceptibility rates ranged from 5.9% to 100%; however, 19 of 21 studies reported >70% non-susceptibility. Extensively drug-resistant Acinetobacter baumannii complex had total (100%) resistance in five of six studies. Carbapenem-resistant Acinetobacter spp. had non-susceptibility rates to TMP-SMX of >80% in 22 of 26 studies. One study on polymyxin-resistant A. baumannii showed a susceptibility rate of 54.2% (13/24). Only seven case reports evaluated TMP-SMX for Acinetobacter spp. infections, mainly in combination with other agents; all cases were deemed therapeutic successes. Although TMP-SMX is not usually active against Acinetobacter spp., it might be considered in cases where there are no other options., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Objective: To study the characteristics, risk factors and outcomes of intensive care unit (ICU) patients with carbapenem-resistant (CRKp) and carbapenem-susceptible (CSKp) Klebsiella pneumoniae infections., Methods: A retrospective cohort of patients with K. pneumoniae infections in an eight-bed ICU between January 2006 and October 2009., Results: During the study period, 104 patients were diagnosed with K. pneumoniae infection (80 CRKp and 24 CSKp). Isolation of CRKp increased gradually during the study period, while isolation of CSKp remained constant. The mean age of patients was 66.3 ± 14.3 years. The mean APACHE II score was 17.9 ± 6.9. The median duration of ICU stay until the infection was 15 days. Thirty five patients (33.7%) had primary and 30 (28.8%) had secondary bacteremia. Seventy-two patients (69.2%) died in the ICU. No independent risk factors for development of CRKp infections were identified in the multivariate analysis. Treatment failure (p = 0.001) was the only independent predictor of mortality in the multivariate analysis (APACHE II, shock, multi-organ failure, respiratory failure, acute renal failure, acidosis and extensive-drug resistance were included in the model). No difference in mortality was found between patients with CRKp and CSKp isolates., Conclusions: Infection due to K. pneumoniae in the ICU was associated with high mortality. Control of the infection was the most important determinant of the outcome of critically ill patients., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Multidrug-resistant (MDR) Acinetobacter baumannii infections have emerged as a serious threat worldwide. As novel agents have yet to be developed, understanding the effectiveness and safety of older antibiotics has become a priority. The purpose of this systematic review was to summarise the available clinical evidence on the use of tetracyclines for the treatment of A. baumannii infections. Ten retrospective studies regarding doxycycline and minocycline for the treatment of 185 A. baumannii infections (of which 65.4% were respiratory infections and 13% were bloodstream infections) in 156 patients were available. In most cases (86.4%), tetracyclines were administered in combination with another agent. The usual dosage of doxycycline or minocycline was 100mg intravenous or per os twice daily (usually with a 200mg loading dose for minocycline). Clinical success was achieved in 120 (76.9%) of 156 patients; in 87 (71.9%) of 121 respiratory infections and in 21 (87.5%) of 24 bloodstream infections. Twenty-two deaths occurred in 100 recorded cases. Microbiological eradication was attained in 72 (71.3%) of 101 available cases and documented microbiological eradication was reached in 59 (66.3%) of 89 available cases. Adverse events were noted in only 1 of 88 cases. Overall, although tetracycline-containing regimens showed encouraging results, more data from larger comparative trials are required to establish a role for these antibiotics in the treatment of MDR A. baumannii infections., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

OBJECT The aim of this study was to evaluate the effectiveness of antimicrobial-impregnated and -coated shunt catheters (antimicrobial catheters) in reducing the risk of infection in patients undergoing CSF shunting or ventricular drainage. METHODS The PubMed and Scopus databases were searched. Catheter implantation was classified as either shunting (mainly ventriculoperitoneal shunting) or ventricular drainage (mainly external [EVD]). Studies evaluating antibioticimpregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs) were included. A random effects model meta-analysis was performed. RESULTS Thirty-six studies (7 randomized and 29 nonrandomized, 16,796 procedures) were included. The majority of data derive from studies on the effectiveness of AICs, followed by studies on the effectiveness of SCCs. Statistical heterogeneity was observed in several analyses. Antimicrobial shunt catheters (AICs, SCCs) were associated with lower risk for CSF catheter-associated infections than conventional catheters (CCs) (RR 0.44, 95% CI 0.35-0.56). Fewer infections developed in the patients treated with antimicrobial catheters regardless of randomization, number of participating centers, funding, shunting or ventricular drainage, definition of infections, de novo implantation, and rate of infections in the study. There was no difference regarding gram-positive bacteria, all staphylococci, coagulase-negative streptococci, and Staphylococcus aureus, when analyzed separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA, RR 2.64, 95% CI 1.26-5.51), nonstaphylococcal (RR 1.75, 95% CI 1.22-2.52), and gram-negative bacterial (RR 2.13, 95% CI 1.33-3.43) infections increased with antimicrobial shunt catheters. CONCLUSIONS Based on data mainly from nonrandomized studies, AICs and SCCs reduce the risk for infection in patients undergoing CSF shunting. Future studies should evaluate the higher risk for MRSA and gram-negative infections. Additional trials are needed to investigate the comparative effectiveness of the different types of antimicrobial catheters.

Background: Linezolid containing regimens have been proposed as potentially valuable alternatives for the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant TB (XDR-TB)., Methods: A systematic review and meta-analysis was conducted to assess the efficacy, safety and tolerability of linezolid for drug-resistant TB (DR-TB) treatment. We searched the Cochrane Controlled Trial Registry, PubMed, Embase, Science Citation Index Expanded (SCI) and China National Knowledge Infrastructure (CNKI), database up to May 2014 to identify studies providing data of the use of linezolid for the treatment of DR-TB., Results: The search yielded 15 studies (367 patients) including one randomized controlled trial (RCT), covering 239 patients who could be evaluated for effectiveness; 83% [95% confidence interval (CI), 75-90%; I(2)=62.8%] had a favorable outcome, defined as either cure or treatment completion. The pooled rate of culture conversion was 89% (95% CI, 83-95%; I(2)=49.6%). Between the group receiving daily linezolid doses of ≤600 or >600 mg, the mortality was considerably lower in patients treated with less than 600 mg/day (P value <0.001). Of 367 patients for whom data on safety was available, peripheral neuropathy (31%, 95% CI, 19-42%; I(2)=81.7%) and anemia (25%, 95% CI, 15-34%; I(2)=76.6%) were the main adverse effects. Patients receiving less than 600 mg/day were more likely to experience nervous system adverse events (P value <0.01)., Conclusions: The available evidence suggests that linezolid could be considered as a promising option as treatment of MDR/XDR TB. Randomized trials are warranted to define the dose and frequency of administration.

We sought to evaluate published evidence regarding clinical or microbiological outcomes related to the use of inhaled antibiotics other than aminoglycosides, polymyxins and aztreonam. A systematic search of PubMed and Scopus databases as well as bibliographies of eligible articles was performed. In total, 34 eligible studies were identified. Among several inhaled β-lactams, ceftazidime was used with varying success in the prevention and treatment of ventilator-associated pneumonia (VAP) and improved clinical outcomes in chronic Pseudomonas aeruginosa lower respiratory tract infections (LRTIs) in patients with cystic fibrosis (CF) or bronchiectasis. Inhaled vancomycin, as an adjunctive therapy, was effective in treating Gram-positive VAP, whilst inhaled levofloxacin, ciprofloxacin and an inhaled combination of fosfomycin and tobramycin were associated with improved microbiological or clinical outcomes in chronic LRTI in patients with CF or bronchiectasis. In conclusion, published evidence is heterogeneous with regard to antibiotics used, studied indications, patient populations and study designs. Therefore, although the currently available data are encouraging, no safe conclusion regarding the effectiveness and safety of the drugs in question can be reached., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

The objective of this study was to assess the comparative effectiveness and safety of antistaphylococcal penicillins (ASPs) and cephalosporins for the definitive treatment of patients with meticillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. PubMed and Scopus electronic databases were searched up to December 2013. All-cause mortality was the primary outcome of interest. A meta-analysis of unadjusted and adjusted data was performed. Seven articles (1643 patients) were included; all but one were retrospective studies, and three of them employed propensity score matching. The studies enrolled primarily adults hospitalised in medical wards for primary or secondary community-acquired, healthcare-associated or nosocomial MSSA bacteraemia. Several ASPs and cephalosporins were compared. Unadjusted 30-day mortality was lower in patients treated with ASPs than in those treated with cephalosporins [risk ratio (RR)=0.62, 95% confidence interval (CI) 0.40-0.98]. Propensity score-adjusted 30-day mortality was not different in patients receiving ASPs or cephalosporins (RR=0.75, 95% CI 0.41-1.39). Substantial heterogeneity and publication bias were found in these analyses. Both unadjusted (RR=0.85, 95% CI 0.54-1.32) and adjusted (RR=1.42, 95% CI 0.22-9.06) 90-day mortality did not differ between patients receiving ASPs or cephalosporins. Limited data regarding adverse events, development of resistance and recurrence were available. In conclusion, the limited available published data derive from retrospective studies and show that there appears to be no statistically significant difference in mortality between ASPs and cephalosporins for the treatment of MSSA bacteraemia., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

The objective of this investigation was to evaluate the association between colistin consumption and the isolation of intrinsically resistant to colistin Enterobacteriaceae (IRCE) in a university hospital in Crete, Greece. The database of the microbiological laboratory was reviewed retrospectively during 2006-2010. All positive cultures for IRCE were retrieved. We assessed the total consumption of colistin in medical, surgical, and intensive care units (ICUs). A total of 1,304 single-patient IRCE isolates were recorded. Of these, 466 (35.7%) were hospital-acquired, while 838 (64.3%) were community-acquired. Proteus spp. accounted for 72% of them, Serratia spp. for 16.6%, Morganella morganii for 8.4%, and Providencia spp. for 3%. Urine (44.8%), pus (20.4%), and lower respiratory tract specimens (12.8%) accounted for the majority of specimens. IRCE isolated during the first half (2006 to 1st semester of 2008) and second half (2nd semester of 2008 to 2010) of the study period accounted for 5.8% and 7.4% of Gram-negative isolates, respectively (p < 0.001). Colistin consumption was not different in the two periods in the hospital, but in the ICU, it was higher in the second half of the study period (p = 0.013). Colistin consumption was associated with the isolation of hospital-acquired IRCE (p = 0.037); a trend was noted between colistin consumption and the isolation of IRCE in the ICU (p = 0.057). In this study, colistin consumption was associated with the isolation of hospital-acquired IRCE. The use of colistin increased in the ICU during the study period. Prudent use of colistin is essential for the prevention of nosocomial outbreaks due to resistant IRCE.

Objectives: We sought to examine whether vacuum-assisted closure (VAC) is associated with fewer surgical site infections (SSIs) or infections of chronic wounds than other management procedures for surgical wounds., Methods: The PubMed and Scopus databases were searched systematically. Randomized controlled trials (RCTs) comparing the development of SSIs or infections of chronic wounds between patients treated with VAC for acute or chronic wounds and those whose wounds were treated without VAC were considered eligible for inclusion in the study., Results: Eight RCTs met the inclusion criteria for the study. Four of the studies included chronic or diabetic lower extremity wounds and four included fractures. In three of four studies reporting on fractures, the wounds were not closed post-operatively, whereas in one study primary closure of the wound was performed. With regard to wounds left open after the stabilization of fractures, patients whose wounds were treated with VAC developed fewer SSIs than those whose wounds were treated without VAC ([367 patients (196 with VAC; 171 without VAC) relative risk [RR], 0.47; 95% CI 0.28-0.81]). On the contrary, no difference in the development of SSIs occurred among patients with chronic or diabetic lower-extremity wounds treated with VAC and those whose wounds were treated without VAC ([638 patients (320 with VAC; 318 without VAC) RR 1.67; 95% CI: 0.71-3.94])., Conclusion: The available evidence suggests that the development of infections in wounds treated with VAC depends on the type of wound being treated.

Objective: To evaluate the characteristics and outcomes of cancer patients with extensively drug-resistant (XDR) Pseudomonas aeruginosa infections., Methods: This was a retrospective cohort of P. aeruginosa infections in cancer patients in Crete, Greece. Patients were followed until discharge. Mortality, predictors of mortality and risk factors for XDR P. aeruginosa infection were studied., Results: Ninety seven episodes (89 patients) of P. aeruginosa infections (52 with bacteremia) were included in the study. In 22 cases, the infection was due to XDR isolates. All XDR isolates were susceptible to colistin and variably resistant to almost all other antibiotics. The multivariate analysis showed that the independent risk factors for XDR P. aeruginosa infection were hematologic malignancy (OR 40.7, 95 % CI 4.5-367.6) and prior fluoroquinolone use (OR 11.0, 95 % CI 2.0-60.5); lymphopenia was inversely associated with XDR infections (OR 0.16, 95 % CI 0.03-0.92). Mortality was 43 %; infection-related mortality was 24 %. Bacteremia (OR 8.47, 95 % CI 2.38-30.15), infection due to XDR isolates (OR 5.11, 95 % CI 1.15-22.62) and age (OR 1.05, 95 % CI 1.00-1.09) were independently associated with mortality., Conclusion: Mortality in cancer patients with P. aeruginosa infections was high. Infection due to XDR isolates was independently associated with mortality.

Here we review the effectiveness and safety of high-dose tigecycline (200mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100mg every 12h (q12h) group and 69.6% (16/23) in the 75mg q12h group (P=0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P>0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200mg and 150mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100mg q12h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50mg q12h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

We evaluated the number of deaths attributable to carbapenem-resistant Enterobacteriaceae by using studies from around the world published before April 9, 2012. Attributable death was defined as the difference in all-cause deaths between patients with carbapenem-resistant infections and those with carbapenem-susceptible infections. Online databases were searched, and data were qualitatively synthesized and pooled in a metaanalysis. Nine studies met inclusion criteria: 6 retrospective case-control studies, 2 retrospective cohort studies, and 1 prospective cohort study. Klebsiella pneumoniae was the causative pathogen in 8 studies; bacteremia was the only infection in 5 studies. We calculated that 26%-44% of deaths in 7 studies were attributable to carbapenem resistance, and in 2 studies, which included bacteremia and other infections, -3% and -4% of deaths were attributable to carbapenem resistance. Pooled outcomes showed that the number of deaths was significantly higher in patients with carbapenem-resistant infections and that the number of deaths attributable to carbapenem resistance is considerable.