Systematic review + meta-analysis: 69 (quasi-)randomised trials: N=7,863 pts with sepsis: any BL monoTx vs any combination of BL + AG: N (studies): same BL in both arms: 22; broader-spectrum BL in monoTx arm: 47-lactam (BL) monotherapy (monoTx) vs BL/ aminoglycoside (AG) combination therapy for sepsis-lactam/AG combination Tx does not seem to provide an advantage over -lactam monoTx in septic pts, but increases nephrotoxicityPaul M et al. Cochrane Database Syst Rev 2014;1:CD003344

Impact of time to initiation of antibiotic Tx on in-hospital mortality in pts with severe sepsis or septic shockMulti-centre, retrospective study (2005-2010; Surviving Sepsis Campaign): 165 ICUs in Europe, USA, South-AmericaN=17,990 pts receiving antibiotics after severe sepsis or septic shockIn-hospital mortality: total cohort: 29.7%

Logistic regression model: OR for hospital mortality: adjusted for Sepsis Severity Score, ICU admission source (emergency department, ward vs ICU) and geographic regionFerrer R et al. Crit Care Med 2014;42:1749-551 of 2

Impact of time to initiation of antibiotic Tx on in-hospital mortality in pts with severe sepsis or septic shockRisk of hospital mortality (based on generalised estimating equation population averaged logistic regression model) Assumed patient: from USA, admitted via the emergency department, with Sepsis Severity Score of 52 (median of all observations)

Results similar in pts with severe sepsis and septic shock, regardless of number of organ failure(s)In patients with severe sepsis or septic shock, the risk of in-hospital mortality shows a linear increase with each hour delay in initiation of antibiotic Tx during the first 6 hours after patient identification Ferrer R et al. Crit Care Med 2014;42:1749-552 of 2

Impact of medical education on risk of developing and dying from severe sepsisMatched cohort study (2000-2008, Taiwans National Health Insurance Research Database): 29,697 physicians + 29,697 demographically and socioeconomically matched controls without medical education/backgroundPrimary outcome: Development of severe sepsis:

Secondary outcome: 90-day mortality following severe sepsis: lower for physicians; HR (adjusted for baseline/additional covariates)=0.82; 95% CI: 0.71-0.95Compared with matched controls, physicians seem to have a lower risk of developing and dying from severe sepsisShen HN et al. Crit Care Med 2014;42:816-23*Adjusted for age, sex, income level, urbanisation status, geographic region, Charlson comorbidity score

Clinical risk factors and outcomes associated with FKS mutations in pts with Candida glabrata candidaemiaSingle-centre retrospective study (2009-2012; USA): N=72 pts with C. glabrata bloodstream infection (BSI) N=13 pts (18%) with FKS mutationN=57 pts treated with micafungin 100 mg iv every 24h

Beyda ND et al. Clin Infect Dis 2014;59:819-251 of 2* caspofungin susceptibility test: Sensititre YeastOne, Trek Diagnostic systems, USA; MIC: minimum inhibitory concentration; NPV: negative predictive value; PPV: positive predictive value; Sens.: sensitivity; Spec.: specificityTx failure: assessed at day 14 using consensus definitions of outcomes for antifungal therapy or as a breakthrough infection while receiving an echinocandin for 3 days as empiric therapy

Clinical risk factors and outcomes associated with FKS mutations in pts with Candida glabrata candidaemia

Independent predictor of FKS mutant C. glabrata BSI (multivariate analysis):

Independent predictor(s) of echinocandin Tx failure (multivariate analysis):

Previous echinocandin exposure seems to be a risk factor for FKS mutant C. glabrata BSI and may predict echinocandin Tx failureBeyda ND et al. Clin Infect Dis 2014;59:819-252 of 2

Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance and multi-drug-resistance (MDR)Multi-centre, population-based surveillance study (2008-2013; USA): N=1,380 C. glabrata bloodstream isolates

Antifungal susceptibility testing2008-2013: decrease in absolute # of C. glabrata isolates/study centre BUT % of isolates resistant to any echinocandin remains constant

Pham CD et al. Antimicrob Agents Chemother 2014;58:4690-61 of 2MIC: minimum inhibitory concentration

Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance and multi-drug resistance (MDR)Identification of mutations in FKS genes1,302 isolates screened for mutations, including all 77 isolates with resistant or intermediate MIC value for 1 echinocandin: FKS1 HS1 (hot spot 1): 15 mutations / FKS2 HS1: 35 mutations

All isolates with FKS mutation, except for 1: resistant to 1 echinocandin

FKS mutation detected in 81% of isolates resistant to 1 echinocandin

Only 1 isolate resistant to all 3 echinocandins did not have FKS mutation

Echinocandin resistance among US C. glabrata is a concern, especially since 36% of echinocandin-resistant isolates may be MDRPham CD et al. Antimicrob Agents Chemother 2014;58:4690-62 of 2

De-escalation vs continuation of empirical antimicrobial Tx for severe sepsisMulti-centre, non-blinded, randomised non-inferiority study (2012-2013; France; 9 ICUs; N=116 pts with severe sepsisRandomised to: De-escalation (N=59): after antibiogram, empirical Tx switched to appropriate antibiotic with a narrower spectrum or Continuation of empirical antimicrobial Tx (N=57)FU: 90 days

Primary outcome: Duration of ICU stayLeone M et al. Intensive Care Med 2014;40:1399-4081 of 298

De-escalation vs continuation of empirical antimicrobial Tx for severe sepsisCompared with continuation of empirical antimicrobial Tx, de-escalation seems to increase duration of ICU stay and # of superinfections, but may not increase mortality rate or # of organ failuresLeone M et al. Intensive Care Med 2014;40:1399-4082 of 2*From inclusion to day 28; D-SOFA: changes in Sequential Organ Failure Assessment score

Impact of mandatory infectious disease consultation (IDC) on management of S. aureus (SA) bacteraemia Single-centre, before-after study in adult pt with documented blood cultures positive for SA, surviving >48h from index culture:Mandatory IDC implemented in August 2012: comparison 1-yr period before/after implementationMandatory IDC may positively impact management of SA bacteraemiaSalazar D. IDWeek 2014 abs. 134

Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.This systematic review is an update of previously published versions: Paul M et al. Cochrane Database Syst Rev 2003;3:CD003038 / Paul M et al. BMJ 2004;328:668-72 / Paul M et al. Cochrane Database Syst Rev 2006;1:CD003344.Only 5 of 65 included studies targeted participants with Gram-positive infection. Details regarding the specific antibiotic regimen used can be found in the publication.It should be noted that results for mortality were classified as low quality of evidence, mainly as the result of imprecision, while results for failure were classified as very low quality of evidence, because of indirectness of the outcome and possible detection bias in non-blinded trials. A limitation of this study is the lack of patient stratification according to the presence of septic shock and according to illness severity. Indeed, a meta-analytic/meta-regression study by Kumar et al. (Kumar A et al. Crit Care Med 2010;38:1651-64) showed that combination therapy may improve survival and clinical response of high-risk life-threatening infections, particularly those associated with septic shock, but may be detrimental to low-risk patients. Moreover, patients were not stratified according to the time period/frequency of aminoglycoside use. Whereas e.g. in Sweden the main use of aminoglycosides in this setting is limited to 1 single dose usage in the most severely ill patients with sepsis or septic shock, aminoglycosides were used for a considerably longer period of time in many old studies included in this meta-analysis. Therefore, it is dangerous to draw conclusions from this meta-analysis. Another limitation of this meta-analysis is the open design of many studies, leading to an increased risk of bias (e.g. patients receiving combination therapy may have been more severely ill).

AE: adverse eventall-cause mortalityclinical failureresistanceTx: treatment*Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.This study confirms, in the largest population of patients with severe sepsis and septic shock reported to date, that delay in antibiotic administration was associated with increased in-hospital mortality, across all areas in the hospital and across all levels of organ dysfunction. Thus, despite recent improvements in the management of patients with septic shock, the results of the retrospective study published by Kumar et al. in 2006 (Kumar et al. Crit Care Med 2006;34:1589-96, showing a 7.6% increase in the risk of death per hour delay in initiation of antibiotic therapy after onset of hypotension in patients with septic shock) are still valid. Consequently, it remains very important to identify and treat septic patients in the hospital setting as soon as possible. A limitation of this study is its retrospective character, i.e. risk of confounding variables. Indeed, appropriateness of antibiotic therapy was not assessed in this study, although inappropriate or inadequate antibiotic choices may confound the results. In addition, the reasons for delay in antibiotic administration were not assessed.

CI: confidence intervalICU: intensive care unitOR: odds ratioref.: referenceTx: treatment

*Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.This study confirms, in the largest population of patients with severe sepsis and septic shock reported to date, that delay in antibiotic administration was associated with increased in-hospital mortality, across all areas in the hospital and across all levels of organ dysfunction. Thus, despite recent improvements in the management of patients with septic shock, the results of the retrospective study published by Kumar et al. in 2006 (Kumar et al. Crit Care Med 2006;34:1589-96, showing a 7.6% increase in the risk of death per hour delay in initiation of antibiotic therapy after onset of hypotension in patients with septic shock) are still valid. Consequently, it remains very important to identify and treat septic patients in the hospital setting as soon as possible. A limitation of this study is its retrospective character, i.e. risk of confounding variables. Indeed, appropriateness of antibiotic therapy was not assessed in this study, although inappropriate or inadequate antibiotic choices may confound the results. In addition, the reasons for delay in antibiotic administration were not assessed.

ICU: intensive care unitTx: treatment

*Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.These data suggest that medical knowledge, higher disease awareness and easier healthcare access in physicians may help to reduce their risk of severe sepsis and associated mortality, especially in younger physicians.

CI: confidence interval HR: hazard ratio

*Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.The FKS1, FKS2 and FKS3 genes in C. glabrata encode the enzyme -1,3-glucan synthase, which is inhibited by echinocandins. These data suggest that caspofungin MICs may be useful for identifying clinical significant FKS mutations that are likely to fail treatment with micafungin. A limitation of this study is its single-centre, retrospective design. The incidence of FKS mutations and the frequency of specific mutations may not reflect local epidemiology elsewhere. Moreover, it has not been studied whether MICs generated by the commercial YeastOne susceptibility test correlate with MICs obtained using the CLSI broth microdilution method.

iv: intravenous(ly)MIC: minimum inhibitory concentrationNPV: negative predictive valuePPV: positive predictive valueSens.: sensitivitySpec.: specificityTx: treatment*Reporter comments:This publication was discussed during the IDWeek 2014 session New Anti-infective Clinical Trials That Will Change Your Practice (session 32) by Henry Chambers, Richard Whitley, Thomas Patterson and Andrea Boggild.The FKS1, FKS2 and FKS3 genes in C. glabrata encode the enzyme -1,3-glucan synthase, which is inhibited by echinocandins. These data suggest that caspofungin MICs may be useful for identifying clinical significant FKS mutations that are likely to fail treatment with micafungin. A limitation of this study is its single-centre, retrospective design. The incidence of FKS mutations and the frequency of specific mutations may not reflect local epidemiology elsewhere. Moreover, it has not been studied whether MICs generated by the commercial YeastOne susceptibility test correlate with MICs obtained using the CLSI broth microdilution method.

CI: confidence intervaliv: intravenous(ly)OR: odds ratioTx: treatment*Reporter comments:This publication was discussed during the IDWeek 2014 session Fungal Infections in the ICUAnother View (session 168) by Naomi Ogrady, Luis Ostrosky-Zeichner and Theoklis Zaoutis.The FKS1, FKS2 and FKS3 genes in C. glabrata encode the enzyme -1,3-glucan synthase, which is inhibited by echinocandins. These data suggest that further monitoring of C. glabrata isolates in the USA for echinocandin resistance is warranted.

anidulafungincaspofunginflucoconazoleMIC: minimum inhibitory concentrationmicafungin

*Reporter comments:This publication was discussed during the IDWeek 2014 session Fungal Infections in the ICUAnother View (session 168) by Naomi Ogrady, Luis Ostrosky-Zeichner and Theoklis Zaoutis.The FKS1, FKS2 and FKS3 genes in C. glabrata encode the enzyme -1,3-glucan synthase, which is inhibited by echinocandins. These data suggest that further monitoring of C. glabrata isolates in the USA for echinocandin resistance is warranted.

anidulafungincaspofunginflucoconazoleHS: hot spotMIC: minimum inhibitory concentrationmicafungin

*Reporter comments:This publication was discussed during the IDWeek 2014 session Antimicrobial StewardshipThe Latest Trends and Opportunities (session 68) by Thomas M. File Jr., Elizabeth Dodds-Ashley, Christopher Crnich and Stephan Harbarth.This is the first randomised study comparing de-escalation and continuation of appropriate empirical treatment in patients with severe sepsis. The results of this study do not confirm results from prior observational studies. Most likely, the prolonged antimicrobial use in the de-escalation group was caused by the higher number of superinfections in the de-escalation group. Limitations of this study are the lack of blinding, the relatively small patient numbers, and the lack of clear definition of de-escalation.

CI: confidence intervalFU: follow-upICU: intensive care unitTx: treatment

*Reporter comments:This publication was discussed during the IDWeek 2014 session Antimicrobial StewardshipThe Latest Trends and Opportunities (session 68) by Thomas M. File Jr., Elizabeth Dodds-Ashley, Christopher Crnich and Stephan Harbarth.This is the first randomised study comparing de-escalation and continuation of appropriate empirical treatment in patients with severe sepsis. The results of this study do not confirm results from prior observational studies. Most likely, the prolonged antimicrobial use in the de-escalation group was caused by the higher number of superinfections in the de-escalation group. Limitations of this study are the lack of blinding, the relatively small patient numbers, and the lack of clear definition of de-escalation.

antibioticcatecholamineD-SOFA: changes in Sequential Organ Failure Assessment scoreICU: intensive care unitTx: treatmentventilator

*Reporter comments:This study confirms the findings of a systematic review (Holland TL. JAMA 2014;312:1330-41), indicating that at least 15 observational studies found a clinical benefit of IDC for SA bacteraemia, with 11 of them reporting improved mortality among pts receiving IDC.

MRSA: methicillin-resistant Staphylococcus aureusS. aureus: Staphylococcus aureus*