1 of 2 Universal vs targeted decolonisation to prevent ICU infections: data from REDUCE MRSA trial Huang SS et al. N Engl J Med 2013;368:2255-65 Multi-centre, cluster-randomised study: N=74,256 pts from 74 ICUs: 3 strategy groups: MRSA screening + isolation Targeted decolonisation: MRSA screening + isolation + decolonisation of MRSA carriers (intranasal mupirocin 2x/day for 5 days + daily bathing with chlorhexidine-impregnated cloths) Universal decolonisation: no MRSA screening; decolonisation of all pts (intranasal mupirocin 2x/day for 5 days + daily bathing with chlorhexidine-impregnated cloths for entire ICU stay) Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Top Epidemiology and Infection Control Papers of the Year’ (session 140) by Robert Weinstein and Andreas Widmer. A disadvantage of universal decolonisation would be the potential development of resistance to mupirocin and chlorhexidine (although MRSA resistance to chlorhexidine lacks a standard definition). Therefore, surveillance programmes to monitor for resistance to these agents are required. AE(s): adverse event(s) BSI: bloodstream infection HR: hazard ratio ICU: intensive care unit MRSA: methicillin-resistant Staphylococcus aureus REDUCE: Randomised Evaluation of Decolonisation versus Universal Clearance to Eliminate MRSA

2 of 2 Universal vs targeted decolonisation to prevent ICU infections: data from REDUCE MRSA trial Huang SS et al. N Engl J Med 2013;368:2255-65 MRSA-pos. clinical culture MRSA BSI BSI with any pathogen 54 pts need to undergo universal decolonisation to prevent 1 BSI from any pathogen AEs occurred in 7 pts: mild and related to chlorhexidine Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Top Epidemiology and Infection Control Papers of the Year’ (session 140) by Robert Weinstein and Andreas Widmer. A disadvantage of universal decolonisation would be the potential development of resistance to mupirocin and chlorhexidine (although MRSA resistance to chlorhexidine lacks a standard definition). Therefore, surveillance programmes to monitor for resistance to these agents are required. AE(s): adverse event(s) BSI: bloodstream infection HR: hazard ratio ICU: intensive care unit MRSA: methicillin-resistant Staphylococcus aureus REDUCE: Randomised Evaluation of Decolonisation versus Universal Clearance to Eliminate MRSA In ICU pts, universal decolonisation seems to be more effective than targeted decolonisation, or screening and isolation, in reducing rates of MRSA clinical isolates and BSI from any pathogen

1 of 2 Continuous infusion vs intermittent bolus dosing of β-lactam antibiotics in severe sepsis Dulhunty JM et al. Clin Infect Dis 2013;56:236-44 Multi-centre, prospective, double-blind RCT (Australia, Hong Kong) N=60 ICU pts with severe sepsis in previous 48h, receiving continuous infusion (N=30) or intermittent bolus dosing (N=30) of piperacillin-tazobactam, meropenem and ticarcillin-clavulanate Primary endpoint (pharmacokinetic) Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Antimicrobial Pharmacodynamics in Clinical Practice’ (session 144) by George Drusano and Thomas Lodise. This is the first multi-centre RCT in ICUs that compares continuous and intermittent administration of β-lactam antibiotics. It should be noted that this study was not powered to evaluate any effect on survival or other clinical endpoints. The decreased risk of underdosing with continuous infusion compared with bolus injection was also demonstrated in ECCMID 2013 abs. P906 (Frey OR). ICU: intensive care unit RCT: randomised controlled trial

2 of 2 Continuous infusion vs intermittent bolus dosing of β-lactam antibiotics in severe sepsis Dulhunty JM et al. Clin Infect Dis 2013;56:236-44 Secondary endpoints (clinical) Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Antimicrobial Pharmacodynamics in Clinical Practice’ (session 144) by George Drusano and Thomas Lodise. This is the first multi-centre RCT in ICUs that compares continuous and intermittent administration of β-lactam antibiotics. It should be noted that this study was not powered to evaluate any effect on survival or other clinical endpoints. The decreased risk of underdosing with continuous infusion compared with bolus injection was also demonstrated in ECCMID 2013 abs. P906 (Frey OR). ICU: intensive care unit RCT: randomised controlled trial In critically ill pts with severe sepsis, continuous infusion of β-lactam antibiotics may lead to higher plasma antibiotic concentrations and higher clinical cure rates than intermittent bolus dosing

1 of 2 Extended or continuous vs short-term infusion of β-lactam antibiotics: systematic review and meta-analysis of clinical outcomes Falagas ME et al. Clin Infect Dis 2013;56:272-82 Systematic literature review (January 2012) + meta-analysis: articles reporting on comparative outcomes of pts treated with extended (≥3h) or continuous (24h) vs short-term (20-60 min) iv infusion of carbapenems or piperacillin/tazobactam: 14 studies on 1,229 patients included: Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Antimicrobial Pharmacodynamics in Clinical Practice’ (session 144) by George Drusano and Thomas Lodise. The study has potential limitations: only around 25% of patients were from RCTs and the included studies were heterogeneous in many aspects. Furthermore, it should be noted that the difference in clinical cure between extended/continuous infusion and short-term infusion was not significant. This is the first meta-analysis showing a reduction in mortality with extended/continuous antibiotic infusion in patients with moderate to severe infections. The difference with previous meta-analyses may be explained by different types of antibiotics, different patient populations, different study design and different severity of infections under study. Well-designed RCTs are warranted to validate the findings of the current study and, as the authors themselves point out, “before such approaches become widely applied in clinical practice”. CI: confidence interval ICAAC: Interscience Conference on Antimicrobial Agents and Chemotherapy iv: intravenous(ly) RCT: randomised controlled trial

2 of 2 Extended or continuous vs short-term infusion of β-lactam antibiotics: systematic review and meta-analysis of clinical outcomes Falagas ME et al. Clin Infect Dis 2013;56:272-82 Clinical cure: no statistical difference between extended/continuous and short-term infusions: Risk ratio=1.13; 95% CI: 0.99-1.28; P=0.08 Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Antimicrobial Pharmacodynamics in Clinical Practice’ (session 144) by George Drusano and Thomas Lodise. The study has potential limitations: only around 25% of patients were from RCTs and the included studies were heterogeneous in many aspects. Furthermore, it should be noted that the difference in clinical cure between extended/continuous infusion and short-term infusion was not significant. This is the first meta-analysis showing a reduction in mortality with extended/continuous antibiotic infusion in patients with moderate to severe infections. The difference with previous meta-analyses may be explained by different types of antibiotics, different patient populations, different study design and different severity of infections under study. Well-designed RCTs are warranted to validate the findings of the current study and, as the authors themselves point out, “before such approaches become widely applied in clinical practice”. CI: confidence interval ICAAC: Interscience Conference on Antimicrobial Agents and Chemotherapy iv: intravenous(ly) RCT: randomised controlled trial Mortality seems to be lower for extended or continuous infusion of carbapenems or piperacillin/tazobactam than for short-term infusion

1 of 2 Extended infusion of doripenem vs standard infusion of doripenem and meropenem: clinical outcomes Jogi V. IDWeek 2013 abs. 784 Single-centre, retrospective analysis (pharmacy database; USA) in hospitalised pts with moderate-to-severe infections: 2009-2010: N=134 pts treated with meropenem: standard infusion (30 min) 2011-2012: N=129 pts treated with doripenem: Extended infusion (4h): N=58 (45%) Standard infusion (30 min): N=71 (55%) Main clinical outcomes: mortality or transfer to hospice care (vs discharge to home, long-term care or rehab facility) Reporter comments: This retrospective analysis was started based on the results of a recent multi-centre, randomised, double-blind study comparing doripenem extended infusion (4h infusion of 1 g every 8h for 7 days ) with imipenem-cilistatin (1h infusion every 8h for 10 days) for ventilator-associated pneumonia due to Gram-negative bacteria: Kollef MH et al. Crit Care 2012;16:R218. This trial was prematurely terminated because patients in the doripenem group had higher rates of clinical failure and mortality. It was mentioned in the abstract that baseline data including age, sex, length of admission and ICU stay were comparable between the 2 groups. Weaknesses of this study are its retrospective character (using a historical control) and the relatively low number of patients in the doripenem extended infusion group. Therefore, prospective, preferentially randomised controlled studies in larger patient groups are needed to confirm these findings. CI: confidence interval

2 of 2 Extended infusion of doripenem vs standard infusion of doripenem and meropenem: clinical outcomes Jogi V. IDWeek 2013 abs. 784 Odd ratio (OR) for mortality or transfer to hospice care: Doripenem extended infusion vs doripenem standard infusion: OR=4.5; 95% CI:1.5-13; P<0.01 Meropenem standard infusion vs doripenem standard + extended infusion: OR=2.2; 95% CI: 1.2-4; P<0.01 Reporter comments: This retrospective analysis was started based on the results of a recent multi-centre, randomised, double-blind study comparing doripenem extended infusion (4h infusion of 1 g every 8h for 7 days ) with imipenem-cilistatin (1h infusion every 8h for 10 days) for ventilator-associated pneumonia due to Gram-negative bacteria: Kollef MH et al. Crit Care 2012;16:R218. This trial was prematurely terminated because patients in the doripenem group had higher rates of clinical failure and mortality. It was mentioned in the abstract that baseline data including age, sex, length of admission and ICU stay were comparable between the 2 groups. Weaknesses of this study are its retrospective character (using a historical control) and the relatively low number of patients in the doripenem extended infusion group. Therefore, prospective, preferentially randomised controlled studies in larger patient groups are needed to confirm these findings. CI: confidence interval Mortality seems to be higher for extended infusion of doripenem than for standard infusion. However, compared to meropenem standard infusion, mortality may be lower in the total doripenem group (extended + standard infusion)

1 of 2 Impact of addition of rifampicin to colistin on mortality due to extensively drug-resistant (XDR) Acinetobacter baumannii infections Durante-Mangoni E et al. Clin Infect Dis 2013;57:349-58 Multi-centre, open-label, phase III RCT (Italy; 2008-2011) N=210 ICU pts with life-threatening nosocomial infection due to XDR A. baumannii susceptible to colistin (MIC ≤2 mg/l), randomised to: Colistin alone (2.106 U every 8h iv): N=105 Colistin (2.106 U every 8h iv) + rifampicin (600 mg every 12 h iv): N=105 Median treatment duration: 12.5 days Safety Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Combination Therapy to Combat Antimicrobial Resistance and Optimize Therapy’ (session 2) by Nasia Safdar, Henry Chambers and Dimitrios Kontoyiannis. Nowadays, the adequate colistin dosages are 6x106 IU once daily, or even 9x106 IU first dosis followed by 4.5 x106 IU every 12h. CI: confidence interval iv: intravenously MIC: minimum inhibitory concentration pts: patients RCT: randomised controlled trial

2 of 2 Impact of addition of rifampicin to colistin on mortality due to extensively drug-resistant (XDR) Acinetobacter baumannii infections Durante-Mangoni E et al. Clin Infect Dis 2013;57:349-58 Efficacy Multivariable logistic regression: Treatment arm is NOT an independent predictor of 30-day mortality: OR=0.88; 95% CI: 0.46-1.69; P=0.71 Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Combination Therapy to Combat Antimicrobial Resistance and Optimize Therapy’ (session 2) by Nasia Safdar, Henry Chambers and Dimitrios Kontoyiannis. Nowadays, the adequate colistin dosages are 6x106 IU once daily, or even 9x106 IU first dosis followed by 4.5 x106 IU every 12h. CI: confidence interval iv: intravenously MIC: minimum inhibitory concentration pts: patients RCT: randomised controlled trial Rifampicin should not be combined with colistin in routine clinical practice, as it does not seem to reduce 30-day mortality in serious XDR A. baumannii infections compared with colistin alone

1 of 2 Aggressive vs conservative initiation of antimicrobial treatment for suspected ICU-acquired infections (IAI) Hranjec T et al. Lancet Infect Dis 2012;12:774-80 Single-centre, 2-year, quasi-experimental, before-after observational cohort study (USA) in adult pts admitted to surgical ICU: Sep 2008 − Aug 2009: Aggressive strategy: Antimicrobial treatment (Tx) started if clinical suspicion of infection Sep 2009 − Aug 2010: Conservative strategy: Antimicrobial Tx started only after objective confirmation of infection Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Top Epidemiology and Infection Control Papers of the Year’ (session 140) by Robert Weinstein and Andreas Widmer. Some weaknesses of this study are the lack of randomisation, the single-centre design and the relatively low number of patients. In the publication, several reasons for the improved survival with the conservative strategy were suggested, i.e. (i) higher rate of adequacy of initial treatment in the conservative group; (ii) collateral damage caused by prolonged antimicrobial treatment in the aggressive group; and (iii) increased experience of physicians to recognise, diagnose and treat infections during the conservative strategy period. APACHE: Acute Physiology and Chronic Health Evaluation CI: confidence interval ICU: intensive care unit OR: odds ratio

2 of 2 Aggressive vs conservative initiation of antimicrobial treatment for suspected ICU-acquired infections (IAI) Hranjec T et al. Lancet Infect Dis 2012;12:774-80 Aggressive strategy is a predictor of mortality (univariate analysis, adjusted for age, sex, trauma involvement, acute physiology, APACHE II score and site of infection): Aggressive vs conservative strategy: OR=2.5; 95% CI: 1.5-4.0; P<0.0001 Reporter comments: This publication was discussed during the IDWeek 2013 session ‘Top Epidemiology and Infection Control Papers of the Year’ (session 140) by Robert Weinstein and Andreas Widmer. Some weaknesses of this study are the lack of randomisation, the single-centre design and the relatively low number of patients. In the publication, several reasons for the improved survival with the conservative strategy were suggested, i.e. (i) higher rate of adequacy of initial treatment in the conservative group; (ii) collateral damage caused by prolonged antimicrobial treatment in the aggressive group; and (iii) increased experience of physicians to recognise, diagnose and treat infections during the conservative strategy period. APACHE: Acute Physiology and Chronic Health Evaluation CI: confidence interval ICU: intensive care unit OR: odds ratio Delaying antimicrobial Tx for suspected ICU-acquired infections until objective evidence of infection may not worsen patient mortality

1 of 2 Use of minocycline against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant gram-negative organisms (MDRO) Bishburg E et al. Infect Dis Clin Practice 2013;doi:10.1097/IPC.0b013e31828bbb82 Single-centre, retrospective study (USA; 2009-2012) N=21 pts (22 infections) (25-83 yr) treated with iv minocycline 100 mg every 12h for ≥24h No adverse events attributed to minocycline in any treated patient Reporter comments: This publication was discussed during the IDWeek 2013 session ‘New and Near Available Anti-Infective Therapy’ (session 158) by Michael Dudley, Andrea Boggild and Thomas Patterson. iv: intravenous(ly) Tx: treatment

2 of 2 Use of minocycline against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant gram-negative organisms (MDRO) Bishburg E et al. Infect Dis Clin Practice 2013;doi:10.1097/IPC.0b013e31828bbb82 †Death: 1 patient with neutropenia and severe sepsis: initial Tx: imipenem/ cilastatin → changed to amikacin/minocycline due to persistent fever and KPC-producing K. pneumoniae, sensitive to minocycline Reporter comments: This publication was discussed during the IDWeek 2013 session ‘New and Near Available Anti-Infective Therapy’ (session 158) by Michael Dudley, Andrea Boggild and Thomas Patterson. iv: intravenous(ly) Tx: treatment Iv minocyclin may be used for MRSA and MDRO infections if other Tx options are scarce. Minocycline has a favourable pharmacokinetic profile and allows for completion of Tx with an oral formulation

1 of 2 Impact of vancomycin minimum inhibitory concentration (MIC) on mortality in Staphylococcus aureus bacteraemia (SAB) Van Schooneveld TC. IDWeek 2013 abs. 376 Systematic literature review, meta-analysis and meta-regression: 38 studies reporting on mortality and vancomycin MIC in pts with SAB N=8,039 SAB episodes (mean age: 63 yr) Overall mortality: 25.3% Reporter comments: These findings are in contradiction with the current IDSA guidelines for the treatment of MRSA infections in adults and children, indicating that an alternative to vancomycin should be used for isolates with a MIC >2 µg/ml, and that for isolates with a MIC ≤2 µg/ml, continued use of vancomycin should be guided by the patient’s clinical response (Liu C et al. Clin Infect Dis 2011;52:e18-55). It was not explicitly indicated in the abstract/poster whether patients were actually treated with vancomycin, despite resistance. CI: confidence interval

2 of 2 Impact of vancomycin minimum inhibitory concentration (MIC) on mortality in Staphylococcus aureus bacteraemia (SAB) Van Schooneveld TC. IDWeek 2013 abs. 376 Reporter comments: These findings are in contradiction with the current IDSA guidelines for the treatment of MRSA infections in adults and children, indicating that an alternative to vancomycin should be used for isolates with a MIC >2 µg/ml, and that for isolates with a MIC ≤2 µg/ml, continued use of vancomycin should be guided by the patient’s clinical response (Liu C et al. Clin Infect Dis 2011;52:e18-55). It was not explicitly indicated in the abstract/poster whether patients were actually treated with vancomycin, despite resistance. CI: confidence interval Higher vancomycin MIC values do not seem to be associated with increased mortality in pts with SAB

1 of 2 In vitro activity of ceftolozane/tazobactam (TOL/TAZ) against aerobic Gram-negative organisms causing intra-abdominal infections (IAIs) Sader H. IDWeek 2013 abs. 698 Program to Assess TOL/TAZ Susceptibility (PACTS): Multi-centre surveillance study (Europe, USA; 2012): N=809 isolates of aerobic Gram-negative bacilli from hospitalised pts with diagnosis of IAI MIC: minimum inhibitory concentration P. aeruginosa: Pseudomonas aeruginosa Data from poster

2 of 2 In vitro activity of ceftolozane/tazobactam (TOL/TAZ) against aerobic Gram-negative organisms causing intra-abdominal infections (IAIs) Sader H. IDWeek 2013 abs. 698 MIC: minimum inhibitory concentration P. aeruginosa: Pseudomonas aeruginosa TOL/TAZ demonstrated potent activity against aerobic Gram-neg. IAI-causing pathogens, including ESBL-phenotypes and P. aeruginosa Data from poster

1 of 2 In vitro activity of ceftazidime-avibactam (CAZ-AVI) against Gram-negative pathogens causing bloodstream infections (BSIs) Sader H. IDWeek 2013 abs. 700 Avibactam: novel non-β-lactam β-lactamase inhibitor Multi-centre study (USA; 2012): N=1,462 Gram-negative organisms from hospitalised pts with BSIs Enterobacteriaceae: N=1,269 At CAZ-AVI MIC ≤4 µg/ml (i.e. CLSI susceptible breakpoint for CAZ): 99.8% of strains inhibited → only 2 strains with CAZ-AVI MIC >4 µg/ml: Providencia spp. (8 µg/ml) − E. aerogenes (16 µg/ml) CLSI: Clinical and Laboratory Standards Institute MIC: minimum inhibitory concentration Data from poster

2 of 2 In vitro activity of ceftazidime-avibactam (CAZ-AVI) against Gram-negative pathogens causing bloodstream infections (BSIs) Sader H. IDWeek 2013 abs. 700 E. cloacae: Enterobacter cloacae K. pneumoniae: Klebsiella pneumoniae CAZ/AVI demonstrated potent activity against Gram-neg. BSI-causing organisms, including those resistant to most currently used agents Data from poster